* 300644

GALACTOSIDASE, ALPHA; GLA


Alternative titles; symbols

ALPHA-GALACTOSIDASE A; GALA


HGNC Approved Gene Symbol: GLA

Cytogenetic location: Xq22.1     Genomic coordinates (GRCh38): X:101,397,803-101,407,925 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Xq22.1 Fabry disease 301500 XL 3
Fabry disease, cardiac variant 301500 XL 3

TEXT

Description

The GLA gene encodes alpha-galactosidase (GLA; EC 3.2.1.22), a lysosomal hydrolase.


Cloning and Expression

Calhoun et al. (1985) isolated clones corresponding to the GLA gene from a human liver cDNA library. The 370-amino acid protein has a molecular mass of 41.4 kD. The mature active enzyme is a homodimeric protein.

Bishop et al. (1986) isolated GLA cDNA clones and found an open reading frame of 398 residues with a molecular mass of 45.4 kD. RNA transfer hybridization analysis detected a 1.45-kb transcript. Bishop et al. (1988) determined that the GLA gene lacks a 3-prime untranslated sequence, with the polyadenylation signal included in the coding region. Kornreich et al. (1989) presented the complete nucleotide sequence of the GLA gene.

Using RT-PCR amplification of genomic GLA DNA isolated from normal individuals, Novo et al. (1995) found that a subset of RNA molecules had a 1187U-A conversion which differed from the wildtype cDNA sequence. Multiple genes, pseudogenes, or allelic variants were excluded. Novo et al. (1995) proposed RNA editing as a mechanism responsible for this base change in the GLA RNA, similar to that which has been demonstrated for the nuclear encoded RNA for intestinal apoB (107730) and several subunits of brain L-glutamate receptors such as GLUR2 (138247), GLUR5 (138245), and GLUR6 (138244).


Gene Structure

Bishop et al. (1988) determined that the GLA gene contains 7 exons and spans about 12 kb.


Mapping

The GLA gene was localized to the X chromosome using cell hybridization techniques (Grzeschik, 1972).

From study of radiation-induced segregants in which irradiated human cells are rescued by fusion with hamster cells, Goss and Harris (1977) showed that the order of the following 4 loci on Xq is PGK--alpha-GAL--HPRT--G6PD and that the 3 intervals between these 4 loci are, in relative terms, 0.33, 0.30, and 0.23.

Lusis and West (1976) reported X-linked inheritance of the Gla gene in the mouse. Alpha-GAL, HPRT, PGK and G6PD are X-linked in the rabbit, according to mouse-rabbit hybrid cell studies (Cianfriglia et al., 1979; Echard and Gillois, 1979). By comparable methods, Hors-Cayla et al. (1979) found them to be X-linked also in cattle. Francke and Taggart (1979) assigned HPRT and alpha-GAL to the X chromosome in the Chinese hamster by study of mouse-Chinese hamster hybrid cells.


Molecular Genetics

Davies et al. (1993) demonstrated 3 polymorphic variants in the first exon of the GLA gene, which contains 60 bp of 5-prime untranslated sequence before the methionine initiation codon. Such a high level of polymorphism had not previously been reported and was unusual in such a short stretch of DNA.

In a patient with Fabry disease (301500), Bernstein et al. (1989) identified a mutation in the GLA gene (300644.0001). The substitution altered the enzyme's kinetic properties and stability.

Eng et al. (1993) identified 18 different mutations in the GLA gene (see, e.g., 300644.0012; 300644.0013; 300644.0018-300644.0022) in patients with Fabry disease.

Lai et al. (2003) pointed out that most of the mutations in the GLA gene were identified in Fabry disease patients by genomic sequencing only, and therefore some of the splicing mutations were misclassified as missense mutations. To predict splicing events caused by specific mutations, they conducted a literature search for all published GLA mutations located near splice sites, including exonic point mutations, and performed a splice site score (SSS) analysis. They found 13 donor site mutations, 6 acceptor site mutations, and 1 new exon creation. All mutated splice sites, except for the 1 associated with new exon creation, had a lower SSS than their respective natural sites.

Yasuda et al. (2003) noted that the human GLA gene is one of the rare mammalian genes that has its polyadenylation signal in the coding sequence and lacks a 3-prime untranslated region. In 2 unrelated men with classic Fabry disease, they identified 2 novel frameshift mutations, 1277delAA (300644.0060) and 1284delACTT (300644.0061), which occurred in the 3-prime terminus of the coding region and obliterated the termination codon; the 2-bp deletion also altered the polyadenylation signal. Both mutations generated multiple transcripts of various lengths of 3-prime terminal sequences, some elongated by approximately 1 kb. Northern blot analysis suggested that mRNA degradation did not occur.

Splicing Patterns

In the context of examining splice site mutations in the GLA gene, Lai et al. (2003) discussed the 5 major aberrant splicing patterns caused by mutations in general: exon skipping, cryptic site activation, new site creation, intron retention, and disruption of exonic splicing enhancers (Nakai and Sakamoto, 1994; Cooper and Mattox, 1997). The selection of splicing patterns is based on many factors. When no strong cryptic site or newly created site is available, destruction of either the donor or acceptor splice site causes skipping of the neighboring exon. Cryptic splice sites are normally silent consensus sites that are activated when the authentic site is destroyed by mutation. In general, the distance between the authentic site and the cryptic site is about 100 nucleotides long. Mutations also can result in the creation of a new splice site, which may or may not be associated with destruction of the authentic site. If the authentic site is not altered, the new splice site is always in the upstream region of the authentic site. Intron retention occurs infrequently and sometimes simultaneously with other splicing patterns. Cis element exonic splicing enhancers (ESE) also have a role in the regulation of splicing. See the report of Liu et al. (2001) showing that disruption of an exonic splicing enhancer resulted in missplicing of exon 18 in the BRCA1 gene (113705). Similar mechanisms may explain why many exonic missense or nonsense mutations that are not located at splice sites are associated with exon skipping.


Genotype/Phenotype Correlations

Using the x-ray crystal structure of human alpha-galactosidase reported by Garman and Garboczi (2004), Matsuzawa et al. (2005) performed computerized 3-dimensional structural analysis of the mutant enzyme resulting from 161 missense mutations in the GLA gene causing Fabry disease. Mutations resulting in the severe classic phenotype showed a wide distribution in the number of atoms affected by the mutation, but the majority (82%) had 3 or more affected atoms in the main chain of the protein. Nineteen classic mutations affected the active site or the substrate-binding site of the enzyme. By contrast, 85% of mutations resulting in the milder variant phenotype had less than 3 atoms influenced in the main chain, and none of the variant mutations affected the active site. These results suggested that variant Fabry mutations cause small changes that do not affect the whole protein structure.

Matsuzawa et al. (2005) performed further analysis of 11 specific mutations in the GLA gene, which the authors subdivided into 4 groups according to the clinical and biochemical phenotypes of Fabry disease: classic with a completely dysfunctional and ineffective protein; classic with an unstable and ineffective protein; classic with an unstable but moderately effective protein; and variant with an unstable but effective protein. In particular, the G328R (300644.0010) mutation, which results in an unstable, ineffective protein, had 77 and 53 affected atoms in the main and side chains, respectively. The variant mutations Q279E (300644.0008) and M296I (300644.0051) were located apart from the active site and affected less than 3 atoms each in the main chain.

In a Japanese patient with the cardiac variant of Fabry disease, Ishii et al. (1992) identified a mutation in the GLA gene (300644.0008) associated with residual GLA enzyme activity. The patient developed dyspnea and bradycardia for the first time at age 60 years and died of heart failure at age 64. He was found to have complete left bundle branch block associated with hypertrophy of the left ventricular wall and interventricular septum. He had no other signs or symptoms characteristic of Fabry disease except proteinuria, which was found after cardiac failure had developed. Myocardial biopsy had shown inclusion bodies on electron microscopic examination. A 39-year-old nephew was asymptomatic but showed a thick interventricular septum and left ventricular wall by echocardiography and magnetic resonance imaging. The mutation in this case, as in 2 other cases of the cardiac form (300644.0003, 300644.0005), was located in exon 6.

Oliveira et al. (2020) reported 11 symptomatic Portuguese males from 10 families with Fabry disease who had a hemizygous F113L (300644.0063) mutation in the GLA gene. All of the patients had a late-onset form of the disorder, manifesting with a cardiac phenotype invariably including cardiomyopathy/hypertrophic cardiomyopathy, and often including other features such as conduction defects, arrhythmias, and myocardial ischemia. Some patients also had cerebrovascular or kidney involvement, although the association with the GLA mutation was confounded by the presence of other risk factors (e.g., hypertension, diabetes, obesity).

In a population of 150 adults with hypertrophic cardiomyopathy in Guimaraes, Portugal, Azevedo et al. (2020) identified 25 patients with Fabry disease, 21 of whom were hemizygous or heterozygous for the F113L mutation in the GLA gene. Geneology studies demonstrated a common ancestor in 17 of the 21 patients. Through pedigree analysis in these patients, Azevedo et al. (2020) identified 120 patients, including 47 males and 73 females, with Fabry disease due to the F113L mutation. The mean age at diagnosis was 46 years, which was similar in both genders. Left ventricular hypertrophy (LVH) was identified in 49 patients, with a male predominance, and most patients were diagnosed with LVH at or after 40 years of age. Albuminuria was identified in 36.1% of patients; however, renal insufficiency was rare and no patient progressed to dialysis. Acroparesthesias were more common in females (34.2% of females and 6.4% of males). Sensorineural hearing loss was more common in males (30.8% of females and 64.4% of males). Strokes and angiokeratomas were rare. Azevedo et al. (2020) concluded that the F113L mutation in the Guimaraes region of Portugal was associated with a cardiac-predominant, late-onset form of Fabry disease.


ALLELIC VARIANTS ( 63 Selected Examples):

.0001 FABRY DISEASE

GLA, ARG356TRP
  
RCV000011459...

In a patient with Fabry disease (301500), Bernstein et al. (1989) identified a 1066C-T transition in the GLA gene, resulting in an arg356-to-trp (R356W) substitution. The substitution altered the enzyme's kinetic properties and stability.


.0002 FABRY DISEASE

GLA, EX3DEL
  
RCV000011460

Fukuhara et al. (1990) reported partial deletion of the GLA gene in a case of Fabry disease (301500). The deletion involved exon 3 and was associated with an A-to-C transversion. The 402-bp deletion was flanked by 6-bp direct repeat sequences. These structures may have promoted 'slipped mispairing' as the origin of the mutation in this family.


.0003 FABRY DISEASE, CARDIAC VARIANT

FABRY DISEASE, INCLUDED
GLA, ARG301GLN
  
RCV000011461...

In a Japanese patient with Fabry disease following an atypical clinical course characterized by late-onset cardiac involvement and significant residual GLA (see 301500), Sakuraba et al. (1990) identified a G-to-A transition in exon 6 of the GLA gene, resulting in an arg301-to-gln (R301Q) substitution.

Sawada et al. (1996) identified the R301Q substitution in a 45-year-old man who developed moderate proteinuria and was found to have the renal histologic findings of Fabry disease, together with a decrease in activity of alpha-galactosidase A in his plasma, urine, leukocytes, and skin fibroblasts. The mutation was inherited from his mother. The patient was unique in that he demonstrated only renal manifestations, whereas all other patients with atypical Fabry disease, including a case with the identical point mutation (Sakuraba et al., 1990), presented with cardiomyopathy.

Kase et al. (2000) characterized this mutant and another, Q279E (300644.0008), in a patient with the cardiac variant of Fabry disease. In contrast to patients with classic Fabry disease, who have no detectable alpha-galactosidase activity, patients with these variants have residual enzyme activity. Compared to normal control cells, fibroblasts from a patient with the Q279E mutation secreted only small amounts of alpha-galactosidase. The authors concluded that these 2 substitutions do not significantly affect enzymatic activity, but the mutant protein levels are decreased presumably in the endoplasmic reticulum of cells.


.0004 FABRY DISEASE

GLA, TRP44TER
  
RCV000011463

In a Japanese patient with classic Fabry disease (301500) and no detectable alpha-galactosidase A activity, Sakuraba et al. (1990) found a G-to-A transition in exon 1 of the GLA gene, resulting in a trp44-to-ter (W44X) substitution.


.0005 FABRY DISEASE, CARDIAC VARIANT

GLA, MET296VAL
  
RCV000011464...

In a 54-year-old man with the cardiac variant of Fabry disease (see 301500), von Scheidt et al. (1991) identified an 886A-G transition in exon 6 of the GLA gene, resulting in a met296-to-val (M296V) substitution. The patient had 'crescendo angina,' relieved by nitroglycerin, as well as electrocardiographic changes, but normal cardiac chamber size and normal systolic and diastolic function by echocardiogram. Cardiac catheterization showed no stenoses of the extramural coronary arteries. Diagnosis of Fabry disease was made by endomyocardial biopsy. Light-microscopic examination showed that approximately half the myocytes contained a centrally stored foamy material that stained metachromatically. By electron microscopy, typical myelin-figure-like concentric lamellar inclusions in lysosomes were observed. Most remarkably, the endothelial cells of the myocardial capillaries were not involved and no changes were observed in specimens of skeletal muscle, liver, rectum, and skin, including small blood vessels and nerves.


.0006 FABRY DISEASE

GLA, EX4DEL
  
RCV000011465

In an 11-year-old boy with Fabry disease (301500), Yokoi et al. (1991) identified a G-to-A transition at the 3-prime consensus sequence (splicing acceptor) of intron 3 of the GLA gene. The mutation resulted in deletion of exon 4 and a frameshift with appearance of a terminating codon in exon 5.


.0007 FABRY DISEASE

GLA, IVS6DS, G-T, +1
  
RCV000011467

In 3 affected brothers from a Japanese family with Fabry disease (301500), Sakuraba et al. (1992) identified deletion of exon 6 due to a G-to-T transversion at the first nucleotide of the 5-prime splice site of intron 6 of the GLA gene. Sakuraba et al. (1992) stated that this was the first G-to-T transversion of a mammalian 5-prime splice site that consistently eliminated the preceding exon. Sakuraba et al. (1992) gave a tabulation of various mammalian 5-prime consensus splice site mutations that lead to exon skipping and in most cases use of cryptic splice sites. They pointed out that glycophorin B (GYPB; 617923) of the Ss blood group (111740) differs from glycophorin A (GYPA; 617922) of the MN blood group (111300) by 2 changes at the 5-prime splice site of intron 3 which presumably took place after duplication of the progenitor gene. As indicated in their Table 1, the gene for growth hormone-like (GH2; 139240) differs from that for growth hormone (GH1; 139250) by a G-to-A transition at position +1 of intron 2 in the duplicated gene (Chen et al., 1989).


.0008 FABRY DISEASE, CARDIAC VARIANT

GLA, GLN279GLU
  
RCV000011468...

Ishii et al. (1992) identified an 835C-G transversion in the GLA gene, resulting in a gln279-to-glu (Q279E) substitution, in a Japanese patient with the cardiac variant of Fabry disease (see 301500). The patient developed dyspnea and bradycardia for the first time at age 60 years and died of heart failure at age 64. He was found to have complete left bundle branch block associated with hypertrophy of the left ventricular wall and interventricular septum. He had no other signs or symptoms characteristic of Fabry disease except proteinuria, which was found after cardiac failure had developed. Myocardial biopsy had shown inclusion bodies on electron microscopic examination. A 39-year-old nephew was asymptomatic but showed a thick interventricular septum and left ventricular wall by echocardiography and magnetic resonance imaging. Both men had some residual alpha-galactosidase A activity. The mutation in this case, as in 2 other cases of the cardiac form (300644.0003, 300644.0005), was located in exon 6. On the other hand, the gly328-to-arg mutation, located at the 3-prime end of exon 6 was associated with classic features of Fabry disease (see 300644.0010).


.0009 FABRY DISEASE

GLA, PRO40SER
  
RCV000011466...

