* 608400

USHERIN; USH2A


Alternative titles; symbols

USH2A GENE
USH2; US2


HGNC Approved Gene Symbol: USH2A

Cytogenetic location: 1q41     Genomic coordinates (GRCh38): 1:215,622,891-216,423,448 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
1q41 Retinitis pigmentosa 39 613809 AR 3
Usher syndrome, type 2A 276901 AR 3

TEXT

Description

Usherin is a transmembrane protein expressed in various tissues including retinal photoreceptors and cochlear hair cells, with a crucial role in photoreceptor survival and cochlear development (summary by Jung et al., 2023).


Cloning and Expression

From the Usher syndrome type IIa (276901) critical region on chromosome 1 established by linkage studies, Eudy et al. (1998) identified the USH2A gene and isolated the corresponding cDNA from a human retina cDNA library. The USH2A gene encodes a 1,551-amino acid protein with a predicted molecular mass of 171.5 kD. Northern blot analysis identified 3 mRNA transcripts of 6.5, 5.0, and 1.9 kb in the retina. Reverse transcriptase PCR identified expression of USH2A in human fetal cochlea, eye, brain, and kidney. The USH2A protein sequence contains laminin epidermal growth factor and fibronectin type III motifs, which are most commonly observed in proteins comprising components of the basal lamina and extracellular matrices and in cell adhesion molecules. In the eye, both Bruch membrane (a specialized basement membrane underlying the retinal pigment epithelium) and the interphotoreceptor cell matrix are rich in extracellular matrix proteins. Extracellular matrix proteins also play a fundamental role in the cochlea: COL1A2 (120160), COL2A1 (120140), and COL3A1 (120180) are highly expressed in the membranous labyrinth of the cochlea. In addition, both X-linked and autosomal forms of Alport syndrome (see 104200) are caused by mutations in collagen type IV genes.

Weston et al. (2000) found a sequence difference in the USH2A gene, resulting in reduction of the total length of the encoded protein, which they designated usherin, from 1,551 to 1,546 amino acids.

Huang et al. (2002) isolated and characterized the mouse and rat orthologs of human USH2A. Like human USH2A, the mouse and rat genes are expressed primarily in retina and cochlea. Mouse Ush2a encodes a 161-kD protein that shows 68% identity and 9% similarity to the human USH2A protein. The predicted amino acid sequence of the mouse and rat proteins, like their human counterpart, contain a leader sequence, an amino-terminal globular domain, 10 laminin epidermal growth factor domains, and 4 carboxy-terminal fibronectin type III motifs. With in situ hybridization, the authors compared the cellular expression of the USH2A gene in rat, mouse, and human retinas. In all 3 species, Ush2a mRNA was expressed in cells of the outer nuclear layer of the retina, one of the target tissues of the disease. In the developing rat retina, Ush2a mRNA expression appeared in the neuroepithelium at embryonic day 17.

Van Wijk et al. (2004) identified novel exons in the USH2A gene and obtained evidence for alternative splicing. The putative 5,202-residue protein encoded by the longest open reading frame harbors, in addition to the known functional domains, 2 laminin G and 28 fibronectin type III repeats, as well as a transmembrane region followed by an intracellular domain with a PDZ-binding domain at its C-terminal end. Semiquantitative expression profile analysis suggested a low level of expression for both the long and the short isoform(s) and partial overlap in spatial and temporal expression patterns.

Using immunofluorescence microscopy in mouse retina, Liu et al. (2007) localized usherin to the apical inner segment recess that wraps around the connecting cilia, which links the inner and outer photoreceptor segments. Usherin also associated transiently with hair bundles in hair cells of the cochlea during early postnatal mouse development.


Gene Structure

Weston et al. (2000) determined that the usherin gene contains 21 exons.

Van Wijk et al. (2004) identified 51 additional exons at the 3-prime end of the USH2A gene, bringing the total number of exons to 72, and Adato et al. (2005) described a new alternatively spliced exon 71.


Mapping

By fluorescence in situ hybridization, Huang et al. (2002) mapped the mouse Ush2a gene to chromosome 1 in a region syntenic to human chromosome 1q41. Rat Ush2a was localized by radiation hybrid analysis to rat chromosome 13.