Koide et al. (1990) described a pro40-to-ser (P40S) mutation in exon 1 of the GLA gene in a patient with Fabry disease (301500) and no detectable alpha-galactosidase A activity.


.0010 FABRY DISEASE

GLA, GLY328ARG
  
RCV000011469...

In a 34-year-old man with typical Fabry disease (301500), Ishii et al. (1992) identified a 982G-A transition in exon 6 of the GLA gene, resulting in a gly328-to-arg (G328R) substitution. This mutation was located at the 3-prime end of exon 6; mutations located at the central or 5-prime end of the exon were associated with the predominantly cardiac form of the disease.


.0011 FABRY DISEASE

GLA, GLU66GLN AND ARG112CYS
  
RCV000011470...

In a 14-year-old boy with classic Fabry disease (301500), Ishii et al. (1992) found 2 point mutations in exon 2 of the GLA gene: a GAG-to-CAG change causing a glu66-to-gln (E66Q) substitution, and a CGC-to-TGC change causing an arg112-to-cys (R112C) substitution.

Lee et al. (2010) presented evidence that the E66Q variant is a functional polymorphism and not disease causing. Substantial residual GLA activity was shown both in the leukocytes of individuals carrying E66Q (19.0 to 30.3% of normal activity) and in transiently overexpressed COS-7 cells (43.8% of normal activity). Although the E66Q-variant GLA was unstable at neutral pH, the enzyme was efficiently expressed in the lysosomes of COS-7 cells. The allele frequency of E66Q determined in 833 unrelated Korean individuals was considered to be high at 1.046%. The variant was found in 5 individuals from 4 Korean families during a screen of patients with Fabry disease. Of the 5 patients carrying E66Q, only 1 patient had proteinuria, and 2 had hypertrophic cardiomyopathy without other signs of the disorder. Lee et al. (2010) suggested that either these patients had a different etiology for their features or that they had a very mild atypical variant of the disease with other genetic or environmental factors contributing to the phenotype.


.0012 FABRY DISEASE

GLA, ASN34SER
  
RCV000011471...

In a patient with classic Fabry disease (301500), Eng et al. (1993) found an A-to-G transition in exon 1 of the GLA gene, resulting in an asn34-to-ser (N34S) substitution.


.0013 FABRY DISEASE

GLA, CYS56GLY
  
RCV000011472

In an English patient with classic Fabry disease (301500), Eng et al. (1993) found a T-to-G transversion in exon 1 of the GLA gene, resulting in a cys56-to-gly (C56G) substitution.


.0014 FABRY DISEASE

GLA, PRO146SER
  
RCV000011473

In a Dutch patient with mild Fabry disease (301500), deJong et al. (1993) found a C-to-T transition in exon 3 of the GLA gene, resulting in a pro146-to-ser (P146S) substitution.


.0015 FABRY DISEASE

GLA, ALA156THR
  
RCV000011474

In a Danish patient with classic Fabry disease (301500), Madsen et al. (1993) found a G-to-A transition in exon 3 of the GLA gene, resulting in an ala156-to-thr (A156T) substitution.


.0016 FABRY DISEASE

GLA, TRP162ARG
  
RCV000011475...

In an Italian patient with classic Fabry disease (301500), Eng et al. (1993) found a T-to-C transition in exon 3 of the GLA gene, resulting in a trp162-to-arg (W162R) substitution.


.0017 FABRY DISEASE

GLA, CYS202TRP
  
RCV000011476

In a Dutch patient with classic Fabry disease (301500), deJong et al. (1993) found a T-to-G transversion in exon 4 of the GLA gene, resulting in a cys202-to-trp (C202W) substitution.


.0018 FABRY DISEASE

GLA, ASN215SER
  
RCV000011477...

Eng et al. (1993) and Davies et al. (1993) described an A-to-G transition in exon 5 of the GLA gene, resulting in an asn215-to-ser (N215S) substitution. The patients had mild forms of Fabry disease (301500) and residual enzyme activity.


.0019 FABRY DISEASE

GLA, ARG227GLN
  
RCV000011478...

In a patient with classic Fabry disease (301500), Eng et al. (1993) described an G-to-A transition in exon 5 of the GLA gene, resulting in an arg227-to-gln (R227Q) substitution. This mutation conforms to the CG-to-TG mutation 'hotspot' rule. In the complementary, antisense strand, 5-prime--xxxCGAxxx--3-prime is read as 3-prime--xxxGCTxxx--5-prime. Methylation of the cytosine in the CpG of the antisense codon with subsequent deamidation converts the antisense codon to GTT, which corresponds to the sense codon CAA. Read 5-prime to 3-prime, the CG in the sense strand has been changed to TG in the antisense strand; hence, the designation CG-to-TG 'hotspot' rule.


.0020 FABRY DISEASE

GLA, ARG227TER
  
RCV000011479...

In patients with Fabry disease (301500), Eng et al. (1993) and Davies et al. (1993) identified a C-to-T transition in exon 5 of the GLA gene, resulting in an arg227-to-ter (R227X) substitution. The mutation conforms to the CG-to-TG rule and has been found in more than 1 unrelated patient.


.0021 FABRY DISEASE

GLA, ASP264VAL
  
RCV000011480...

In a Scottish/English patient with classic Fabry disease (301500), Eng et al. (1993) found an A-to-T transversion in exon 5 of the GLA gene, resulting in an asp264-to-val (D264V) substitution.


.0022 FABRY DISEASE

GLA, ASP266VAL
  
RCV000011481...

In an African American patient with classic Fabry disease (301500), Eng et al. (1993) found an A-to-T transversion in exon 5 of the GLA gene, resulting in an asp266-to-val (D266V) substitution.


.0023 FABRY DISEASE

GLA, VAL269ALA
  
RCV000011482

In an English patient with classic Fabry disease (301500), Davies et al. (1993) found a GTG-to-GCG mutation in exon 6 of the GLA gene, resulting in a val269-to-ala (V269A) substitution.


.0024 FABRY DISEASE

GLA, TRP287TER
  
RCV000011483

In an English patient with classic Fabry disease (301500), Davies et al. (1993) found a TGG-to-TGA mutation in exon 6 of the GLA gene, resulting in a trp287-to-ter (W287X) substitution.


.0025 FABRY DISEASE

GLA, SER297PHE
  
RCV000011484

In an Italian patient with classic Fabry disease (301500), Eng et al. (1993) found a TCT-to-TTT mutation in exon 6 of the GLA gene, resulting in a ser297-to-phe (S297F) substitution.


.0026 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE

GLA, ASP313TYR
  
RCV000011486...

This variant, formerly titled FABRY DISEASE, has been reclassified based on the findings of Yasuda et al. (2003).

In a German patient with classic Fabry disease (301500), Eng et al. (1993) found a GAT-to-TAT mutation in exon 6 of the GLA gene, resulting in an asp313-to-tyr (D313Y) substitution.

Yasuda et al. (2003) found that expression of the D313Y variant in COS-7 cells resulted in 60% residual enzyme activity and that the enzyme was localized to lysosomes. In addition, the D313Y variant was found in 0.45% of 883 normal X chromosomes. Molecular homology modeling showed that the D313Y variant did not markedly disrupt enzyme structure. The variant enzyme was stable at lysosomal pH (4.5), but had decreased activity at neutral pH (7.4). Overall, the findings suggested that the D313Y variant is a functional polymorphism rather than a disease-causing variant.

Lenders et al. (2013) noted that the possible pathogenicity of the D313Y variant is controversial. They reported a large family in which 9 females and 1 male carried a heterozygous D313Y mutation; one of the females with the variant was deceased. Seven of the 8 who underwent brain imaging had multifocal white matter lesions, including several young individuals without cardiovascular risk factors. The white matter lesions were primarily subcortical and punctate, but some also were confluent with a periventricular localization. Brain MRI in 2 family members who did not carry the D313Y variant showed no white matter lesions. GLA enzyme activities were normal in carrier leukocytes, but were decreased in plasma. Lyso-Gb3 levels in plasma, which are increased in patients with Fabry disease, were normal. The proband, who carried the D313Y variant, had a peripheral small-fiber neuropathy with decreased intraepithelial nerve fiber density on nerve biopsy. None of the variant carriers had other evidence of Fabry disease, but Lenders et al. (2013) postulated that the D313Y variant may act as a predisposing factor for neurologic manifestations.

Niemann et al. (2013) reported a father and daughter with the D313Y variant. The daughter presented with diffuse skin lesions and nonspecific arm pain. Plasma GLA enzyme activity was mildly decreased. Skin biopsy showed keratosis pilaris rubra atrophicans, but no Fabry angioma. Her 53-year-old father had no clinical manifestations of Fabry disease, although his plasma GLA enzyme activity was also decreased. Lyso-Gb3 was below normal in the daughter and undetectable in the father. Niemann et al. (2013) concluded that the D313Y variant is not clinically relevant for Fabry disease. The authors also suggested that pure assessment of GLA activity and even genetic testing is not sufficient for diagnosing Fabry disease.


.0027 FABRY DISEASE

GLA, GLN327LYS
  
RCV000011487

In an English patient with classic Fabry disease (301500), Davies et al. (1993) found a CAA-to-AAA mutation in exon 6 of the GLA gene, resulting in a gln327-to-lys (Q327K) substitution.


.0028 FABRY DISEASE

GLA, GLY328ALA
  
RCV000011488...

In a Scottish/Irish patient with classic Fabry disease (301500), Eng et al. (1993) found a GGG-to-GCG mutation in exon 6 of the GLA gene, resulting in a gly328-to-ala (G328A) substitution. A different mutation has also been described in the same codon (see 300644.0010).


.0029 FABRY DISEASE

GLA, TRP340TER
  
RCV000011489...

In an African American patient with classic Fabry disease (301500), Eng et al. (1993) found a nonsense TGG-to-TGA mutation in exon 7 of the GLA gene, resulting in a trp340-to-ter (W340X) substitution.


.0030 FABRY DISEASE

GLA, ARG342GLN
  
RCV000011490...

In a Dutch patient with classic Fabry disease (301500), deJong et al. (1993) found a CGA-to-CAA mutation in exon 7 of the GLA gene, resulting in an arg342-to-gln (R342Q) substitution. This mutation conforms to the CG-to-TG 'hotspot' rule.

Germain (2001) described a patient with Fabry disease due to the R342Q mutation who also had Klippel-Trenaunay-Weber syndrome (149000). The 30-year-old man had a complex vascular and cutaneous malformation. Skin examination showed numerous angiokeratomas, which had developed only on the right part of the body, with a sharp delineation in the midline of the trunk. The R342Q mutation was demonstrated in DNA extracted from fibroblast cultures established from both affected and unaffected skin areas, thus excluding the hypothesis of somatic mosaicism or revertant mosaicism. The patient had hypertrophy of the right leg, with dilated and varicose superficial veins.


.0031 FABRY DISEASE

GLA, ARG342TER
  
RCV000011491...

In a Greek/English patient with classic Fabry disease (301500), Davies et al. (1993) found a CGA-to-TGA mutation in exon 7 of the GLA gene, resulting in an arg342-to-ter (R342X) substitution.


.0032 FABRY DISEASE

GLA, GLY361ARG
  
RCV000011492

In an English patient with classic Fabry disease (301500), Davies et al. (1993) found a GGA-to-CGA mutation in exon 7 of the GLA gene, resulting in a gly361-to-arg (G361R) substitution.


.0033 FABRY DISEASE

GLA, GLU398TER
  
RCV000011493

In a Hispanic patient with classic Fabry disease (301500), Eng et al. (1993) found a nonsense GAA-to-TAA mutation in exon 7 of the GLA gene, resulting in a glu398-to-ter (E398X) substitution.


.0034 FABRY DISEASE

GLA, IVSDS, GT-GG, +2
  
RCV000011485

In a Sephardic Jewish patient with classic Fabry disease (301500), Eng et al. (1993) found a T-to-G mutation at nucleotide +2 of the donor splice site of intron 2 of the GLA gene.


.0035 FABRY DISEASE

GLA, IVS5AS, DEL -2,-3
  
RCV000153317...

In an Irish patient with classic Fabry disease (301500), Eng et al. (1993) found a deletion of 2 nucleotides (-2 and -3) of the acceptor splice site of intron 5 of the GLA gene. The mutation is therefore tcag/exon 6 to tg/exon 6.


.0036 FABRY DISEASE

GLA, ALA143THR
  
RCV000011495...

In a 34-year-old man with Fabry disease (301500), Nance et al. (2006) identified a G-to-A transition in the GLA gene, resulting in an ala143-to-thr (A143T) substitution. The patient had a 5-year history of progressive activity-induced leg and foot cramps and fasciculations with pain. No other stigmata of Fabry disease was present. His mother, who also carried the mutation, had a similar phenotype.


.0037 FABRY DISEASE

GLA, 13-BP DEL, NT125
  
RCV000011496

In a Japanese patient with severe Fabry disease (301500), Ishii et al. (1991) identified a 13-bp deletion in exon 1 of the GLA gene. The deletion is flanked by a TGGG direct repeat.


.0038 FABRY DISEASE

GLA, 1-BP DEL, NT716
   RCV000011497

In an English patient with severe Fabry disease (301500), Davies et al. (1993) found a 1-bp deletion at nucleotide 716 in exon 5 of the GLA gene.


.0039 FABRY DISEASE

GLA, 2-BP DEL, NT773
  
RCV000011498

In a Portuguese patient with severe Fabry disease (301500), Eng et al. (1993) found a 2-bp deletion at nucleotide 773 in exon 5 of the GLA gene.


.0040 FABRY DISEASE

GLA, 5-BP INS, NT954
  
RCV000011499

In a German patient with severe Fabry disease (301500), Eng et al. (1993) found a 5-bp insertion starting at nucleotide 954 of exon 6 of the GLA gene.


.0041 FABRY DISEASE

GLA, 11-BP DEL, NT1016
  
RCV000011500

In a German patient with severe Fabry disease (301500), Eng et al. (1993) found an 11-bp deletion starting at nucleotide 1016 of exon 7 of the GLA gene.


.0042 FABRY DISEASE

GLA, 1-BP INS, NT1040
  
RCV000011501

In a Dutch patient with severe Fabry disease (301500), deJong et al. (1993) found a 1-bp insertion at nucleotide 1040 of exon 7 of the GLA gene.


.0043 FABRY DISEASE

GLA, 53-BP DEL, NT1123
  
RCV000011502

In a Dutch patient with severe Fabry disease (301500), Eng et al. (1993) found a 53-bp deletion starting at nucleotide 1123 of exon 7 of the GLA gene.


.0044 FABRY DISEASE

GLA, 2-BP DEL, NT1176
   RCV000011503

In a Dutch patient with severe Fabry disease (301500), deJong et al. (1993) found a 2-bp deletion at nucleotide 1176 of exon 7 of the GLA gene. The deletion had a 6-bp inverted repeat at the breakpoint junction.


.0045 FABRY DISEASE

GLA, 3-BP DEL, 1208AAG
  
RCV000011504...

In an English patient with moderate Fabry disease (301500), Eng et al. (1993) found a 3-bp deletion (1208delAAG) in exon 7 of the GLA gene, resulting in the deletion of arg405.


.0046 FABRY DISEASE

GLA, EX1-2DEL
   RCV000011505

In a Slavic patient with severe Fabry disease (301500), Kornreich et al. (1990) found a 4.6-kb deletion that included exons 1 and 2 of the GLA gene. The deletion breakpoints had a CCA direct repeat suggesting a possible functional role of this short sequence in illegitimate recombination.


.0047 FABRY DISEASE

GLA, EX3-4DEL
   RCV000011506

In affected members of a Hispanic family with severe Fabry disease (301500), Kornreich et al. (1990) found a 3.2-kb deletion in the GLA gene that included exons 3 and 4. The 2 breakpoints occurred in Alu repetitive elements and Alu-Alu recombination is the probable mechanism of this deletion.