Gene Function

Adato et al. (2005) described usherin alternative transcripts in the murine inner ear encoding several predicted transmembrane usherin isoforms with modular ectodomains of different lengths. They identified a 24-amino acid peptide, encoded by a novel exon, within the cytoplasmic region and found it to be predominantly expressed in the inner ear but not in the retina. In mouse and rat inner ears, a transmembrane usherin was present at the base of the differentiating stereocilia, which make up the mechanosensitive hair bundles receptive to sound. Usherin immunolabeling was transient in the hair bundles of cochlear hair cells (HCs), but persisted in mature hair bundles of vestibular HCs. Coimmunoprecipitation and in vitro binding assays demonstrated that the usherin cytodomain can bind to whirlin (WHRN; 607928) and harmonin (USH1C; 605242), 2 PDZ domain-containing proteins that are defective in genetic forms of isolated deafness (see 607084) and Usher type IC (276904), respectively. These PDZ proteins are suitable to provide the anchoring of interstereocilia lateral links to the F-actin core of stereocilia. The authors suggested that congenital deafness in Usher types I and II (see 276901) shares similar pathogenic mechanisms, i.e., the disruption of hair bundle links-mediated adhesion forces that are essential for the proper organization of growing hair bundles.

Reiners et al. (2005) demonstrated a molecular interaction between the scaffold protein harmonin, the USH2A protein usherin, VLGR1 (USH2C; 602851), and NBC3 (SLC4A7; 603353). The authors pinpointed these interactions to the PDZ1 domain of harmonin and the PDZ-binding motifs at the C termini of the USH2 proteins and NBC3. USH2A, VLGR1, and NBC3 are coexpressed with the USH1 protein harmonin in the synaptic terminals of both retinal photoreceptors and inner ear hair cells. In hair cells, these USH proteins are also localized in the signal uptaking stereocilia. The authors concluded that the USH2 proteins and NBC3 are partners in the supramolecular USH protein network in the retina and inner ear.

By yeast 2-hybrid analysis using deletion constructs of lebercilin (611408) and the intracellular region of USH2A isoform B, van Wijk et al. (2009) showed that the intermediate filament region of NLP(isoB) (NINL; 609580) interacts with lebercilin and USH2A(isoB), whereas no interaction was detected for NLP(isoA). Coimmunoprecipitation and GST pull-down assays confirmed interaction between NLP(isoB) and lebercilin and USH2A. Recombinant NLP(isoB), lebercilin, and USH2A(isoB) were all found to colocalize at the centrosomes in human retinal pigment epithelial (ARPE-19) cells. Staining of adult rat retinal sections with specific antibodies against all 3 proteins revealed their colocalization at the basal bodies of the photoreceptor-connecting cilia. A truncation mutation (611408.0003) in lebercilin reduced interaction and colocalization with NLP(isoB); however, RNAi knockdown of both endogenous NLP and lebercilin in ciliated ARPE-19 cells did not result in altered protein localization of NLP or lebercilin.

In coimmunoprecipitation studies, Ebermann et al. (2010) demonstrated interaction of USH2A with the first and second PDZ domains of PDZD7 (612971); a truncated version of USH2A without the C-terminal PDZ-binding motif showed reduced interaction.


Molecular Genetics

Usher Syndrome Type IIA

Among 96 patients with Usher syndrome type IIa (276901), Eudy et al. (1998) identified 3 mutations in the USH2A gene (608400.0001-608400.0003), all of which resulted in frameshifts and premature terminations. A 2299delG mutation (608400.0001), originally reported as 2314delG, was the most frequent mutant allele, occurring in 21 cases.

In a mutation search of 57 independent USH2A probands, Weston et al. (2000) identified 15 mutations in the USH2A gene. Of 114 independent USH2A alleles, 58 harbored probable pathologic mutations. Ten cases were true homozygotes and 10 were compound heterozygotes; 18 heterozygotes with only 1 identifiable mutation were observed. The 2299delG allele was the most frequent mutant allele, observed in 31 of 192 alleles (16%).

Dreyer et al. (2000) screened the USH2A gene for mutations in 31 unrelated patients from Denmark and Norway with Usher syndrome type II. The 2299delG mutation accounted for 44% of disease alleles. They found 16 novel putative disease-causing mutations, of which 12 were private and 4 were shared by unrelated patients.

In 12 unrelated patients with Usher syndrome, each with 1 mutation in exons 1 to 21 of the USH2A gene, van Wijk et al. (2004) identified a second pathogenic USH2A mutation in the 51 additional USH2A exons that they identified. The novel mutations included 3 different truncating mutations and 2 missense mutations (see, .e.g., 608400.0007-608400.0009). The presence of pathogenic mutations in the novel exons indicated that at least 1 of the putative long isoforms of the USH2A protein plays a role in both hearing and vision.

Aller et al. (2006) identified mutations in the USH2A gene in 14 of 32 unrelated Spanish patients with Usher syndrome, nonsyndromic retinal degeneration, or nonsyndromic deafness in whom 2 disease-causing mutations could not be found after screening the first 21 exons of the USH2A gene. Analysis of the 51 new exons identified by van Wijk et al. (2004) and the 1 new exon identified by Adato et al. (2005) yielded 14 novel mutations, including 7 missense, 5 frameshift, 1 duplication, and 1 putative splice site mutation. Most of the patients had previously been reported by Aller et al. (2004). All of the individuals with 2 mutations were clinically diagnosed with Usher syndrome type IIa.

Baux et al. (2007) identified 34 distinct mutations in the USH2A gene in affected individuals from 25 families with Usher syndrome. Two of the alleles were complex with 3 and 2 mutations in cis, respectively. Only 5 families carried both mutations in the first 21 exons, indicating that screening of the entire gene is necessary for accurate and complete mutational analysis.

To explore the spectrum of USH2A disease-causing mutations among Scandinavian USH2 cases, Dreyer et al. (2008) performed extensive DNA sequence analysis of the full-size USH2A gene in patients from 118 unrelated families, of which 27 had previously been found to carry mutations in exons 1 to 21. In all, 122 USH2A DNA sequence alterations were identified, of which 57 were predicted to be pathogenic, 7 were considered to be of uncertain pathogenicity, and 58 were predicted to be benign variants. Of 36 novel pathogenic USH2A mutations, 31 were located in exons 22 to 73, specific to the long isoform (see, e.g., 608400.0013). USH2A mutations were identified in 89 (75.4%) of 118 families. In 79 (88.8%) of these 89 families, 2 pathogenic mutations were identified, whereas in 10 families (11.2%) the second mutation remained unidentified. In 5 (4.2%) of the 118 families the USH phenotype could be explained by mutations in the CLRN1 gene (606397).

Yan et al. (2009) identified mutant USH2A alleles in 12 (60%) of 20 American patients of European ancestry with Usher syndrome type IIa. Seven (35%) patients had only 1 pathogenic mutation, and 8 patients did not have USH2A mutations. There were 5 novel mutations and 5 previously reported mutations, consisting of 3 missense, 3 frameshift, and 4 nonsense. The 2299delG mutation was the most common, accounting for 38.9% of mutant alleles.

McGee et al. (2010) screened the long isoform of USH2A in 108 patients diagnosed with Usher syndrome type IIa and identified at least 1 deleterious mutation in at least 57% of cases.

Retinitis Pigmentosa 39

Rivolta et al. (2002) identified autosomal recessive retinitis pigmentosa (RP39; 613809) without hearing loss due to mutation in the USH2A gene inherited by uniparental paternal disomy (C759F; 608400.0006). Zlotogora (2004) reviewed examples in which uniparental disomy had been established as the cause of an autosomal recessive disorder. One of 6 such disorders listed for chromosome 1, the most for any single chromosome, was autosomal recessive retinitis pigmentosa without hearing loss due to mutation in the USH2A gene.

McGee et al. (2010) screened the long isoform of USH2A in 80 patients with nonsyndromic autosomal recessive RP and identified at least 1 deleterious mutation in 19% of cases. The authors stated that their findings supported USH2A as the most common known cause of RP in the United States.

In a cohort of 94 Korean probands with RP, Jung et al. (2023) analyzed the USH2A gene and identified 10 probands who were compound heterozygous for mutations in the USH2A gene (e.g., 608400.0016-608400.0018). Hearing tests were not performed because no hearing problems were reported by any of the probands.

Cosegregation of Usher Syndrome and Retinitis Pigmentosa

In a consanguineous family of Iraqi Jewish origin in which some members had USH2 and others had nonsyndromic retinitis pigmentosa, Kaiserman et al. (2007) identified 3 pathogenic mutations in the USH2A gene. Patients with USH2A were compound heterozygous for 2 null mutations (608400.0010-608400.0011), whereas patients with nonsyndromic RP were compound heterozygous for 1 of the null mutations and a novel missense mutation (608400.0012).