.0048 FABRY DISEASE

GLA, EX3-7DEL
   RCV000011507

In an English patient with severe Fabry disease (301500), Kornreich et al. (1990) found a 4.5-kb deletion in the GLA gene that included exons 3 to 6 and a portion of exon 7. The deletion breakpoints had an AAG direct repeat suggesting a possible functional role of this short sequence in illegitimate recombination.


.0049 FABRY DISEASE

GLA, EX6-7DEL
   RCV000011508

In an Irish/German patient with severe Fabry disease (301500), Kornreich et al. (1990) found a deletion of 1.7 kb in the GLA gene that included exons 6 and 7.


.0050 FABRY DISEASE

GLA, EX2-6DUP
   RCV000011509

In an English patient with severe Fabry disease (301500), Kornreich et al. (1990) found a duplication of 8.1 kb that included exons 2 to 5 and part of exon 6 of the GLA gene. The duplicated area was flanked by a TAGACA direct repeat.


.0051 FABRY DISEASE, CARDIAC VARIANT

GLA, MET296ILE
  
RCV000011510

In a study of left ventricular hypertrophy in Japan, Nakao et al. (1995) found 7 of 230 males (3%) with low plasma alpha-galactosidase activity but none of the typical manifestations of Fabry disease (see 301500), namely, angiokeratoma, acroparesthesias, hypohidrosis, or corneal opacities. One of the patients had a met296-to-ile (M296I) mutation in exon 6 of the GLA gene, whereas a second had an ala20-to-pro (A20P) mutation in exon 1 (300644.0052).


.0052 FABRY DISEASE, CARDIAC VARIANT

GLA, ALA20PRO
  
RCV000011511

.0053 FABRY DISEASE

GLA, 3-BP DEL, PHE383DEL
  
RCV000011512

Cariolou et al. (1996) described a novel trinucleotide deletion in the GLA gene in a Greek patient with Fabry disease (301500). This deletion led to loss of phenylalanine-383. The phenotype in this patient was unusual in that diffuse facial telangiectasia was present.


.0054 FABRY DISEASE

GLA, SER65THR
  
RCV000011513

In 2 unrelated Chinese patients with Fabry disease (301500), living in Taiwan, Chen et al. (1998) identified a G-to-C transversion in the last nucleotide of exon 1 of the GLA gene, which not only resulted in a ser65-to-thr (S65T) substitution but probably also caused a splicing defect.

Lai et al. (2003) demonstrated that the S65T mutation does not affect enzyme function. Instead it results in activation of a weak cryptic site 14 nucleotides downstream and results in an insertion of 14 bp and a frameshift stop at codon 106. This splicing abnormality was thought to be more consistent with the clinical presentation of the patient with classic Fabry disease.


.0055 FABRY DISEASE

GLA, TYR365TER
  
RCV000011514...

In affected members of a family with Fabry disease (301500), Miyamura et al. (1996) identified a mutation in the GLA gene, resulting in a tyr365-to-ter (Y365X) substitution and truncation of the C terminus by 65 amino acid residues. In a heterozygote of this family, although the mutant and normal alleles were equally transcribed in cultured fibroblasts, lymphocyte alpha-galactosidase A activity was approximately 30% of the normal control, and severe clinical symptoms were apparent. COS-1 cells transfected with this mutant cDNA showed a complete loss of its enzymatic activity. Furthermore, cells cotransfected with mutant and wildtype cDNAs showed approximately 30% of the enzyme activity of those with wildtype alone, which suggested a dominant-negative effect of this mutation and implied the importance of the C terminus for its activity. Generating mutant cDNAs with various deletions of the C terminus, Miyamura et al. (1996) found that enzyme activity was enhanced up to 6-fold compared with wildtype when 2 to 10 amino acid residues were deleted. In contrast, deletion of 12 or more amino acid residues resulted in a complete loss of enzyme activity. These data suggested that the C-terminal region of the GLA protein plays an important role in the regulation its enzyme activity.


.0056 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE

GLA, IVS4AS, G-A, -4
  
RCV000011515...

This variant, previously titled FABRY DISEASE, CARDIAC VARIANT, has been reclassified based on the findings of Chiang et al. (2017).

During the course of mutation analysis of a patient with the cardiac form of Fabry disease (see 301500) who had residual enzyme activity 9.1% of normal, Ishii et al. (2002) were unable to identify any mutation in the exonic or flanking intronic regions of the GLA gene. By RT-PCR of the RNA and direct sequencing of the RT-PCR product, they found an insertion between exons 4 and 5. To characterize further the abnormal splicing, they sequenced intron 4 (nucleotides 8413-10130) of the GLA gene and identified a G-to-A transition at nucleotide 9331 (IVS4+919G-A). This change was not found in 100 unaffected Japanese males. The mutation in the middle of the intron increased the recognition of a normally weak splice site, resulting in the insertion of an additional sequence into the GLA transcript and leading to the cardiac phenotype of Fabry disease.

Chiang et al. (2017) screened for the IVS4+919G-A variant in the Taiwanese population, including 3,268 controls, 3,949 patients from a type 2 diabetes cohort, and 649 patients from heart disease cohorts (heart failure, atrial fibrillation, ventricular tachycardia, and coronary artery disease). In the control sample, 4 males and 2 females carried the variant and only 1 male, who reportedly had a history of heavy smoking and drinking, had heart disease; none of 80 controls who reportedly had cardiomyopathy carried the variant. In the diabetes cohort, 1 of 11 patients who carried the variant had overt heart disease. Among the heart disease cohorts, only 1 patient carried the variant. The authors found that the incidence of the variant in their population was 1/409.


.0057 FABRY DISEASE

GLA, ALA143PRO
  
RCV000011516...

In 4 unrelated patients of Nova Scotian ancestry with Fabry disease (301500), Branton et al. (2002) found an ala143-to-pro (A143P) missense mutation in exon 3 of the GLA gene. Three of the patients were French Acadian; the fourth had a Greek surname but may also have been of French Acadian ancestry (Kopp, 2002).


.0058 FABRY DISEASE

GLA, TYR222TER
  
RCV000011517...

In affected members of a Chinese family with Fabry disease (301500), Yang et al. (2003) identified a nonsense mutation in the GLA gene, a C-to-A transversion resulting in a tyr222-to-ter (Y222X) substitution. The genotype was associated with classic Fabry disease, with unexpectedly rapid deterioration of visual acuity.


.0059 FABRY DISEASE

GLA, THR410ALA
  
RCV000011518

In affected members of a Chinese family with Fabry disease (301500), Yang et al. (2003) identified an A-to-G transition in the GLA gene, resulting in a thr410-to-ala (T410A) substitution. The T410A mutation was associated with a milder form of Fabry disease, with ventricular hypertrophy and neuropathic pain.


.0060 FABRY DISEASE

GLA, 2-BP DEL, 1277AA
  
RCV000011519...

In a patient with classic Fabry disease (301500), Yasuda et al. (2003) identified a 2-bp deletion, 1277delAA, causing a frameshift, in the GLA gene. The patient was a 51-year-old Swedish man who had onset of acroparesthesias at 10 years of age and subsequently had gastrointestinal manifestations, including abdominal pain and chronic diarrhea. He developed hypertrophic cardiomyopathy and, because of atrial ventricular block, required a pacemaker. His renal function was normal, with only a trace of urinary protein.


.0061 FABRY DISEASE

GLA, 4-BP DEL, 1284ACTT
  
RCV000011520

In a patient with classic Fabry disease (301500), Yasuda et al. (2003) identified a 4-bp deletion, 1284delACTT, in the GLA gene. The patient was a 51-year-old Brazilian man who had childhood onset of acroparesthesias, angiokeratoma, hypohidrosis, and corneal opacities. He had microalbuminuria, which may have been secondary to his diabetes mellitus, but retained normal renal function. He had no evidence of cardiac or cerebral involvement.


.0062 FABRY DISEASE

GLA, ASN272SER
  
RCV000011521

In affected members of a Slovenian family with Fabry disease (301500), Verovnik et al. (2004) identified a 10523A-G transition in exon 6 of the GLA gene, resulting in an asn272-to-ser (N272S) substitution. The 7 affected males, including a set of twins, showed decreased to absent alpha-galactosidase activity and had symptoms of classic Fabry disease, but there was considerable variability in their organ involvement, particularly renal: 3 were on dialysis, but 4 had only mild to moderate proteinuria. The 10 affected females had much milder symptoms, with no renal failure, severe cardiac disease, or stroke. Verovnik et al. (2004) stated that this was the first reported Slovenian family with Fabry disease.


.0063 FABRY DISEASE, CARDIAC VARIANT

GLA, PHE113LEU
  
RCV000991314...

In 11 symptomatic Portuguese males from 10 families and in 2 Italian males identified by newborn screening with Fabry disease (301500), Oliveira et al. (2020) identified hemizygosity for a c.337T-C transition (c.337T-C, NM_000169.2) in the GLA gene, resulting in a phe113-to-leu (F113L) substitution. The mutation was identified by Sanger sequencing of the GLA gene or by next-generation sequencing of a multigene panel testing for hypertrophic cardiomyopathy. The symptomatic men had a late-onset cardiac phenotype. Microsatellite analysis showed that all of the alleles were on the same GLA haplotype, suggesting inheritance from a common ancestor.


REFERENCES

  1. Azevedo, O., Gal, A., Faria, R., Gaspar, P., Miltenberger-Miltenyi, G., Gago, M. F., Dias, F., Martins, A., Rodrigues, J., Reimao, P., Pereira, O., Simoes, S., Lopes, E., Guimaraes, M. J., Sousa, N., Cunha, D. Founder effect of Fabry disease due to p.F113L mutation: clinical profile of a late-onset phenotype. Molec. Genet. Metab. 129: 150-160, 2020. [PubMed: 31519519, related citations] [Full Text]

  2. Bernstein, H. S., Bishop, D. F., Astrin, K. H., Kornreich, R., Eng, C. M., Sakuraba, H., Desnick, R. J. Fabry disease: six gene rearrangements and an exonic point mutation in the alpha-galactosidase gene. J. Clin. Invest. 83: 1390-1399, 1989. [PubMed: 2539398, related citations] [Full Text]

  3. Bishop, D. F., Calhoun, D. H., Bernstein, H. S., Hantzopoulos, P., Quinn, M., Desnick, R. J. Human alpha-galactosidase A: nucleotide sequence of a cDNA clone encoding the mature enzyme. Proc. Nat. Acad. Sci. 83: 4859-4863, 1986. [PubMed: 3014515, related citations] [Full Text]

  4. Bishop, D. F., Kornreich, R., Desnick, R. J. Structural organization of the human alpha-galactosidase A gene: further evidence for the absence of a 3-prime untranslated region. Proc. Nat. Acad. Sci. 85: 3903-3907, 1988. [PubMed: 2836863, related citations] [Full Text]

  5. Branton, M. H., Schiffmann, R., Sabnis, S. G., Murray, G. J., Quirk, J. M., Altarescu, G., Goldfarb, L., Brady, R. O., Balow, J. E., Austin, H. A., III, Kopp, J. B. Natural history of Fabry renal disease: influence of alpha-galactosidase A activity and genetic mutations on clinical course. Medicine 81: 122-138, 2002. [PubMed: 11889412, related citations] [Full Text]

  6. Calhoun, D. H., Bishop, D. F., Bernstein, H. S., Quinn, M., Hantzopoulos, P., Desnick, R. J. Fabry disease: isolation of a cDNA clone encoding human alpha-galactosidase A. Proc. Nat. Acad. Sci. 82: 7364-7368, 1985. [PubMed: 2997789, related citations] [Full Text]

  7. Cariolou, M. A., Christodoulides, M., Manoli, P., Kokkofitou, A., Tsambaos, D. Novel trinucleotide deletion in Fabry's disease. Hum. Genet. 97: 468-470, 1996. [PubMed: 8834244, related citations] [Full Text]

  8. Chen, C.-H., Shyu, P.-W., Wu, S.-J., Sheu, S.-S., Desnick, R. J., Hsiao, K.-J. Identification of a novel point mutation (S65T) in alpha-galactosidase A gene in Chinese patients with Fabry disease. Hum. Mutat. 11: 328-330, 1998. [PubMed: 9554750, related citations] [Full Text]

  9. Chen, E. Y., Liao, Y.-C., Smith, D. H., Barrera-Saldana, H. A., Gelinas, R. E., Seeburg, P. H. The human growth hormone locus: nucleotide sequence, biology, and evolution. Genomics 4: 479-497, 1989. [PubMed: 2744760, related citations] [Full Text]

  10. Chiang, H.-L., Wang, N. H.-H., Song, I.-W., Chang, C.-P., Wen, M.-S., Chien, Y.-H., Hwu, W.-L., Tsai, F.-J., Chen, Y.-T., Wu, J.-Y. Genetic epidemiological study doesn't support GLA IVS4+919G-A variant is (sic) a significant mutation in Fabry disease. Molec. Genet. Metab. 121: 22-27, 2017. [PubMed: 28377241, related citations] [Full Text]

  11. Cianfriglia, M., Miggiano, V. C., Meo, T., Muller, H. J., Muller, E., Battistuzzi, G. Evidence for synteny between the rabbit gene loci coding for HPRT, PGK and G6PD in mouse-rabbit somatic cell hybrids. (Abstract) Cytogenet. Cell Genet. 25: 142, 1979.

  12. Cooper, T. A., Mattox, W. The regulation of splice-site selection, and its role in human disease. Am. J. Hum. Genet. 61: 259-266, 1997. [PubMed: 9311728, related citations] [Full Text]

  13. Davies, J. P., Winchester, B. G., Malcolm, S. Mutation analysis in patients with the typical form of Anderson-Fabry disease. Hum. Molec. Genet. 2: 1051-1053, 1993. [PubMed: 8395937, related citations] [Full Text]

  14. Davies, J. P., Winchester, B. G., Malcolm, S. Sequence variations in the first exon of alpha-galactosidase A. J. Med. Genet. 30: 658-663, 1993. [PubMed: 8411052, related citations] [Full Text]

  15. deJong, J. G. N., Jansen, P. P. M., van den Berg, C. J. M. G., Hamel, B. C. J., Wevers, R. A., Ploos van Amstel, J. K. Genetic heterogeneity in Fabry's disease: mutations in the alpha-galactosidase A gene. Proceedings of the 2nd International Duodecim Symposium. Molecular Biology of Lysosomal Disease, Majik, Finland 1993.

  16. Echard, G., Gillois, M. Rabbit gene mapping: G6PD--alpha-GAL-PGK--HPRT synteny. (Abstract) Cytogenet. Cell Genet. 25: 148, 1979.

  17. Eng, C. M., Desnick, R. J. Molecular basis of Fabry disease: mutations and polymorphisms in the human alpha-galactosidase A gene. Hum. Mutat. 3: 103-111, 1994. [PubMed: 7911050, related citations] [Full Text]

  18. Eng, C. M., Resnick-Silverman, L. A., Niehaus, D. J., Astrin, K. H., Desnick, R. J. Nature and frequency of mutations in the alpha-galactosidase A gene that cause Fabry disease. Am. J. Hum. Genet. 53: 1186-1197, 1993. [PubMed: 7504405, related citations]

  19. Francke, U., Taggart, R. T. Regional mapping of SOD-1 on mouse chromosome 16, and of HPRT and alpha-GAL (Ags) on mouse X, using Chinese hamster-mouse T(X;16)16H somatic cell hybrids. (Abstract) Cytogenet. Cell Genet. 25: 155-156, 1979.