Genotype/Phenotype Correlations

To investigate genotype/phenotype correlations, Aller et al. (2004) screened 191 unrelated Spanish patients with syndromic or nonsyndromic retinal diseases, or with nonsyndromic hearing impairment, for the 2299delG (608400.0001) and C759F (608400.0006) mutations in the USH2A gene. They found that the 2299delG mutation was present in patients with clinical signs of Usher syndrome type II or of atypical Usher syndrome, whereas the C759F mutation, whether or not it was associated with the 2299delG mutation, was identified in cases with nonsyndromic retinitis pigmentosa (RP). Aller et al. (2004) concluded that sensorineural hearing loss in patients with RP may depend on the nature and association of the USH2A allelic variants present.

Bernal et al. (2005) studied 28 Spanish patients with Usher syndrome type II, identifying 10 different pathogenic mutations and 17 polymorphisms in the USH2A gene. They observed discordant phenotypes in sib pairs from 2 unrelated families and noted that Liu et al. (1999) had reported clinical differences in monozygotic twins with Usher syndrome type II and had suggested that variation in the expression of the USH2A gene is not determined simply by genetic factors.


Animal Model

Liu et al. (2007) found that Ush2a knockout in mice led to progressive photoreceptor degeneration and a moderate but nonprogressive hearing impairment, mimicking the visual and hearing defects in USH2A patients.


ALLELIC VARIANTS ( 18 Selected Examples):

.0001 USHER SYNDROME, TYPE IIA

USH2A, 1-BP DEL, 2299G
  
RCV000002445...

By heteroduplex analysis, Eudy et al. (1998) identified a 2299delG mutation (originally reported by them as 2314delG) in the USH2A gene in 21 of 96 probands with Usher syndrome type IIa (USH2A; 276901); 8 of them were homozygous and 13 heterozygous. All but 2 were of northern European ancestry (Swedish, Dutch, German, or English). The 2 non-northern European patients were both homozygous for the 2299G deletion; one was from Spain and the other was an African American from Nebraska, U.S. Examination of various haplotypes failed to reveal any substantial disequilibrium with the 2299delG mutation, suggesting that the mutation did not arise in a common ancestor. The 2299delG mutation caused a frameshift at codon 772, after which the open reading frame continued for 20 codons and ended as TAG.

Liu et al. (1999) performed a mutation analysis of the USH2A gene in 23 families with Usher syndrome, 10 of which had a diagnosis of atypical Usher syndrome, from the United Kingdom and China. They found that most of the families with USH2 carried the 2299delG mutation. Of 12 families with the 2299delG mutation, 8 families had the typical USH2 phenotype (congenital moderate to severe hearing impairment, normal vestibular function, and postpubertal onset of retinitis pigmentosa). However, 5 affected individuals from the remaining 4 families carrying the 2299delG mutation showed atypical Usher syndrome features, with progressive hearing impairment, variable vestibular function, and RP. An isolated patient with the mutation was typical of USH2 in all aspects, including nonprogressive hearing loss, but had absent vestibular function, which is a critical discriminator in clinical classification.

Weston et al. (2000) revised numbering for the sequence of the USH2A gene, taking into account a significant sequence difference. The 2299delG mutation reported by Eudy et al. (1998) is correctly referred to as 2299delG. The sequence difference reduces the length of the usherin protein from 1551 to 1546 amino acids.

Weston et al. (2000) found the 2299delG mutation to be the most frequent, having a frequency of 31 in 192 alleles (16%) in their series.

Dreyer et al. (2001) presented data indicating that the widespread geographic distribution of the 2299delG mutation is the result of an ancestral mutation that spread throughout Europe and into the New World as a result of migration. Various studies had reported a range of frequencies (from 0.16 to 0.44) among patients with Usher syndrome, depending on the geographic origin of the patients. Dreyer et al. (2001) performed haplotype analysis on DNA samples from 116 unrelated patients with Usher syndrome type IIa; the patients were from 14 countries and represented 148 2299delG alleles. On the basis of 6 single-nucleotide polymorphisms (SNPs) within the USH2A gene, 12 core haplotypes were observed in a panel of normal chromosomes. However, in their patient analysis, only 1 core haplotype was associated with the 2299delG mutation.

Ouyang et al. (2004) confirmed that 2299delG is the most common mutation in USH2A, accounting for 77.5% of the pathologic alleles. In 5 of the 24 patients, the 2299delG mutation was present in homozygous state; in 3 it was present in compound heterozygous state with other mutations; and in 16 it was present in heterozygous state.

Baux et al. (2007) identified the 2299delG mutation, which results in a frameshift at codon 767, in 22% of mutated alleles in their study of 25 affected families.

Yan et al. (2009) identified the 2299delG mutation in 38.9% of mutant alleles among 12 American probands of European descent with Usher syndrome type IIa.


.0002 USHER SYNDROME, TYPE IIA

USH2A, 1-BP DEL, 2898G
  
RCV000002446...

In patients with Usher syndrome type IIa (USH2A; 276901), Eudy et al. (1998) found a 1-bp deletion, reported by them as 2913delG, in the USH2A gene. This mutation is correctly referred to as 2898delG (T967FS) (Weston et al., 2000).


.0003 USHER SYNDROME, TYPE IIA

USH2A, 2-BP DEL, 4338CT
  
RCV000002447...

In the Louisiana Acadian population with Usher syndrome type IIa (USH2A; 276901), Eudy et al. (1998) found heterozygosity for a dinucleotide deletion that they reported as 4353-4delCT. This mutation is correctly referred to as 4338-9delCT (C1447FS) (Weston et al., 2000).

Ebermann et al. (2009) identified the homozygous 4338delCT mutation in 4 of 9 French Canadian families with Usher syndrome type IIa from Quebec and New Brunswick, the former Acadia. Affected individuals from 2 additional families carried the mutation in heterozygosity. Altogether, the 4338delCT mutation accounted for 10 (55.6%) of 18 disease alleles. Haplotype analysis indicated a founder effect. The findings indicated that the Acadian and Quebec populations share common ancestors.

Ebermann et al. (2010) studied 2 French Canadian sisters with USH2A who were homozygous for the 4338delCT mutation in the USH2A gene, and identified an additional de novo heterozygous frameshift mutation in the PDZD7 gene (612971.0001) in 1 of the sisters, who had earlier-onset and more severe retinal disease. The PDZD7 mutation was not present in the other sister, who had a much milder retinal phenotype. Ebermann et al. (2010) concluded that PDZD7 is a retinal disease modifier in patients with USH2A.


.0004 USHER SYNDROME, TYPE IIA

USH2A, LEU260TER
  
RCV000002448

In members of a Swedish family with type IIa Usher syndrome (USH2A; 276901), Weston et al. (2000) identified a 779T-G transversion in the USH2A gene, resulting in a leu260-to-ter (L260X) change. The mutation was present in compound heterozygous state with the 2299delG mutation (608400.0001).


.0005 USHER SYNDROME, TYPE IIA

USH2A, CYS319TYR
  
RCV000002449...

Weston et al. (2000) found homozygosity for a cys319-to-tyr (C319Y) mutation in the USH2A gene in a proband with Usher syndrome type IIa (USH2A; 276901) from a Hispanic American family.


.0006 RETINITIS PIGMENTOSA 39

USH2A, CYS759PHE (rs80338902)
  
RCV000002450...

Rivolta et al. (2000) described a cys759-to-phe (C759F) missense mutation caused by a G-T change in the USH2A gene that was associated with autosomal recessive retinitis pigmentosa without hearing loss (RP39; 613809). The amino acid at this position is within the fifth laminin-epidermal growth factor-like domain and participates in a presumed disulfide bridge. The mutation was found in 4.5% of 224 patients with recessive RP.

Rivolta et al. (2002) reported a patient with RP without hearing loss caused by a homozygous C759F mutation in the USH2A gene. Her father was heterozygous for this change, and her mother was a noncarrier. Further evaluation with microsatellite markers revealed that the patient had inherited 2 copies of chromosome 1 from her father and none from her mother. The 2 paternally derived copies of chromosome 1 were heteroallelic from the centromere to the proximal short and long arms. The distal regions of the short and long arms of chromosome 1 were homoallelic, including the region of 1q with the mutant USH2A allele. This genetic pattern is compatible with uniparental primary heterodisomy with regions of homozygosity arising through a nondisjunction event during paternal meiosis I and subsequent trisomy rescue or gamete complementation. A paternal second cousin of the patient also had RP and had an identical heterozygous mutation in the USH2A gene in the same codon. However, the analysis of an isocoding polymorphism 20 bp away and closely linked microsatellite markers in the patient and family members indicated that the 2 mutant alleles were unlikely to be identical by descent and that the 2 relatives fortuitously had RP and a mutation in the same codon of the USH2A gene.