  20. Fukuhara, Y., Sakuraba, H., Oshima, A., Shimmoto, M., Nagao, Y., Nadaoka, Y., Suzuki, T., Suzuki, Y. Partial deletion of human alpha-galactosidase A gene in Fabry disease: direct repeat sequences as a possible cause of slipped mispairing. Biochem. Biophys. Res. Commun. 170: 296-300, 1990. [PubMed: 2164807, related citations] [Full Text]

  21. Garman, S. C., Garboczi, D. N. The molecular defect leading to Fabry disease: structure of human alpha-galactosidase. J. Molec. Biol. 337: 319-335, 2004. [PubMed: 15003450, related citations] [Full Text]

  22. Germain, D. P. Co-occurrence and contribution of Fabry disease and Klippel-Trenaunay-Weber syndrome to a patient with atypical skin lesions. Clin. Genet. 60: 63-67, 2001. [PubMed: 11531972, related citations] [Full Text]

  23. Goss, S. J., Harris, H. Gene transfer by means of cell fusion. I. Statistical mapping of the human X-chromosome by analysis of radiation-induced gene segregation. J. Cell Sci. 25: 17-37, 1977. [PubMed: 561093, related citations] [Full Text]

  24. Grzeschik, K.-H. Personal Communication. Leiden, The Netherlands 1972.

  25. Hasholt, L., Sorensen, S. A., Wandall, A., Andersen, E. B., Arlien-Soborg, P. A Fabry's disease heterozygote with a new mutation: biochemical, ultrastructural, and clinical investigations. J. Med. Genet. 27: 303-306, 1990. [PubMed: 2161929, related citations] [Full Text]

  26. Hasholt, L., Sorensen, S. A. Lysosomal alpha-galactosidase in endothelial cell cultures established from a Fabry hemizygous and normal umbilical veins. Hum. Genet. 72: 72-76, 1986. [PubMed: 3002954, related citations] [Full Text]

  27. Hors-Cayla, M. C., Heuertz, S., Van Cong, N., Benne, F. Cattle gene mapping by somatic cell hybridization. (Abstract) Cytogenet. Cell Genet. 25: 165-166, 1979.

  28. Ishii, S., Nakao, S., Minamikawa-Tachino, R., Desnick, R. J., Fan, J.-Q. Alternative splicing in the alpha-galactosidase A gene: increased exon inclusion results in the Fabry cardiac phenotype. Am. J. Hum. Genet. 70: 994-1002, 2002. [PubMed: 11828341, images, related citations] [Full Text]

  29. Ishii, S., Sakuraba, H., Shimmoto, M., Minamikawa-Tachino, R., Suzuki, T., Suzuki, Y. Fabry disease: detection of a 13-bp deletion in alpha-galactosidase A gene and its application to gene diagnosis of heterozygotes.. Ann. Neurol. 29: 560-564, 1991. [PubMed: 1650161, related citations] [Full Text]

  30. Ishii, S., Sakuraba, H., Suzuki, Y. Point mutations in the upstream region of the alpha-galactosidase A gene exon 6 in an atypical variant of Fabry disease. Hum. Genet. 89: 29-32, 1992. [PubMed: 1315715, related citations] [Full Text]

  31. Kase, R., Bierfreund, U., Klein, A., Kolter, T., Utsumi, K., Itoh, K., Sandhoff, K., Sakuraba, H. Characterization of two alpha-galactosidase mutants (Q279E and R301Q) found in an atypical variant of Fabry disease. Biochim. Biophys. Acta 1501: 227-235, 2000. [PubMed: 10838196, related citations] [Full Text]

  32. Koide, T., Ishiura, M., Iwai, K., Inoue, M., Kaneda, Y., Okada, Y., Uchida, T. A case of Fabry's disease in a patient with no alpha-galactosidase A activity caused by a single amino acid substitution of pro40 by ser. FEBS Lett. 259: 353-356, 1990. [PubMed: 2152885, related citations] [Full Text]

  33. Kopp, J. B. Personal Communication. Bethesda, Md. 2/20/2002.

  34. Kornreich, R., Bishop, D. F., Desnick, R. J. The gene encoding alpha-galactosidase A and gene rearrangements causing Fabry disease. Trans. Assoc. Am. Phys. 102: 30-43, 1989. [PubMed: 2561643, related citations]

  35. Kornreich, R., Bishop, D. F., Desnick, R. J. Alpha-galactosidase A gene rearrangements causing Fabry disease: identification of short direct repeats at breakpoints in an Alu-rich gene. J. Biol. Chem. 265: 9319-9326, 1990. [PubMed: 2160973, related citations]

  36. Lai, L.-W., Whitehair, O., Wu, M.-J., O'Meara, M., Lien, Y.-H. H. Analysis of splice-site mutations of the alpha-galactosidase A gene in Fabry disease. Clin. Genet. 63: 476-482, 2003. [PubMed: 12786754, related citations] [Full Text]

  37. Lee, B. H., Heo, S. H., Kim, G.-H., Park, J.-Y., Kim, W.-S., Kang, D.-H., Choe, K. H., Kim, W.-H., Yang, S. H., Yoo, H.-W. Mutations of the GLA gene in Korean patients with Fabry disease and frequency of the E66Q allele as a functional variant in Korean newborns. J. Hum. Genet. 55: 512-517, 2010. [PubMed: 20505683, related citations] [Full Text]

  38. Lenders, M., Duning, T., Schelleckes, M., Schmitz, B., Stander, S., Rolfs, A., Brand, S.-M., Brand, E. Multifocal white matter lesions associated with the D313Y mutation of the alpha-galactosidase A gene. PLoS One 8: e55565, 2013. Note: Electronic Article. [PubMed: 23393592, related citations] [Full Text]

  39. Liu, H.-X., Cartegni, L., Zhang, M. Q., Krainer, A. R. A mechanism for exon skipping caused by nonsense or missense mutations in BRCA1 and other genes. Nature Genet. 27: 55-58, 2001. [PubMed: 11137998, related citations] [Full Text]

  40. Lusis, A. J., West, J. D. X-linked inheritance of a structural gene for alpha-galactosidase in Mus musculus. Biochem. Genet. 14: 849-855, 1976. [PubMed: 1008807, related citations] [Full Text]

  41. Madsen, K. M., Hasholt, L., Fermer, M. L., Dahl, N. Identification of mutations in Danish families with Fabry's disease. Proc. 2nd Int. Duodecim Symposium. Molecular Biology of Lysosomal Disease, Majik, Finland 1993.

  42. Matsuzawa, F., Aikawa, S., Doi, H., Okumiya, T., Sakuraba, H. Fabry disease: correlation between structural changes in a-galactosidase, and clinical and biochemical phenotypes. Hum. Genet. 117: 317-328, 2005. [PubMed: 15924232, related citations] [Full Text]

  43. Miyamura, N., Araki, E., Matsuda, K., Yoshimura, R., Furukawa, N., Tsuruzoe, K., Shirotani, T., Kishikawa, H., Yamaguchi, K., Shichiri, M. A carboxy-terminal truncation of human alpha-galactosidase A in a heterozygous female with Fabry disease and modification of the enzymatic activity by the carboxy-terminal domain: increased, reduced, or absent enzyme activity depending on number of amino acid residues deleted. J. Clin. Invest. 98: 1809-1817, 1996. [PubMed: 8878432, related citations] [Full Text]

  44. Nakai, K., Sakamoto, H. Construction of a novel database containing aberrant splicing mutations of mammalian genes. Gene 141: 171-177, 1994. [PubMed: 8163185, related citations] [Full Text]

  45. Nakao, S., Takenaka, T., Maeda, M., Kodama, C., Tanaka, A., Tahara, M., Yoshida, A., Kuriyama, M., Hayashibe, H., Sakuraba, H., Tanaka, H. An atypical variant of Fabry's disease in men with left ventricular hypertrophy. New Eng. J. Med. 333: 288-293, 1995. [PubMed: 7596372, related citations] [Full Text]

  46. Nance, C. S., Klein, C. J., Banikazemi, M., Dikman, S. H., Phelps, R. G., McArthur, J. C., Rodriguez, M., Desnick, R. J. Later-onset Fabry disease: an adult variant presenting with the cramp-fasciculation syndrome. Arch. Neurol. 63: 453-457, 2006. [PubMed: 16533976, related citations] [Full Text]

  47. Niemann, M., Rolfs, A., Giese, A., Mascher, H., Breunig, F., Ertl, G., Wanner, C., Weidemann, F. Lyso-Gb3 indicates that the alpha-galactosidase A mutation D313Y is not clinically relevant for Fabry disease. JIMD Rep. 7: 99-102, 2013. [PubMed: 23430502, related citations] [Full Text]

  48. Novo, F. J., Kruszewski, A., MacDermot, K. D., Goldspink, G., Gorecki, D. C. Editing of human alpha-galactosidase RNA resulting in a pyrimidine to purine conversion. Nucleic Acids Res. 23: 2636-2640, 1995. [PubMed: 7503918, related citations] [Full Text]

  49. O'Brien, S. J. The extent and character of biochemical genetic variation in the domestic cat. J. Hered. 71: 2-8, 1980.

  50. Oliveira, J. P., Nowak, A., Barbey, F., Torres, M., Nunes, J. P., Teixeira-e-Costa, F., Carvalho, F., Sampaio, S., Tavares, I., Pereira, O., Soares, A. L., Carmona, C, Cardoso, M.-T., Jurca-Simina, I. E., Spada, M., Ferreira, S., Germain, D. P. Fabry disease caused by the GLA p.Phe113Leu (p.F113L) variant: natural history in males. Europ. J. Med. Genet. 63: 103703, 2020. Note: Electronic Article. [PubMed: 31200018, related citations] [Full Text]

  51. Sakuraba, H., Eng, C. M., Desnick, R. J., Bishop, D. F. Invariant exon skipping in the human alpha-galactosidase A pre-mRNA: a g(+1) to t substitution in a 5-prime-splice site causing Fabry disease. Genomics 12: 643-650, 1992. [PubMed: 1315304, related citations] [Full Text]

  52. Sakuraba, H., Oshima, A., Fukuhara, Y., Shimmoto, M., Nagao, Y., Bishop, D. F., Desnick, R. J., Suzuki, Y. Identification of point mutations in the alpha-galactosidase A gene in classical and atypical hemizygotes with Fabry disease. Am. J. Hum. Genet. 47: 784-789, 1990. [PubMed: 2171331, related citations]

  53. Sawada, K., Mizoguchi, K., Hishida, A., Kaneko, E., Koide, Y., Nishimura, K., Kimura, M. Point mutation in the alpha-galactosidase A gene of atypical Fabry disease with only nephropathy. Clin. Nephrol. 45: 289-294, 1996. [PubMed: 8738659, related citations]

  54. Verovnik, F., Benko, D., Vujkovac, B., Linthorst, G. E. Remarkable variability in renal disease in a large Slovenian family with Fabry disease. Europ. J. Hum. Genet. 12: 678-681, 2004. [PubMed: 15162124, related citations] [Full Text]

  55. von Scheidt, W., Eng, C. M., Fitzmaurice, T. F., Erdmann, E., Hubner, G., Olsen, E. G. J., Christomanou, H., Kandolf, R., Bishop, D. F., Desnick, R. J. An atypical variant of Fabry's disease with manifestations confined to the myocardium. New Eng. J. Med. 324: 395-399, 1991. [PubMed: 1846223, related citations] [Full Text]

  56. Yang, C.-C., Lai, L.-W., Whitehair, O., Hwu, W.-L., Chiang, S.-C., Lien, Y.-H. H. Two novel mutations in the alpha-galactosidase A gene in Chinese patients with Fabry disease. Clin. Genet. 63: 205-209, 2003. [PubMed: 12694230, related citations] [Full Text]

  57. Yasuda, M., Shabbeer, J., Benson, S. D., Maire, I., Burnett, R. M., Desknick, R. J. Fabry disease: characterization of alpha-galactosidase A double mutations and the D313Y plasma enzyme pseudodeficiency allele. Hum. Mutat. 22: 486-492, 2003. [PubMed: 14635108, related citations] [Full Text]

  58. Yasuda, M., Shabbeer, J., Osawa, M., Desnick, R. J. Fabry disease: novel alpha-galactosidase A 3-prime-terminal mutations result in multiple transcripts due to aberrant 3-prime-end formation. Am. J. Hum. Genet. 73: 162-173, 2003. [PubMed: 12796853, images, related citations] [Full Text]

  59. Yokoi, T., Shinoda, K., Ohno, I., Kato, K., Miyawaki, T., Taniguchi, N. A 3-prime splice site consensus sequence mutation in the intron 3 of the alpha-galactosidase A gene in a patient with Fabry disease. Jpn. J. Hum. Genet. 36: 245-250, 1991. [PubMed: 1753437, related citations] [Full Text]


Hilary J. Vernon - updated : 10/20/2022
Hilary J. Vernon - updated : 09/09/2021
Ada Hamosh - updated : 06/15/2017
Cassandra L. Kniffin - updated : 12/5/2013
Cassandra L. Kniffin - updated : 11/1/2010
Creation Date:
Cassandra L. Kniffin : 3/21/2007
carol : 10/24/2022
carol : 10/20/2022
carol : 09/22/2022
carol : 04/22/2022
carol : 09/09/2021
mgross : 03/29/2018
carol : 06/16/2017
carol : 06/15/2017
carol : 10/17/2016
carol : 12/18/2013
ckniffin : 12/5/2013
wwang : 12/8/2010
ckniffin : 11/1/2010
wwang : 9/2/2009
terry : 12/17/2007
terry : 8/6/2007
wwang : 4/3/2007
ckniffin : 3/29/2007
carol : 3/28/2007
carol : 3/28/2007
ckniffin : 3/23/2007
ckniffin : 3/23/2007

* 300644

GALACTOSIDASE, ALPHA; GLA


Alternative titles; symbols

ALPHA-GALACTOSIDASE A; GALA


HGNC Approved Gene Symbol: GLA

SNOMEDCT: 124464003, 16652001;   ICD10CM: E75.21;  


Cytogenetic location: Xq22.1     Genomic coordinates (GRCh38): X:101,397,803-101,407,925 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Xq22.1 Fabry disease 301500 X-linked 3
Fabry disease, cardiac variant 301500 X-linked 3

TEXT

Description

The GLA gene encodes alpha-galactosidase (GLA; EC 3.2.1.22), a lysosomal hydrolase.


Cloning and Expression

Calhoun et al. (1985) isolated clones corresponding to the GLA gene from a human liver cDNA library. The 370-amino acid protein has a molecular mass of 41.4 kD. The mature active enzyme is a homodimeric protein.

Bishop et al. (1986) isolated GLA cDNA clones and found an open reading frame of 398 residues with a molecular mass of 45.4 kD. RNA transfer hybridization analysis detected a 1.45-kb transcript. Bishop et al. (1988) determined that the GLA gene lacks a 3-prime untranslated sequence, with the polyadenylation signal included in the coding region. Kornreich et al. (1989) presented the complete nucleotide sequence of the GLA gene.

Using RT-PCR amplification of genomic GLA DNA isolated from normal individuals, Novo et al. (1995) found that a subset of RNA molecules had a 1187U-A conversion which differed from the wildtype cDNA sequence. Multiple genes, pseudogenes, or allelic variants were excluded. Novo et al. (1995) proposed RNA editing as a mechanism responsible for this base change in the GLA RNA, similar to that which has been demonstrated for the nuclear encoded RNA for intestinal apoB (107730) and several subunits of brain L-glutamate receptors such as GLUR2 (138247), GLUR5 (138245), and GLUR6 (138244).


Gene Structure

Bishop et al. (1988) determined that the GLA gene contains 7 exons and spans about 12 kb.


Mapping

The GLA gene was localized to the X chromosome using cell hybridization techniques (Grzeschik, 1972).

From study of radiation-induced segregants in which irradiated human cells are rescued by fusion with hamster cells, Goss and Harris (1977) showed that the order of the following 4 loci on Xq is PGK--alpha-GAL--HPRT--G6PD and that the 3 intervals between these 4 loci are, in relative terms, 0.33, 0.30, and 0.23.

Lusis and West (1976) reported X-linked inheritance of the Gla gene in the mouse. Alpha-GAL, HPRT, PGK and G6PD are X-linked in the rabbit, according to mouse-rabbit hybrid cell studies (Cianfriglia et al., 1979; Echard and Gillois, 1979). By comparable methods, Hors-Cayla et al. (1979) found them to be X-linked also in cattle. Francke and Taggart (1979) assigned HPRT and alpha-GAL to the X chromosome in the Chinese hamster by study of mouse-Chinese hamster hybrid cells.