Pozo et al. (2015) noted that 15 families with RP had been reported to have a homozygous C759F variant (rs80338902) in the USH2A gene. In all reviewed cases, the segregation data either were not shown or were inconclusive. Pozo et al. (2015) restudied a Spanish family (S23) in which Bernal et al. (2003) had identified homozygosity for C759F in 2 affected and 2 unaffected sibs. By next-generation sequencing, they identified homozygosity for an R560C mutation in the PDE6B gene (180072.0008) that segregated with the disorder in the family and was absent in 200 control individuals. Pozo et al. (2015) suggested that the C759F variant might not be pathogenic and proposed genetic reevaluation of other reported families with the C759F variant.

In a discovery cohort of 186 unrelated probands with autosomal recessive retinal degeneration without childhood hearing loss, Lenassi et al. (2015) found the c.2276G-T transversion in USH2A gene, resulting in a C759F substitution, in 11 alleles (once in homozygosity). In the replication cohort of 84 unrelated probands with autosomal recessive retinal degeneration, the allele was found 5 times, once in homozygosity; and in a third panel of 187 patients with nonsyndromic adult-onset autosomal recessive retinitis pigmentosa, it was found 5 times, once in homozygosity. Lenassi et al. (2015) noted that the C759F mutation is often considered to be the most common disease-causing variant in patients with nonsyndromic retinitis pigmentosa.

To assess the role of the C759F mutation in autosomal recessive retinitis pigmentosa and Usher syndrome type 2, Perez-Carro et al. (2018) performed a comprehensive genetic and clinical study of 57 families with affected members who carried the C759F mutation on at least 1 allele. Of the 57 probands, 11 were homozygous for the mutation, 42 were compound heterozygous with another mutation in the USH2A gene, and the remaining 4 also carried mutations in RP1 (603937), PROM1 (604365), or CNGB1 (600724). The 2 patients with PROM1 and CNGB1 mutations, and 1 patient with mutated RP1, were homozygous for those mutations in addition to the C759F mutation in USH2A; the second patient with mutation in RP1 was heterozygous for that mutation. The authors noted that although the C759F variant is enriched in the Spanish population, no homozygous individuals had been identified in control populations, even in Spanish population databases. Perez-Carro et al. (2018) stated that the C759F mutation alters a highly conserved residue in a domain that enhances USH2A stability in the basement membrane by prompting its interaction with collagen IV (see 120070). The mutation was also predicted to disrupt a disulfide bridge, leading to erroneous protein folding and instability. While Pozo et al. (2015) had questioned the pathogenicity of the C759F variant, at least in homozygosity, Perez-Carro et al. (2018) pointed out that no other candidate variants in the USH2A or any other RP genes that could explain the phenotypes were found in their patients by next-generation sequencing. They concluded that C759F homozygosity is associated with a later diagnosis of RP and slower progression of visual field loss, with a very late hypoacusis diagnosis (around the seventh decade).


.0007 USHER SYNDROME, TYPE IIA

USH2A, TRP3955TER
  
RCV000002451...

In 2 patients with Usher syndrome type IIa (USH2A; 276901), van Wijk et al. (2004) found compound heterozygosity for a trp3955-to-ter (W3955X) mutation in the USH2A gene and 2 different mutations: a 949C-A transversion in one patient, resulting in an arg317-to-arg mutation (R317R; 608400.0008), which was predicted to create an additional 5-prime splice site in exon 5; and a 1256G-T transversion, resulting in a cys419-to-phe substitution (C419F; 608400.0009) in the second patient.


.0008 USHER SYNDROME, TYPE IIA

USH2A, 949C-A, ARG317ARG
  
RCV000002452...

For discussion of the arg317-to-arg (R317R) mutation in the USH2A gene that was found in compound heterozygous state in patients with Usher syndrome type IIa (USH2A; 276901) by van Wijk et al. (2004), see 608400.0007.