Molecular Genetics

Davies et al. (1993) demonstrated 3 polymorphic variants in the first exon of the GLA gene, which contains 60 bp of 5-prime untranslated sequence before the methionine initiation codon. Such a high level of polymorphism had not previously been reported and was unusual in such a short stretch of DNA.

In a patient with Fabry disease (301500), Bernstein et al. (1989) identified a mutation in the GLA gene (300644.0001). The substitution altered the enzyme's kinetic properties and stability.

Eng et al. (1993) identified 18 different mutations in the GLA gene (see, e.g., 300644.0012; 300644.0013; 300644.0018-300644.0022) in patients with Fabry disease.

Lai et al. (2003) pointed out that most of the mutations in the GLA gene were identified in Fabry disease patients by genomic sequencing only, and therefore some of the splicing mutations were misclassified as missense mutations. To predict splicing events caused by specific mutations, they conducted a literature search for all published GLA mutations located near splice sites, including exonic point mutations, and performed a splice site score (SSS) analysis. They found 13 donor site mutations, 6 acceptor site mutations, and 1 new exon creation. All mutated splice sites, except for the 1 associated with new exon creation, had a lower SSS than their respective natural sites.

Yasuda et al. (2003) noted that the human GLA gene is one of the rare mammalian genes that has its polyadenylation signal in the coding sequence and lacks a 3-prime untranslated region. In 2 unrelated men with classic Fabry disease, they identified 2 novel frameshift mutations, 1277delAA (300644.0060) and 1284delACTT (300644.0061), which occurred in the 3-prime terminus of the coding region and obliterated the termination codon; the 2-bp deletion also altered the polyadenylation signal. Both mutations generated multiple transcripts of various lengths of 3-prime terminal sequences, some elongated by approximately 1 kb. Northern blot analysis suggested that mRNA degradation did not occur.

Splicing Patterns

In the context of examining splice site mutations in the GLA gene, Lai et al. (2003) discussed the 5 major aberrant splicing patterns caused by mutations in general: exon skipping, cryptic site activation, new site creation, intron retention, and disruption of exonic splicing enhancers (Nakai and Sakamoto, 1994; Cooper and Mattox, 1997). The selection of splicing patterns is based on many factors. When no strong cryptic site or newly created site is available, destruction of either the donor or acceptor splice site causes skipping of the neighboring exon. Cryptic splice sites are normally silent consensus sites that are activated when the authentic site is destroyed by mutation. In general, the distance between the authentic site and the cryptic site is about 100 nucleotides long. Mutations also can result in the creation of a new splice site, which may or may not be associated with destruction of the authentic site. If the authentic site is not altered, the new splice site is always in the upstream region of the authentic site. Intron retention occurs infrequently and sometimes simultaneously with other splicing patterns. Cis element exonic splicing enhancers (ESE) also have a role in the regulation of splicing. See the report of Liu et al. (2001) showing that disruption of an exonic splicing enhancer resulted in missplicing of exon 18 in the BRCA1 gene (113705). Similar mechanisms may explain why many exonic missense or nonsense mutations that are not located at splice sites are associated with exon skipping.


Genotype/Phenotype Correlations

Using the x-ray crystal structure of human alpha-galactosidase reported by Garman and Garboczi (2004), Matsuzawa et al. (2005) performed computerized 3-dimensional structural analysis of the mutant enzyme resulting from 161 missense mutations in the GLA gene causing Fabry disease. Mutations resulting in the severe classic phenotype showed a wide distribution in the number of atoms affected by the mutation, but the majority (82%) had 3 or more affected atoms in the main chain of the protein. Nineteen classic mutations affected the active site or the substrate-binding site of the enzyme. By contrast, 85% of mutations resulting in the milder variant phenotype had less than 3 atoms influenced in the main chain, and none of the variant mutations affected the active site. These results suggested that variant Fabry mutations cause small changes that do not affect the whole protein structure.

Matsuzawa et al. (2005) performed further analysis of 11 specific mutations in the GLA gene, which the authors subdivided into 4 groups according to the clinical and biochemical phenotypes of Fabry disease: classic with a completely dysfunctional and ineffective protein; classic with an unstable and ineffective protein; classic with an unstable but moderately effective protein; and variant with an unstable but effective protein. In particular, the G328R (300644.0010) mutation, which results in an unstable, ineffective protein, had 77 and 53 affected atoms in the main and side chains, respectively. The variant mutations Q279E (300644.0008) and M296I (300644.0051) were located apart from the active site and affected less than 3 atoms each in the main chain.

In a Japanese patient with the cardiac variant of Fabry disease, Ishii et al. (1992) identified a mutation in the GLA gene (300644.0008) associated with residual GLA enzyme activity. The patient developed dyspnea and bradycardia for the first time at age 60 years and died of heart failure at age 64. He was found to have complete left bundle branch block associated with hypertrophy of the left ventricular wall and interventricular septum. He had no other signs or symptoms characteristic of Fabry disease except proteinuria, which was found after cardiac failure had developed. Myocardial biopsy had shown inclusion bodies on electron microscopic examination. A 39-year-old nephew was asymptomatic but showed a thick interventricular septum and left ventricular wall by echocardiography and magnetic resonance imaging. The mutation in this case, as in 2 other cases of the cardiac form (300644.0003, 300644.0005), was located in exon 6.

Oliveira et al. (2020) reported 11 symptomatic Portuguese males from 10 families with Fabry disease who had a hemizygous F113L (300644.0063) mutation in the GLA gene. All of the patients had a late-onset form of the disorder, manifesting with a cardiac phenotype invariably including cardiomyopathy/hypertrophic cardiomyopathy, and often including other features such as conduction defects, arrhythmias, and myocardial ischemia. Some patients also had cerebrovascular or kidney involvement, although the association with the GLA mutation was confounded by the presence of other risk factors (e.g., hypertension, diabetes, obesity).

In a population of 150 adults with hypertrophic cardiomyopathy in Guimaraes, Portugal, Azevedo et al. (2020) identified 25 patients with Fabry disease, 21 of whom were hemizygous or heterozygous for the F113L mutation in the GLA gene. Geneology studies demonstrated a common ancestor in 17 of the 21 patients. Through pedigree analysis in these patients, Azevedo et al. (2020) identified 120 patients, including 47 males and 73 females, with Fabry disease due to the F113L mutation. The mean age at diagnosis was 46 years, which was similar in both genders. Left ventricular hypertrophy (LVH) was identified in 49 patients, with a male predominance, and most patients were diagnosed with LVH at or after 40 years of age. Albuminuria was identified in 36.1% of patients; however, renal insufficiency was rare and no patient progressed to dialysis. Acroparesthesias were more common in females (34.2% of females and 6.4% of males). Sensorineural hearing loss was more common in males (30.8% of females and 64.4% of males). Strokes and angiokeratomas were rare. Azevedo et al. (2020) concluded that the F113L mutation in the Guimaraes region of Portugal was associated with a cardiac-predominant, late-onset form of Fabry disease.


ALLELIC VARIANTS 63 Selected Examples):

.0001   FABRY DISEASE

GLA, ARG356TRP
SNP: rs104894827, ClinVar: RCV000011459, RCV001781217, RCV003398483

In a patient with Fabry disease (301500), Bernstein et al. (1989) identified a 1066C-T transition in the GLA gene, resulting in an arg356-to-trp (R356W) substitution. The substitution altered the enzyme's kinetic properties and stability.


.0002   FABRY DISEASE

GLA, EX3DEL
SNP: rs2147477260, rs2147478154, ClinVar: RCV000011460

Fukuhara et al. (1990) reported partial deletion of the GLA gene in a case of Fabry disease (301500). The deletion involved exon 3 and was associated with an A-to-C transversion. The 402-bp deletion was flanked by 6-bp direct repeat sequences. These structures may have promoted 'slipped mispairing' as the origin of the mutation in this family.


.0003   FABRY DISEASE, CARDIAC VARIANT

FABRY DISEASE, INCLUDED
GLA, ARG301GLN
SNP: rs104894828, ClinVar: RCV000011461, RCV000011462, RCV000244581, RCV000723405, RCV000845380

In a Japanese patient with Fabry disease following an atypical clinical course characterized by late-onset cardiac involvement and significant residual GLA (see 301500), Sakuraba et al. (1990) identified a G-to-A transition in exon 6 of the GLA gene, resulting in an arg301-to-gln (R301Q) substitution.

Sawada et al. (1996) identified the R301Q substitution in a 45-year-old man who developed moderate proteinuria and was found to have the renal histologic findings of Fabry disease, together with a decrease in activity of alpha-galactosidase A in his plasma, urine, leukocytes, and skin fibroblasts. The mutation was inherited from his mother. The patient was unique in that he demonstrated only renal manifestations, whereas all other patients with atypical Fabry disease, including a case with the identical point mutation (Sakuraba et al., 1990), presented with cardiomyopathy.

Kase et al. (2000) characterized this mutant and another, Q279E (300644.0008), in a patient with the cardiac variant of Fabry disease. In contrast to patients with classic Fabry disease, who have no detectable alpha-galactosidase activity, patients with these variants have residual enzyme activity. Compared to normal control cells, fibroblasts from a patient with the Q279E mutation secreted only small amounts of alpha-galactosidase. The authors concluded that these 2 substitutions do not significantly affect enzymatic activity, but the mutant protein levels are decreased presumably in the endoplasmic reticulum of cells.


.0004   FABRY DISEASE

GLA, TRP44TER
SNP: rs104894829, ClinVar: RCV000011463

In a Japanese patient with classic Fabry disease (301500) and no detectable alpha-galactosidase A activity, Sakuraba et al. (1990) found a G-to-A transition in exon 1 of the GLA gene, resulting in a trp44-to-ter (W44X) substitution.


.0005   FABRY DISEASE, CARDIAC VARIANT

GLA, MET296VAL
SNP: rs104894830, ClinVar: RCV000011464, RCV000179267, RCV001185735

In a 54-year-old man with the cardiac variant of Fabry disease (see 301500), von Scheidt et al. (1991) identified an 886A-G transition in exon 6 of the GLA gene, resulting in a met296-to-val (M296V) substitution. The patient had 'crescendo angina,' relieved by nitroglycerin, as well as electrocardiographic changes, but normal cardiac chamber size and normal systolic and diastolic function by echocardiogram. Cardiac catheterization showed no stenoses of the extramural coronary arteries. Diagnosis of Fabry disease was made by endomyocardial biopsy. Light-microscopic examination showed that approximately half the myocytes contained a centrally stored foamy material that stained metachromatically. By electron microscopy, typical myelin-figure-like concentric lamellar inclusions in lysosomes were observed. Most remarkably, the endothelial cells of the myocardial capillaries were not involved and no changes were observed in specimens of skeletal muscle, liver, rectum, and skin, including small blood vessels and nerves.


.0006   FABRY DISEASE

GLA, EX4DEL
SNP: rs869312287, ClinVar: RCV000011465

In an 11-year-old boy with Fabry disease (301500), Yokoi et al. (1991) identified a G-to-A transition at the 3-prime consensus sequence (splicing acceptor) of intron 3 of the GLA gene. The mutation resulted in deletion of exon 4 and a frameshift with appearance of a terminating codon in exon 5.


.0007   FABRY DISEASE

GLA, IVS6DS, G-T, +1
SNP: rs1603038103, ClinVar: RCV000011467

In 3 affected brothers from a Japanese family with Fabry disease (301500), Sakuraba et al. (1992) identified deletion of exon 6 due to a G-to-T transversion at the first nucleotide of the 5-prime splice site of intron 6 of the GLA gene. Sakuraba et al. (1992) stated that this was the first G-to-T transversion of a mammalian 5-prime splice site that consistently eliminated the preceding exon. Sakuraba et al. (1992) gave a tabulation of various mammalian 5-prime consensus splice site mutations that lead to exon skipping and in most cases use of cryptic splice sites. They pointed out that glycophorin B (GYPB; 617923) of the Ss blood group (111740) differs from glycophorin A (GYPA; 617922) of the MN blood group (111300) by 2 changes at the 5-prime splice site of intron 3 which presumably took place after duplication of the progenitor gene. As indicated in their Table 1, the gene for growth hormone-like (GH2; 139240) differs from that for growth hormone (GH1; 139250) by a G-to-A transition at position +1 of intron 2 in the duplicated gene (Chen et al., 1989).


.0008   FABRY DISEASE, CARDIAC VARIANT

GLA, GLN279GLU
SNP: rs28935485, ClinVar: RCV000011468, RCV001781218

Ishii et al. (1992) identified an 835C-G transversion in the GLA gene, resulting in a gln279-to-glu (Q279E) substitution, in a Japanese patient with the cardiac variant of Fabry disease (see 301500). The patient developed dyspnea and bradycardia for the first time at age 60 years and died of heart failure at age 64. He was found to have complete left bundle branch block associated with hypertrophy of the left ventricular wall and interventricular septum. He had no other signs or symptoms characteristic of Fabry disease except proteinuria, which was found after cardiac failure had developed. Myocardial biopsy had shown inclusion bodies on electron microscopic examination. A 39-year-old nephew was asymptomatic but showed a thick interventricular septum and left ventricular wall by echocardiography and magnetic resonance imaging. Both men had some residual alpha-galactosidase A activity. The mutation in this case, as in 2 other cases of the cardiac form (300644.0003, 300644.0005), was located in exon 6. On the other hand, the gly328-to-arg mutation, located at the 3-prime end of exon 6 was associated with classic features of Fabry disease (see 300644.0010).


.0009   FABRY DISEASE

GLA, PRO40SER
SNP: rs104894831, ClinVar: RCV000011466, RCV000729403

Koide et al. (1990) described a pro40-to-ser (P40S) mutation in exon 1 of the GLA gene in a patient with Fabry disease (301500) and no detectable alpha-galactosidase A activity.


.0010   FABRY DISEASE

GLA, GLY328ARG
SNP: rs104894832, ClinVar: RCV000011469, RCV000723846

In a 34-year-old man with typical Fabry disease (301500), Ishii et al. (1992) identified a 982G-A transition in exon 6 of the GLA gene, resulting in a gly328-to-arg (G328R) substitution. This mutation was located at the 3-prime end of exon 6; mutations located at the central or 5-prime end of the exon were associated with the predominantly cardiac form of the disease.


.0011   FABRY DISEASE

GLA, GLU66GLN AND ARG112CYS
SNP: rs104894833, rs104894834, gnomAD: rs104894833, ClinVar: RCV000011470, RCV000150750, RCV000482440, RCV000728539, RCV000780291, RCV000822343, RCV002321570, RCV003162613

In a 14-year-old boy with classic Fabry disease (301500), Ishii et al. (1992) found 2 point mutations in exon 2 of the GLA gene: a GAG-to-CAG change causing a glu66-to-gln (E66Q) substitution, and a CGC-to-TGC change causing an arg112-to-cys (R112C) substitution.

Lee et al. (2010) presented evidence that the E66Q variant is a functional polymorphism and not disease causing. Substantial residual GLA activity was shown both in the leukocytes of individuals carrying E66Q (19.0 to 30.3% of normal activity) and in transiently overexpressed COS-7 cells (43.8% of normal activity). Although the E66Q-variant GLA was unstable at neutral pH, the enzyme was efficiently expressed in the lysosomes of COS-7 cells. The allele frequency of E66Q determined in 833 unrelated Korean individuals was considered to be high at 1.046%. The variant was found in 5 individuals from 4 Korean families during a screen of patients with Fabry disease. Of the 5 patients carrying E66Q, only 1 patient had proteinuria, and 2 had hypertrophic cardiomyopathy without other signs of the disorder. Lee et al. (2010) suggested that either these patients had a different etiology for their features or that they had a very mild atypical variant of the disease with other genetic or environmental factors contributing to the phenotype.


.0012   FABRY DISEASE

GLA, ASN34SER
SNP: rs104894835, ClinVar: RCV000011471, RCV000723530

In a patient with classic Fabry disease (301500), Eng et al. (1993) found an A-to-G transition in exon 1 of the GLA gene, resulting in an asn34-to-ser (N34S) substitution.


.0013   FABRY DISEASE

GLA, CYS56GLY
SNP: rs104894836, ClinVar: RCV000011472

In an English patient with classic Fabry disease (301500), Eng et al. (1993) found a T-to-G transversion in exon 1 of the GLA gene, resulting in a cys56-to-gly (C56G) substitution.


.0014   FABRY DISEASE

GLA, PRO146SER
SNP: rs104894837, ClinVar: RCV000011473

In a Dutch patient with mild Fabry disease (301500), deJong et al. (1993) found a C-to-T transition in exon 3 of the GLA gene, resulting in a pro146-to-ser (P146S) substitution.


.0015   FABRY DISEASE

GLA, ALA156THR
SNP: rs28935195, ClinVar: RCV000011474

In a Danish patient with classic Fabry disease (301500), Madsen et al. (1993) found a G-to-A transition in exon 3 of the GLA gene, resulting in an ala156-to-thr (A156T) substitution.


.0016   FABRY DISEASE

GLA, TRP162ARG
SNP: rs28935196, ClinVar: RCV000011475, RCV003137512

In an Italian patient with classic Fabry disease (301500), Eng et al. (1993) found a T-to-C transition in exon 3 of the GLA gene, resulting in a trp162-to-arg (W162R) substitution.


.0017   FABRY DISEASE

GLA, CYS202TRP
SNP: rs104894838, ClinVar: RCV000011476

In a Dutch patient with classic Fabry disease (301500), deJong et al. (1993) found a T-to-G transversion in exon 4 of the GLA gene, resulting in a cys202-to-trp (C202W) substitution.


.0018   FABRY DISEASE

GLA, ASN215SER
SNP: rs28935197, gnomAD: rs28935197, ClinVar: RCV000011477, RCV000157896, RCV000618059, RCV000844705, RCV001798000

Eng et al. (1993) and Davies et al. (1993) described an A-to-G transition in exon 5 of the GLA gene, resulting in an asn215-to-ser (N215S) substitution. The patients had mild forms of Fabry disease (301500) and residual enzyme activity.


.0019   FABRY DISEASE

GLA, ARG227GLN
SNP: rs104894840, ClinVar: RCV000011478, RCV000157898

In a patient with classic Fabry disease (301500), Eng et al. (1993) described an G-to-A transition in exon 5 of the GLA gene, resulting in an arg227-to-gln (R227Q) substitution. This mutation conforms to the CG-to-TG mutation 'hotspot' rule. In the complementary, antisense strand, 5-prime--xxxCGAxxx--3-prime is read as 3-prime--xxxGCTxxx--5-prime. Methylation of the cytosine in the CpG of the antisense codon with subsequent deamidation converts the antisense codon to GTT, which corresponds to the sense codon CAA. Read 5-prime to 3-prime, the CG in the sense strand has been changed to TG in the antisense strand; hence, the designation CG-to-TG 'hotspot' rule.


.0020   FABRY DISEASE

GLA, ARG227TER
SNP: rs104894841, ClinVar: RCV000011479, RCV000157897

In patients with Fabry disease (301500), Eng et al. (1993) and Davies et al. (1993) identified a C-to-T transition in exon 5 of the GLA gene, resulting in an arg227-to-ter (R227X) substitution. The mutation conforms to the CG-to-TG rule and has been found in more than 1 unrelated patient.


.0021   FABRY DISEASE

GLA, ASP264VAL
SNP: rs28935486, ClinVar: RCV000011480, RCV000724649

In a Scottish/English patient with classic Fabry disease (301500), Eng et al. (1993) found an A-to-T transversion in exon 5 of the GLA gene, resulting in an asp264-to-val (D264V) substitution.


.0022   FABRY DISEASE

GLA, ASP266VAL
SNP: rs28935487, ClinVar: RCV000011481, RCV000733417

In an African American patient with classic Fabry disease (301500), Eng et al. (1993) found an A-to-T transversion in exon 5 of the GLA gene, resulting in an asp266-to-val (D266V) substitution.


.0023   FABRY DISEASE

GLA, VAL269ALA
SNP: rs28935488, ClinVar: RCV000011482

In an English patient with classic Fabry disease (301500), Davies et al. (1993) found a GTG-to-GCG mutation in exon 6 of the GLA gene, resulting in a val269-to-ala (V269A) substitution.


.0024   FABRY DISEASE

GLA, TRP287TER
SNP: rs104894839, ClinVar: RCV000011483

In an English patient with classic Fabry disease (301500), Davies et al. (1993) found a TGG-to-TGA mutation in exon 6 of the GLA gene, resulting in a trp287-to-ter (W287X) substitution.


.0025   FABRY DISEASE

GLA, SER297PHE
SNP: rs28935489, ClinVar: RCV000011484

In an Italian patient with classic Fabry disease (301500), Eng et al. (1993) found a TCT-to-TTT mutation in exon 6 of the GLA gene, resulting in a ser297-to-phe (S297F) substitution.


.0026   RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE

GLA, ASP313TYR
SNP: rs28935490, gnomAD: rs28935490, ClinVar: RCV000011486, RCV000035314, RCV000172895, RCV000250525, RCV000346926, RCV000487818, RCV000769536

This variant, formerly titled FABRY DISEASE, has been reclassified based on the findings of Yasuda et al. (2003).

In a German patient with classic Fabry disease (301500), Eng et al. (1993) found a GAT-to-TAT mutation in exon 6 of the GLA gene, resulting in an asp313-to-tyr (D313Y) substitution.

Yasuda et al. (2003) found that expression of the D313Y variant in COS-7 cells resulted in 60% residual enzyme activity and that the enzyme was localized to lysosomes. In addition, the D313Y variant was found in 0.45% of 883 normal X chromosomes. Molecular homology modeling showed that the D313Y variant did not markedly disrupt enzyme structure. The variant enzyme was stable at lysosomal pH (4.5), but had decreased activity at neutral pH (7.4). Overall, the findings suggested that the D313Y variant is a functional polymorphism rather than a disease-causing variant.

Lenders et al. (2013) noted that the possible pathogenicity of the D313Y variant is controversial. They reported a large family in which 9 females and 1 male carried a heterozygous D313Y mutation; one of the females with the variant was deceased. Seven of the 8 who underwent brain imaging had multifocal white matter lesions, including several young individuals without cardiovascular risk factors. The white matter lesions were primarily subcortical and punctate, but some also were confluent with a periventricular localization. Brain MRI in 2 family members who did not carry the D313Y variant showed no white matter lesions. GLA enzyme activities were normal in carrier leukocytes, but were decreased in plasma. Lyso-Gb3 levels in plasma, which are increased in patients with Fabry disease, were normal. The proband, who carried the D313Y variant, had a peripheral small-fiber neuropathy with decreased intraepithelial nerve fiber density on nerve biopsy. None of the variant carriers had other evidence of Fabry disease, but Lenders et al. (2013) postulated that the D313Y variant may act as a predisposing factor for neurologic manifestations.

Niemann et al. (2013) reported a father and daughter with the D313Y variant. The daughter presented with diffuse skin lesions and nonspecific arm pain. Plasma GLA enzyme activity was mildly decreased. Skin biopsy showed keratosis pilaris rubra atrophicans, but no Fabry angioma. Her 53-year-old father had no clinical manifestations of Fabry disease, although his plasma GLA enzyme activity was also decreased. Lyso-Gb3 was below normal in the daughter and undetectable in the father. Niemann et al. (2013) concluded that the D313Y variant is not clinically relevant for Fabry disease. The authors also suggested that pure assessment of GLA activity and even genetic testing is not sufficient for diagnosing Fabry disease.


.0027   FABRY DISEASE

GLA, GLN327LYS
SNP: rs28935491, ClinVar: RCV000011487

In an English patient with classic Fabry disease (301500), Davies et al. (1993) found a CAA-to-AAA mutation in exon 6 of the GLA gene, resulting in a gln327-to-lys (Q327K) substitution.


.0028   FABRY DISEASE

GLA, GLY328ALA
SNP: rs28935492, ClinVar: RCV000011488, RCV000723545

In a Scottish/Irish patient with classic Fabry disease (301500), Eng et al. (1993) found a GGG-to-GCG mutation in exon 6 of the GLA gene, resulting in a gly328-to-ala (G328A) substitution. A different mutation has also been described in the same codon (see 300644.0010).


.0029   FABRY DISEASE

GLA, TRP340TER
SNP: rs104894842, ClinVar: RCV000011489, RCV000727594

In an African American patient with classic Fabry disease (301500), Eng et al. (1993) found a nonsense TGG-to-TGA mutation in exon 7 of the GLA gene, resulting in a trp340-to-ter (W340X) substitution.


.0030   FABRY DISEASE

GLA, ARG342GLN
SNP: rs28935493, ClinVar: RCV000011490, RCV000723455

In a Dutch patient with classic Fabry disease (301500), deJong et al. (1993) found a CGA-to-CAA mutation in exon 7 of the GLA gene, resulting in an arg342-to-gln (R342Q) substitution. This mutation conforms to the CG-to-TG 'hotspot' rule.

Germain (2001) described a patient with Fabry disease due to the R342Q mutation who also had Klippel-Trenaunay-Weber syndrome (149000). The 30-year-old man had a complex vascular and cutaneous malformation. Skin examination showed numerous angiokeratomas, which had developed only on the right part of the body, with a sharp delineation in the midline of the trunk. The R342Q mutation was demonstrated in DNA extracted from fibroblast cultures established from both affected and unaffected skin areas, thus excluding the hypothesis of somatic mosaicism or revertant mosaicism. The patient had hypertrophy of the right leg, with dilated and varicose superficial veins.


.0031   FABRY DISEASE

GLA, ARG342TER
SNP: rs104894843, ClinVar: RCV000011491, RCV000723730, RCV003398484

In a Greek/English patient with classic Fabry disease (301500), Davies et al. (1993) found a CGA-to-TGA mutation in exon 7 of the GLA gene, resulting in an arg342-to-ter (R342X) substitution.


.0032   FABRY DISEASE

GLA, GLY361ARG
SNP: rs28935494, ClinVar: RCV000011492

In an English patient with classic Fabry disease (301500), Davies et al. (1993) found a GGA-to-CGA mutation in exon 7 of the GLA gene, resulting in a gly361-to-arg (G361R) substitution.


.0033   FABRY DISEASE

GLA, GLU398TER
SNP: rs104894844, gnomAD: rs104894844, ClinVar: RCV000011493

In a Hispanic patient with classic Fabry disease (301500), Eng et al. (1993) found a nonsense GAA-to-TAA mutation in exon 7 of the GLA gene, resulting in a glu398-to-ter (E398X) substitution.


.0034   FABRY DISEASE

GLA, IVSDS, GT-GG, +2
SNP: rs387906483, ClinVar: RCV000011485

In a Sephardic Jewish patient with classic Fabry disease (301500), Eng et al. (1993) found a T-to-G mutation at nucleotide +2 of the donor splice site of intron 2 of the GLA gene.


.0035   FABRY DISEASE

GLA, IVS5AS, DEL -2,-3
SNP: rs797044498, ClinVar: RCV000153317, RCV001386713

In an Irish patient with classic Fabry disease (301500), Eng et al. (1993) found a deletion of 2 nucleotides (-2 and -3) of the acceptor splice site of intron 5 of the GLA gene. The mutation is therefore tcag/exon 6 to tg/exon 6.


.0036   FABRY DISEASE

GLA, ALA143THR
SNP: rs104894845, gnomAD: rs104894845, ClinVar: RCV000011495, RCV000157242, RCV000211872, RCV000224064, RCV000618614, RCV000845429

In a 34-year-old man with Fabry disease (301500), Nance et al. (2006) identified a G-to-A transition in the GLA gene, resulting in an ala143-to-thr (A143T) substitution. The patient had a 5-year history of progressive activity-induced leg and foot cramps and fasciculations with pain. No other stigmata of Fabry disease was present. His mother, who also carried the mutation, had a similar phenotype.


.0037   FABRY DISEASE

GLA, 13-BP DEL, NT125
SNP: rs1603047806, ClinVar: RCV000011496

In a Japanese patient with severe Fabry disease (301500), Ishii et al. (1991) identified a 13-bp deletion in exon 1 of the GLA gene. The deletion is flanked by a TGGG direct repeat.


.0038   FABRY DISEASE

GLA, 1-BP DEL, NT716
ClinVar: RCV000011497

In an English patient with severe Fabry disease (301500), Davies et al. (1993) found a 1-bp deletion at nucleotide 716 in exon 5 of the GLA gene.


.0039   FABRY DISEASE

GLA, 2-BP DEL, NT773
SNP: rs869312398, ClinVar: RCV000011498

In a Portuguese patient with severe Fabry disease (301500), Eng et al. (1993) found a 2-bp deletion at nucleotide 773 in exon 5 of the GLA gene.


.0040   FABRY DISEASE

GLA, 5-BP INS, NT954
SNP: rs1603038220, ClinVar: RCV000011499

In a German patient with severe Fabry disease (301500), Eng et al. (1993) found a 5-bp insertion starting at nucleotide 954 of exon 6 of the GLA gene.


.0041   FABRY DISEASE

GLA, 11-BP DEL, NT1016
SNP: rs1603037764, ClinVar: RCV000011500

In a German patient with severe Fabry disease (301500), Eng et al. (1993) found an 11-bp deletion starting at nucleotide 1016 of exon 7 of the GLA gene.


.0042   FABRY DISEASE

GLA, 1-BP INS, NT1040
SNP: rs1928137855, ClinVar: RCV000011501

In a Dutch patient with severe Fabry disease (301500), deJong et al. (1993) found a 1-bp insertion at nucleotide 1040 of exon 7 of the GLA gene.


.0043   FABRY DISEASE

GLA, 53-BP DEL, NT1123
SNP: rs1603037323, ClinVar: RCV000011502

In a Dutch patient with severe Fabry disease (301500), Eng et al. (1993) found a 53-bp deletion starting at nucleotide 1123 of exon 7 of the GLA gene.


.0044   FABRY DISEASE

GLA, 2-BP DEL, NT1176
ClinVar: RCV000011503

In a Dutch patient with severe Fabry disease (301500), deJong et al. (1993) found a 2-bp deletion at nucleotide 1176 of exon 7 of the GLA gene. The deletion had a 6-bp inverted repeat at the breakpoint junction.


.0045   FABRY DISEASE

GLA, 3-BP DEL, 1208AAG
SNP: rs869312241, ClinVar: RCV000011504, RCV001781219

In an English patient with moderate Fabry disease (301500), Eng et al. (1993) found a 3-bp deletion (1208delAAG) in exon 7 of the GLA gene, resulting in the deletion of arg405.


.0046   FABRY DISEASE

GLA, EX1-2DEL
ClinVar: RCV000011505

In a Slavic patient with severe Fabry disease (301500), Kornreich et al. (1990) found a 4.6-kb deletion that included exons 1 and 2 of the GLA gene. The deletion breakpoints had a CCA direct repeat suggesting a possible functional role of this short sequence in illegitimate recombination.


.0047   FABRY DISEASE

GLA, EX3-4DEL
ClinVar: RCV000011506

In affected members of a Hispanic family with severe Fabry disease (301500), Kornreich et al. (1990) found a 3.2-kb deletion in the GLA gene that included exons 3 and 4. The 2 breakpoints occurred in Alu repetitive elements and Alu-Alu recombination is the probable mechanism of this deletion.


.0048   FABRY DISEASE

GLA, EX3-7DEL
ClinVar: RCV000011507

In an English patient with severe Fabry disease (301500), Kornreich et al. (1990) found a 4.5-kb deletion in the GLA gene that included exons 3 to 6 and a portion of exon 7. The deletion breakpoints had an AAG direct repeat suggesting a possible functional role of this short sequence in illegitimate recombination.