.0009 USHER SYNDROME, TYPE IIA

USH2A, CYS419PHE
  
RCV000002453...

For discussion of the cys419-to-phe (C419F) mutation in the USH2A gene that was found in compound heterozygous state in patients with Usher syndrome type IIa (USH2A; 276901) by van Wijk et al. (2004), see 608400.0007.


.0010 USHER SYNDROME, TYPE IIA

RETINITIS PIGMENTOSA 39, INCLUDED
USH2A, 4-BP INS, NT239
  
RCV000002454...

In a consanguineous family of Iraqi Jewish origin in which some members had Usher syndrome type IIa (USH2A; 276901) and others had nonsyndromic retinitis pigmentosa (RP39; 613809), Kaiserman et al. (2007) identified compound heterozygosity for 2 null mutations in the USH2A gene in those affected with USH2A: a 4-bp insertion (239_242insCGAT) resulting in a frameshift at position 80 (Thr80fs), and a 2209C-T transition resulting in an arg737-to-ter (R737X; 608400.0011) substitution. In those affected with nonsyndromic RP, they identified compound heterozygosity for one of the null mutations and a 14021A-G transition resulting in an arg4674-to-gly substitution (R4674G; 608400.0012).


.0011 USHER SYNDROME, TYPE IIA

RETINITIS PIGMENTOSA 39, INCLUDED
USH2A, ARG737TER
  
RCV000002456...

For discussion of the arg737-to-ter (R737X) mutation in the USH2A gene that was found in compound heterozygous state in a family in which some members had Usher syndrome type IIa (USH2A; 276901) and others had nonsyndromic retinitis pigmentosa (RP39; 613809) by Kaiserman et al. (2007), see 608400.0010.


.0012 RETINITIS PIGMENTOSA 39

USH2A, ARG4674GLY
  
RCV000002458...

For discussion of the arg4674-to-gly (R4674G) mutation in the USH2A gene that was found in compound heterozygous state in a family in which some members had Usher syndrome type IIa (USH2A; 276901) and others had nonsyndromic retinitis pigmentosa (RP39; 613809) by Kaiserman et al. (2007), see 608400.0010.


.0013 USHER SYNDROME, TYPE IIA

USH2A, IVS40AS, A-G, -2144
  
RCV000023700...

In a French patient with Usher syndrome type IIa (USH2A; 276901), Vache et al. (2012) identified compound heterozygosity for 2 mutations in the USH2A gene: a heterozygous A-to-G transition deep within intron 40 (c.7595-2144) and a 1-bp duplication (3129dupT; 608400.0014), resulting in a frameshift. Two other individuals in a different branch of the family had the intron 41 mutation and a different heterozygous frameshift mutation, 8890dupT (608400.0015). The intron 41 mutation was found only after RT-PCR amplification of RNA from nasal cells in 1 patient showed an aberrant USH2A out-of-frame transcript predicted to result in a truncated protein that would not be anchored to the cell membrane. DNA studies showed that the A-to-G transition resulted in activation of a pseudoexon between exons 40 and 41, causing a 153-bp insertion and a frameshift. The nomenclature used for this insertion was r.7594_7595ins7595-2296_7595-2143. This mutation was not found in 338 alleles. However, this mutation was found in 4 of 20 USH2A patients with no identified mutation or only a single pathogenic mutation, as well as in 4 of 18 Spanish patients with incomplete USH2A genotypes. Vache et al. (2012) noted that the identification of a deep intronic mutation in a pseudoexon raised the possibility of a new therapeutic strategy using antisense oligonucleotide chemistry to restore normal splicing via exon skipping.


.0014 USHER SYNDROME, TYPE IIA

USH2A, 1-BP DUP, 3129T
  
RCV000023701

For discussion of the 1-bp duplication in the USH2A gene (3129dupT) that was found in compound heterozygous state in a patient with Usher syndrome type IIa (USH2A; 276901) by Vache et al. (2012), see 608400.0013.


.0015 USHER SYNDROME, TYPE IIA

USH2A, 1-BP DUP, 8890T
  
RCV000023702...

For discussion of the 1-bp duplication in the USH2A gene (8890dupT) that was found in compound heterozygous state in patients with Usher syndrome type IIa (USH2A; 276901) by Vache et al. (2012), see 608400.0013.