.0049   FABRY DISEASE

GLA, EX6-7DEL
ClinVar: RCV000011508

In an Irish/German patient with severe Fabry disease (301500), Kornreich et al. (1990) found a deletion of 1.7 kb in the GLA gene that included exons 6 and 7.


.0050   FABRY DISEASE

GLA, EX2-6DUP
ClinVar: RCV000011509

In an English patient with severe Fabry disease (301500), Kornreich et al. (1990) found a duplication of 8.1 kb that included exons 2 to 5 and part of exon 6 of the GLA gene. The duplicated area was flanked by a TAGACA direct repeat.


.0051   FABRY DISEASE, CARDIAC VARIANT

GLA, MET296ILE
SNP: rs104894846, ClinVar: RCV000011510

In a study of left ventricular hypertrophy in Japan, Nakao et al. (1995) found 7 of 230 males (3%) with low plasma alpha-galactosidase activity but none of the typical manifestations of Fabry disease (see 301500), namely, angiokeratoma, acroparesthesias, hypohidrosis, or corneal opacities. One of the patients had a met296-to-ile (M296I) mutation in exon 6 of the GLA gene, whereas a second had an ala20-to-pro (A20P) mutation in exon 1 (300644.0052).


.0052   FABRY DISEASE, CARDIAC VARIANT

GLA, ALA20PRO
SNP: rs104894847, ClinVar: RCV000011511

See 300644.0051 and Nakao et al. (1995).


.0053   FABRY DISEASE

GLA, 3-BP DEL, PHE383DEL
SNP: rs1057519609, ClinVar: RCV000011512

Cariolou et al. (1996) described a novel trinucleotide deletion in the GLA gene in a Greek patient with Fabry disease (301500). This deletion led to loss of phenylalanine-383. The phenotype in this patient was unusual in that diffuse facial telangiectasia was present.


.0054   FABRY DISEASE

GLA, SER65THR
SNP: rs104894848, ClinVar: RCV000011513

In 2 unrelated Chinese patients with Fabry disease (301500), living in Taiwan, Chen et al. (1998) identified a G-to-C transversion in the last nucleotide of exon 1 of the GLA gene, which not only resulted in a ser65-to-thr (S65T) substitution but probably also caused a splicing defect.

Lai et al. (2003) demonstrated that the S65T mutation does not affect enzyme function. Instead it results in activation of a weak cryptic site 14 nucleotides downstream and results in an insertion of 14 bp and a frameshift stop at codon 106. This splicing abnormality was thought to be more consistent with the clinical presentation of the patient with classic Fabry disease.


.0055   FABRY DISEASE

GLA, TYR365TER
SNP: rs104894849, gnomAD: rs104894849, ClinVar: RCV000011514, RCV001781220

In affected members of a family with Fabry disease (301500), Miyamura et al. (1996) identified a mutation in the GLA gene, resulting in a tyr365-to-ter (Y365X) substitution and truncation of the C terminus by 65 amino acid residues. In a heterozygote of this family, although the mutant and normal alleles were equally transcribed in cultured fibroblasts, lymphocyte alpha-galactosidase A activity was approximately 30% of the normal control, and severe clinical symptoms were apparent. COS-1 cells transfected with this mutant cDNA showed a complete loss of its enzymatic activity. Furthermore, cells cotransfected with mutant and wildtype cDNAs showed approximately 30% of the enzyme activity of those with wildtype alone, which suggested a dominant-negative effect of this mutation and implied the importance of the C terminus for its activity. Generating mutant cDNAs with various deletions of the C terminus, Miyamura et al. (1996) found that enzyme activity was enhanced up to 6-fold compared with wildtype when 2 to 10 amino acid residues were deleted. In contrast, deletion of 12 or more amino acid residues resulted in a complete loss of enzyme activity. These data suggested that the C-terminal region of the GLA protein plays an important role in the regulation its enzyme activity.


.0056   RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE

GLA, IVS4AS, G-A, -4
SNP: rs199473684, gnomAD: rs199473684, ClinVar: RCV000011515, RCV000154318, RCV000728949, RCV000769537, RCV000844706, RCV002362578

This variant, previously titled FABRY DISEASE, CARDIAC VARIANT, has been reclassified based on the findings of Chiang et al. (2017).

During the course of mutation analysis of a patient with the cardiac form of Fabry disease (see 301500) who had residual enzyme activity 9.1% of normal, Ishii et al. (2002) were unable to identify any mutation in the exonic or flanking intronic regions of the GLA gene. By RT-PCR of the RNA and direct sequencing of the RT-PCR product, they found an insertion between exons 4 and 5. To characterize further the abnormal splicing, they sequenced intron 4 (nucleotides 8413-10130) of the GLA gene and identified a G-to-A transition at nucleotide 9331 (IVS4+919G-A). This change was not found in 100 unaffected Japanese males. The mutation in the middle of the intron increased the recognition of a normally weak splice site, resulting in the insertion of an additional sequence into the GLA transcript and leading to the cardiac phenotype of Fabry disease.

Chiang et al. (2017) screened for the IVS4+919G-A variant in the Taiwanese population, including 3,268 controls, 3,949 patients from a type 2 diabetes cohort, and 649 patients from heart disease cohorts (heart failure, atrial fibrillation, ventricular tachycardia, and coronary artery disease). In the control sample, 4 males and 2 females carried the variant and only 1 male, who reportedly had a history of heavy smoking and drinking, had heart disease; none of 80 controls who reportedly had cardiomyopathy carried the variant. In the diabetes cohort, 1 of 11 patients who carried the variant had overt heart disease. Among the heart disease cohorts, only 1 patient carried the variant. The authors found that the incidence of the variant in their population was 1/409.


.0057   FABRY DISEASE

GLA, ALA143PRO
SNP: rs104894845, gnomAD: rs104894845, ClinVar: RCV000011516, RCV000157890

In 4 unrelated patients of Nova Scotian ancestry with Fabry disease (301500), Branton et al. (2002) found an ala143-to-pro (A143P) missense mutation in exon 3 of the GLA gene. Three of the patients were French Acadian; the fourth had a Greek surname but may also have been of French Acadian ancestry (Kopp, 2002).


.0058   FABRY DISEASE

GLA, TYR222TER
SNP: rs104894851, ClinVar: RCV000011517, RCV000730382

In affected members of a Chinese family with Fabry disease (301500), Yang et al. (2003) identified a nonsense mutation in the GLA gene, a C-to-A transversion resulting in a tyr222-to-ter (Y222X) substitution. The genotype was associated with classic Fabry disease, with unexpectedly rapid deterioration of visual acuity.


.0059   FABRY DISEASE

GLA, THR410ALA
SNP: rs104894852, ClinVar: RCV000011518

In affected members of a Chinese family with Fabry disease (301500), Yang et al. (2003) identified an A-to-G transition in the GLA gene, resulting in a thr410-to-ala (T410A) substitution. The T410A mutation was associated with a milder form of Fabry disease, with ventricular hypertrophy and neuropathic pain.


.0060   FABRY DISEASE

GLA, 2-BP DEL, 1277AA
SNP: rs869312249, gnomAD: rs869312249, ClinVar: RCV000011519, RCV001781221

In a patient with classic Fabry disease (301500), Yasuda et al. (2003) identified a 2-bp deletion, 1277delAA, causing a frameshift, in the GLA gene. The patient was a 51-year-old Swedish man who had onset of acroparesthesias at 10 years of age and subsequently had gastrointestinal manifestations, including abdominal pain and chronic diarrhea. He developed hypertrophic cardiomyopathy and, because of atrial ventricular block, required a pacemaker. His renal function was normal, with only a trace of urinary protein.


.0061   FABRY DISEASE

GLA, 4-BP DEL, 1284ACTT
SNP: rs869312250, ClinVar: RCV000011520

In a patient with classic Fabry disease (301500), Yasuda et al. (2003) identified a 4-bp deletion, 1284delACTT, in the GLA gene. The patient was a 51-year-old Brazilian man who had childhood onset of acroparesthesias, angiokeratoma, hypohidrosis, and corneal opacities. He had microalbuminuria, which may have been secondary to his diabetes mellitus, but retained normal renal function. He had no evidence of cardiac or cerebral involvement.


.0062   FABRY DISEASE

GLA, ASN272SER
SNP: rs28935495, ClinVar: RCV000011521

In affected members of a Slovenian family with Fabry disease (301500), Verovnik et al. (2004) identified a 10523A-G transition in exon 6 of the GLA gene, resulting in an asn272-to-ser (N272S) substitution. The 7 affected males, including a set of twins, showed decreased to absent alpha-galactosidase activity and had symptoms of classic Fabry disease, but there was considerable variability in their organ involvement, particularly renal: 3 were on dialysis, but 4 had only mild to moderate proteinuria. The 10 affected females had much milder symptoms, with no renal failure, severe cardiac disease, or stroke. Verovnik et al. (2004) stated that this was the first reported Slovenian family with Fabry disease.


.0063   FABRY DISEASE, CARDIAC VARIANT

GLA, PHE113LEU
SNP: rs869312142, ClinVar: RCV000991314, RCV001636724, RCV001781617, RCV002453751

In 11 symptomatic Portuguese males from 10 families and in 2 Italian males identified by newborn screening with Fabry disease (301500), Oliveira et al. (2020) identified hemizygosity for a c.337T-C transition (c.337T-C, NM_000169.2) in the GLA gene, resulting in a phe113-to-leu (F113L) substitution. The mutation was identified by Sanger sequencing of the GLA gene or by next-generation sequencing of a multigene panel testing for hypertrophic cardiomyopathy. The symptomatic men had a late-onset cardiac phenotype. Microsatellite analysis showed that all of the alleles were on the same GLA haplotype, suggesting inheritance from a common ancestor.


See Also:

Eng and Desnick (1994); Hasholt et al. (1990); Hasholt and Sorensen (1986); O'Brien (1980)

REFERENCES

  1. Azevedo, O., Gal, A., Faria, R., Gaspar, P., Miltenberger-Miltenyi, G., Gago, M. F., Dias, F., Martins, A., Rodrigues, J., Reimao, P., Pereira, O., Simoes, S., Lopes, E., Guimaraes, M. J., Sousa, N., Cunha, D. Founder effect of Fabry disease due to p.F113L mutation: clinical profile of a late-onset phenotype. Molec. Genet. Metab. 129: 150-160, 2020. [PubMed: 31519519] [Full Text: https://doi.org/10.1016/j.ymgme.2019.07.012]

  2. Bernstein, H. S., Bishop, D. F., Astrin, K. H., Kornreich, R., Eng, C. M., Sakuraba, H., Desnick, R. J. Fabry disease: six gene rearrangements and an exonic point mutation in the alpha-galactosidase gene. J. Clin. Invest. 83: 1390-1399, 1989. [PubMed: 2539398] [Full Text: https://doi.org/10.1172/JCI114027]

  3. Bishop, D. F., Calhoun, D. H., Bernstein, H. S., Hantzopoulos, P., Quinn, M., Desnick, R. J. Human alpha-galactosidase A: nucleotide sequence of a cDNA clone encoding the mature enzyme. Proc. Nat. Acad. Sci. 83: 4859-4863, 1986. [PubMed: 3014515] [Full Text: https://doi.org/10.1073/pnas.83.13.4859]

  4. Bishop, D. F., Kornreich, R., Desnick, R. J. Structural organization of the human alpha-galactosidase A gene: further evidence for the absence of a 3-prime untranslated region. Proc. Nat. Acad. Sci. 85: 3903-3907, 1988. [PubMed: 2836863] [Full Text: https://doi.org/10.1073/pnas.85.11.3903]

  5. Branton, M. H., Schiffmann, R., Sabnis, S. G., Murray, G. J., Quirk, J. M., Altarescu, G., Goldfarb, L., Brady, R. O., Balow, J. E., Austin, H. A., III, Kopp, J. B. Natural history of Fabry renal disease: influence of alpha-galactosidase A activity and genetic mutations on clinical course. Medicine 81: 122-138, 2002. [PubMed: 11889412] [Full Text: https://doi.org/10.1097/00005792-200203000-00003]

  6. Calhoun, D. H., Bishop, D. F., Bernstein, H. S., Quinn, M., Hantzopoulos, P., Desnick, R. J. Fabry disease: isolation of a cDNA clone encoding human alpha-galactosidase A. Proc. Nat. Acad. Sci. 82: 7364-7368, 1985. [PubMed: 2997789] [Full Text: https://doi.org/10.1073/pnas.82.21.7364]

  7. Cariolou, M. A., Christodoulides, M., Manoli, P., Kokkofitou, A., Tsambaos, D. Novel trinucleotide deletion in Fabry's disease. Hum. Genet. 97: 468-470, 1996. [PubMed: 8834244] [Full Text: https://doi.org/10.1007/BF02267068]

  8. Chen, C.-H., Shyu, P.-W., Wu, S.-J., Sheu, S.-S., Desnick, R. J., Hsiao, K.-J. Identification of a novel point mutation (S65T) in alpha-galactosidase A gene in Chinese patients with Fabry disease. Hum. Mutat. 11: 328-330, 1998. [PubMed: 9554750] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1998)11:4<328::AID-HUMU11>3.0.CO;2-N]

  9. Chen, E. Y., Liao, Y.-C., Smith, D. H., Barrera-Saldana, H. A., Gelinas, R. E., Seeburg, P. H. The human growth hormone locus: nucleotide sequence, biology, and evolution. Genomics 4: 479-497, 1989. [PubMed: 2744760] [Full Text: https://doi.org/10.1016/0888-7543(89)90271-1]

  10. Chiang, H.-L., Wang, N. H.-H., Song, I.-W., Chang, C.-P., Wen, M.-S., Chien, Y.-H., Hwu, W.-L., Tsai, F.-J., Chen, Y.-T., Wu, J.-Y. Genetic epidemiological study doesn't support GLA IVS4+919G-A variant is (sic) a significant mutation in Fabry disease. Molec. Genet. Metab. 121: 22-27, 2017. [PubMed: 28377241] [Full Text: https://doi.org/10.1016/j.ymgme.2017.03.005]

  11. Cianfriglia, M., Miggiano, V. C., Meo, T., Muller, H. J., Muller, E., Battistuzzi, G. Evidence for synteny between the rabbit gene loci coding for HPRT, PGK and G6PD in mouse-rabbit somatic cell hybrids. (Abstract) Cytogenet. Cell Genet. 25: 142, 1979.

  12. Cooper, T. A., Mattox, W. The regulation of splice-site selection, and its role in human disease. Am. J. Hum. Genet. 61: 259-266, 1997. [PubMed: 9311728] [Full Text: https://doi.org/10.1086/514856]

  13. Davies, J. P., Winchester, B. G., Malcolm, S. Mutation analysis in patients with the typical form of Anderson-Fabry disease. Hum. Molec. Genet. 2: 1051-1053, 1993. [PubMed: 8395937] [Full Text: https://doi.org/10.1093/hmg/2.7.1051]

  14. Davies, J. P., Winchester, B. G., Malcolm, S. Sequence variations in the first exon of alpha-galactosidase A. J. Med. Genet. 30: 658-663, 1993. [PubMed: 8411052] [Full Text: https://doi.org/10.1136/jmg.30.8.658]

  15. deJong, J. G. N., Jansen, P. P. M., van den Berg, C. J. M. G., Hamel, B. C. J., Wevers, R. A., Ploos van Amstel, J. K. Genetic heterogeneity in Fabry's disease: mutations in the alpha-galactosidase A gene. Proceedings of the 2nd International Duodecim Symposium. Molecular Biology of Lysosomal Disease, Majik, Finland 1993.

  16. Echard, G., Gillois, M. Rabbit gene mapping: G6PD--alpha-GAL-PGK--HPRT synteny. (Abstract) Cytogenet. Cell Genet. 25: 148, 1979.

  17. Eng, C. M., Desnick, R. J. Molecular basis of Fabry disease: mutations and polymorphisms in the human alpha-galactosidase A gene. Hum. Mutat. 3: 103-111, 1994. [PubMed: 7911050] [Full Text: https://doi.org/10.1002/humu.1380030204]

  18. Eng, C. M., Resnick-Silverman, L. A., Niehaus, D. J., Astrin, K. H., Desnick, R. J. Nature and frequency of mutations in the alpha-galactosidase A gene that cause Fabry disease. Am. J. Hum. Genet. 53: 1186-1197, 1993. [PubMed: 7504405]

  19. Francke, U., Taggart, R. T. Regional mapping of SOD-1 on mouse chromosome 16, and of HPRT and alpha-GAL (Ags) on mouse X, using Chinese hamster-mouse T(X;16)16H somatic cell hybrids. (Abstract) Cytogenet. Cell Genet. 25: 155-156, 1979.

  20. Fukuhara, Y., Sakuraba, H., Oshima, A., Shimmoto, M., Nagao, Y., Nadaoka, Y., Suzuki, T., Suzuki, Y. Partial deletion of human alpha-galactosidase A gene in Fabry disease: direct repeat sequences as a possible cause of slipped mispairing. Biochem. Biophys. Res. Commun. 170: 296-300, 1990. [PubMed: 2164807] [Full Text: https://doi.org/10.1016/0006-291x(90)91273-u]

  21. Garman, S. C., Garboczi, D. N. The molecular defect leading to Fabry disease: structure of human alpha-galactosidase. J. Molec. Biol. 337: 319-335, 2004. [PubMed: 15003450] [Full Text: https://doi.org/10.1016/j.jmb.2004.01.035]

  22. Germain, D. P. Co-occurrence and contribution of Fabry disease and Klippel-Trenaunay-Weber syndrome to a patient with atypical skin lesions. Clin. Genet. 60: 63-67, 2001. [PubMed: 11531972] [Full Text: https://doi.org/10.1034/j.1399-0004.2001.600110.x]

  23. Goss, S. J., Harris, H. Gene transfer by means of cell fusion. I. Statistical mapping of the human X-chromosome by analysis of radiation-induced gene segregation. J. Cell Sci. 25: 17-37, 1977. [PubMed: 561093] [Full Text: https://doi.org/10.1242/jcs.25.1.17]

  24. Grzeschik, K.-H. Personal Communication. Leiden, The Netherlands 1972.

  25. Hasholt, L., Sorensen, S. A., Wandall, A., Andersen, E. B., Arlien-Soborg, P. A Fabry's disease heterozygote with a new mutation: biochemical, ultrastructural, and clinical investigations. J. Med. Genet. 27: 303-306, 1990. [PubMed: 2161929] [Full Text: https://doi.org/10.1136/jmg.27.5.303]

  26. Hasholt, L., Sorensen, S. A. Lysosomal alpha-galactosidase in endothelial cell cultures established from a Fabry hemizygous and normal umbilical veins. Hum. Genet. 72: 72-76, 1986. [PubMed: 3002954] [Full Text: https://doi.org/10.1007/BF00278821]

  27. Hors-Cayla, M. C., Heuertz, S., Van Cong, N., Benne, F. Cattle gene mapping by somatic cell hybridization. (Abstract) Cytogenet. Cell Genet. 25: 165-166, 1979.

  28. Ishii, S., Nakao, S., Minamikawa-Tachino, R., Desnick, R. J., Fan, J.-Q. Alternative splicing in the alpha-galactosidase A gene: increased exon inclusion results in the Fabry cardiac phenotype. Am. J. Hum. Genet. 70: 994-1002, 2002. [PubMed: 11828341] [Full Text: https://doi.org/10.1086/339431]

  29. Ishii, S., Sakuraba, H., Shimmoto, M., Minamikawa-Tachino, R., Suzuki, T., Suzuki, Y. Fabry disease: detection of a 13-bp deletion in alpha-galactosidase A gene and its application to gene diagnosis of heterozygotes.. Ann. Neurol. 29: 560-564, 1991. [PubMed: 1650161] [Full Text: https://doi.org/10.1002/ana.410290517]

  30. Ishii, S., Sakuraba, H., Suzuki, Y. Point mutations in the upstream region of the alpha-galactosidase A gene exon 6 in an atypical variant of Fabry disease. Hum. Genet. 89: 29-32, 1992. [PubMed: 1315715] [Full Text: https://doi.org/10.1007/BF00207037]

  31. Kase, R., Bierfreund, U., Klein, A., Kolter, T., Utsumi, K., Itoh, K., Sandhoff, K., Sakuraba, H. Characterization of two alpha-galactosidase mutants (Q279E and R301Q) found in an atypical variant of Fabry disease. Biochim. Biophys. Acta 1501: 227-235, 2000. [PubMed: 10838196] [Full Text: https://doi.org/10.1016/s0925-4439(00)00024-7]

  32. Koide, T., Ishiura, M., Iwai, K., Inoue, M., Kaneda, Y., Okada, Y., Uchida, T. A case of Fabry's disease in a patient with no alpha-galactosidase A activity caused by a single amino acid substitution of pro40 by ser. FEBS Lett. 259: 353-356, 1990. [PubMed: 2152885] [Full Text: https://doi.org/10.1016/0014-5793(90)80046-l]

  33. Kopp, J. B. Personal Communication. Bethesda, Md. 2/20/2002.

  34. Kornreich, R., Bishop, D. F., Desnick, R. J. The gene encoding alpha-galactosidase A and gene rearrangements causing Fabry disease. Trans. Assoc. Am. Phys. 102: 30-43, 1989. [PubMed: 2561643]

  35. Kornreich, R., Bishop, D. F., Desnick, R. J. Alpha-galactosidase A gene rearrangements causing Fabry disease: identification of short direct repeats at breakpoints in an Alu-rich gene. J. Biol. Chem. 265: 9319-9326, 1990. [PubMed: 2160973]

  36. Lai, L.-W., Whitehair, O., Wu, M.-J., O'Meara, M., Lien, Y.-H. H. Analysis of splice-site mutations of the alpha-galactosidase A gene in Fabry disease. Clin. Genet. 63: 476-482, 2003. [PubMed: 12786754] [Full Text: https://doi.org/10.1034/j.1399-0004.2003.00077.x]

  37. Lee, B. H., Heo, S. H., Kim, G.-H., Park, J.-Y., Kim, W.-S., Kang, D.-H., Choe, K. H., Kim, W.-H., Yang, S. H., Yoo, H.-W. Mutations of the GLA gene in Korean patients with Fabry disease and frequency of the E66Q allele as a functional variant in Korean newborns. J. Hum. Genet. 55: 512-517, 2010. [PubMed: 20505683] [Full Text: https://doi.org/10.1038/jhg.2010.58]

  38. Lenders, M., Duning, T., Schelleckes, M., Schmitz, B., Stander, S., Rolfs, A., Brand, S.-M., Brand, E. Multifocal white matter lesions associated with the D313Y mutation of the alpha-galactosidase A gene. PLoS One 8: e55565, 2013. Note: Electronic Article. [PubMed: 23393592] [Full Text: https://doi.org/10.1371/journal.pone.0055565]

  39. Liu, H.-X., Cartegni, L., Zhang, M. Q., Krainer, A. R. A mechanism for exon skipping caused by nonsense or missense mutations in BRCA1 and other genes. Nature Genet. 27: 55-58, 2001. [PubMed: 11137998] [Full Text: https://doi.org/10.1038/83762]

  40. Lusis, A. J., West, J. D. X-linked inheritance of a structural gene for alpha-galactosidase in Mus musculus. Biochem. Genet. 14: 849-855, 1976. [PubMed: 1008807] [Full Text: https://doi.org/10.1007/BF00485346]

  41. Madsen, K. M., Hasholt, L., Fermer, M. L., Dahl, N. Identification of mutations in Danish families with Fabry's disease. Proc. 2nd Int. Duodecim Symposium. Molecular Biology of Lysosomal Disease, Majik, Finland 1993.

  42. Matsuzawa, F., Aikawa, S., Doi, H., Okumiya, T., Sakuraba, H. Fabry disease: correlation between structural changes in a-galactosidase, and clinical and biochemical phenotypes. Hum. Genet. 117: 317-328, 2005. [PubMed: 15924232] [Full Text: https://doi.org/10.1007/s00439-005-1300-5]

  43. Miyamura, N., Araki, E., Matsuda, K., Yoshimura, R., Furukawa, N., Tsuruzoe, K., Shirotani, T., Kishikawa, H., Yamaguchi, K., Shichiri, M. A carboxy-terminal truncation of human alpha-galactosidase A in a heterozygous female with Fabry disease and modification of the enzymatic activity by the carboxy-terminal domain: increased, reduced, or absent enzyme activity depending on number of amino acid residues deleted. J. Clin. Invest. 98: 1809-1817, 1996. [PubMed: 8878432] [Full Text: https://doi.org/10.1172/JCI118981]

  44. Nakai, K., Sakamoto, H. Construction of a novel database containing aberrant splicing mutations of mammalian genes. Gene 141: 171-177, 1994. [PubMed: 8163185] [Full Text: https://doi.org/10.1016/0378-1119(94)90567-3]

  45. Nakao, S., Takenaka, T., Maeda, M., Kodama, C., Tanaka, A., Tahara, M., Yoshida, A., Kuriyama, M., Hayashibe, H., Sakuraba, H., Tanaka, H. An atypical variant of Fabry's disease in men with left ventricular hypertrophy. New Eng. J. Med. 333: 288-293, 1995. [PubMed: 7596372] [Full Text: https://doi.org/10.1056/NEJM199508033330504]

  46. Nance, C. S., Klein, C. J., Banikazemi, M., Dikman, S. H., Phelps, R. G., McArthur, J. C., Rodriguez, M., Desnick, R. J. Later-onset Fabry disease: an adult variant presenting with the cramp-fasciculation syndrome. Arch. Neurol. 63: 453-457, 2006. [PubMed: 16533976] [Full Text: https://doi.org/10.1001/archneur.63.3.453]

  47. Niemann, M., Rolfs, A., Giese, A., Mascher, H., Breunig, F., Ertl, G., Wanner, C., Weidemann, F. Lyso-Gb3 indicates that the alpha-galactosidase A mutation D313Y is not clinically relevant for Fabry disease. JIMD Rep. 7: 99-102, 2013. [PubMed: 23430502] [Full Text: https://doi.org/10.1007/8904_2012_154]

  48. Novo, F. J., Kruszewski, A., MacDermot, K. D., Goldspink, G., Gorecki, D. C. Editing of human alpha-galactosidase RNA resulting in a pyrimidine to purine conversion. Nucleic Acids Res. 23: 2636-2640, 1995. [PubMed: 7503918] [Full Text: https://doi.org/10.1093/nar/23.14.2636]

  49. O'Brien, S. J. The extent and character of biochemical genetic variation in the domestic cat. J. Hered. 71: 2-8, 1980.

  50. Oliveira, J. P., Nowak, A., Barbey, F., Torres, M., Nunes, J. P., Teixeira-e-Costa, F., Carvalho, F., Sampaio, S., Tavares, I., Pereira, O., Soares, A. L., Carmona, C, Cardoso, M.-T., Jurca-Simina, I. E., Spada, M., Ferreira, S., Germain, D. P. Fabry disease caused by the GLA p.Phe113Leu (p.F113L) variant: natural history in males. Europ. J. Med. Genet. 63: 103703, 2020. Note: Electronic Article. [PubMed: 31200018] [Full Text: https://doi.org/10.1016/j.ejmg.2019.103703]

  51. Sakuraba, H., Eng, C. M., Desnick, R. J., Bishop, D. F. Invariant exon skipping in the human alpha-galactosidase A pre-mRNA: a g(+1) to t substitution in a 5-prime-splice site causing Fabry disease. Genomics 12: 643-650, 1992. [PubMed: 1315304] [Full Text: https://doi.org/10.1016/0888-7543(92)90288-4]

  52. Sakuraba, H., Oshima, A., Fukuhara, Y., Shimmoto, M., Nagao, Y., Bishop, D. F., Desnick, R. J., Suzuki, Y. Identification of point mutations in the alpha-galactosidase A gene in classical and atypical hemizygotes with Fabry disease. Am. J. Hum. Genet. 47: 784-789, 1990. [PubMed: 2171331]

  53. Sawada, K., Mizoguchi, K., Hishida, A., Kaneko, E., Koide, Y., Nishimura, K., Kimura, M. Point mutation in the alpha-galactosidase A gene of atypical Fabry disease with only nephropathy. Clin. Nephrol. 45: 289-294, 1996. [PubMed: 8738659]

  54. Verovnik, F., Benko, D., Vujkovac, B., Linthorst, G. E. Remarkable variability in renal disease in a large Slovenian family with Fabry disease. Europ. J. Hum. Genet. 12: 678-681, 2004. [PubMed: 15162124] [Full Text: https://doi.org/10.1038/sj.ejhg.5201184]

  55. von Scheidt, W., Eng, C. M., Fitzmaurice, T. F., Erdmann, E., Hubner, G., Olsen, E. G. J., Christomanou, H., Kandolf, R., Bishop, D. F., Desnick, R. J. An atypical variant of Fabry's disease with manifestations confined to the myocardium. New Eng. J. Med. 324: 395-399, 1991. [PubMed: 1846223] [Full Text: https://doi.org/10.1056/NEJM199102073240607]

  56. Yang, C.-C., Lai, L.-W., Whitehair, O., Hwu, W.-L., Chiang, S.-C., Lien, Y.-H. H. Two novel mutations in the alpha-galactosidase A gene in Chinese patients with Fabry disease. Clin. Genet. 63: 205-209, 2003. [PubMed: 12694230] [Full Text: https://doi.org/10.1034/j.1399-0004.2003.00050.x]

  57. Yasuda, M., Shabbeer, J., Benson, S. D., Maire, I., Burnett, R. M., Desknick, R. J. Fabry disease: characterization of alpha-galactosidase A double mutations and the D313Y plasma enzyme pseudodeficiency allele. Hum. Mutat. 22: 486-492, 2003. [PubMed: 14635108] [Full Text: https://doi.org/10.1002/humu.10275]

  58. Yasuda, M., Shabbeer, J., Osawa, M., Desnick, R. J. Fabry disease: novel alpha-galactosidase A 3-prime-terminal mutations result in multiple transcripts due to aberrant 3-prime-end formation. Am. J. Hum. Genet. 73: 162-173, 2003. [PubMed: 12796853] [Full Text: https://doi.org/10.1086/376608]

  59. Yokoi, T., Shinoda, K., Ohno, I., Kato, K., Miyawaki, T., Taniguchi, N. A 3-prime splice site consensus sequence mutation in the intron 3 of the alpha-galactosidase A gene in a patient with Fabry disease. Jpn. J. Hum. Genet. 36: 245-250, 1991. [PubMed: 1753437] [Full Text: https://doi.org/10.1007/BF01910542]


Contributors:
Hilary J. Vernon - updated : 10/20/2022
Hilary J. Vernon - updated : 09/09/2021
Ada Hamosh - updated : 06/15/2017
Cassandra L. Kniffin - updated : 12/5/2013
Cassandra L. Kniffin - updated : 11/1/2010

Creation Date:
Cassandra L. Kniffin : 3/21/2007

Edit History:
carol : 10/24/2022
carol : 10/20/2022
carol : 09/22/2022
carol : 04/22/2022
carol : 09/09/2021
mgross : 03/29/2018
carol : 06/16/2017
carol : 06/15/2017
carol : 10/17/2016
carol : 12/18/2013
ckniffin : 12/5/2013
wwang : 12/8/2010
ckniffin : 11/1/2010
wwang : 9/2/2009
terry : 12/17/2007
terry : 8/6/2007
wwang : 4/3/2007
ckniffin : 3/29/2007
carol : 3/28/2007
carol : 3/28/2007
ckniffin : 3/23/2007
ckniffin : 3/23/2007