.0016 RETINITIS PIGMENTOSA 39

USH2A, CYS934TRP
  
RCV000132710...

In 5 Korean probands with retinitis pigmentosa (RP39; 613809), Jung et al. (2023) identified compound heterozygosity for a c.2802T-G transversion in exon 13 of the USH2A gene, resulting in a cys934-to-trp (C934W) substitution within the LamE 8 domain, and another missense or truncating mutation in the USH2A gene (e.g., 608400.0017 and 608400.0018). Hearing tests were not performed, but no hearing problems were reported by any of the probands.


.0017 RETINITIS PIGMENTOSA 39

USH2A, 4-BP DEL, 13112AAAT
  
RCV000674880...

In 2 Korean probands with retinitis pigmentosa (RP39; 613809), Jung et al. (2023) identified compound heterozygosity for a 4-bp deletion (c.13112_13115delAAAT) in exon 63 of the USH2A gene, causing a frameshift predicted to result in a premature termination codon (Gln4371fs), and another missense or truncating mutation in the USH2A gene (e.g., 608400.0016). Hearing tests were not performed, but no hearing problems were reported by the probands.


.0018 RETINITIS PIGMENTOSA 39

USH2A, ARG1578CYS
  
RCV001067861...

In 2 Korean probands with retinitis pigmentosa (RP39; 613809), Jung et al. (2023) identified compound heterozygosity for a c.4732C-T transition in exon 22 of the USH2A gene, resulting in an arg1578-to-cys (R1578C) substitution within the LamG 1 domain, and another missense or truncating mutation in the USH2A gene (e.g., 608400.0016). Hearing tests were not performed, but no hearing problems were reported by the probands.


REFERENCES

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  9. Dreyer, B., Tranebjaerg, L., Rosenberg, T., Weston, M. D., Kimberling, W. J., Nilssen, O. Identification of novel USH2A mutations: implications for the structure of USH2A protein. Europ. J. Hum. Genet. 8: 500-506, 2000. [PubMed: 10909849, related citations] [Full Text]

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  13. Huang, D., Eudy, J. D., Uzvolgyi, E., Davis, J. R., Talmadge, C. B., Pretto, D., Weston, M. D., Lehman, J. E., Zhou, M., Seemayer, T. A., Ahmad, I., Kimberling, W. J., Sumegi, J. Identification of the mouse and rat orthologs of the gene mutated in Usher syndrome type IIA and the cellular source of USH2A mRNA in retina, a target tissue of the disease. Genomics 80: 195-203, 2002. [PubMed: 12160733, related citations] [Full Text]

  14. Jung, S., Park, Y. C., Lee, D., Kim, S., Kim, S.-M., Kim, Y., Lee, D., Hyun, J., Koh, I., Lee, J.-Y. Exome sequencing identified five novel USH2A variants in Korean patients with retinitis pigmentosa. Ophthalmic Genet. 44: 163-170, 2023. [PubMed: 36314366, related citations] [Full Text]

  15. Kaiserman, N., Obolensky, A., Banin, E., Sharon, D. Novel USH2A mutations in Israeli patients with retinitis pigmentosa and Usher syndrome type 2. Arch. Ophthal. 125: 219-224, 2007. Note: Erratum: Arch. Ophthal. 125: 1013, 2007. [PubMed: 17296898, related citations] [Full Text]

  16. Lenassi, E., Vincent, A., Li, Z., Saihan, Z., Coffey, A. J., Steele-Stallard, H. B., Moore, A. T., Steel, K. P., Luxon, L. M., Heon, E., Bitner-Glindzicz, M., Webster, A. R. A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants. Europ. J. Hum. Genet. 23: 1318-1327, 2015. [PubMed: 25649381, images, related citations] [Full Text]

  17. Liu, X., Bulgakov, O. V., Darrow, K. N., Pawlyk, B., Adamian, M., Liberman, M. C., Li, T. Usherin is required for maintenance of retinal photoreceptors and normal development of cochlear hair cells. Proc. Nat. Acad. Sci. 104: 4413-4418, 2007. [PubMed: 17360538, images, related citations] [Full Text]

  18. Liu, X.-Z., Hope, C., Liang, C. Y., Zou, J. M., Xu, L. R., Cole, T., Mueller, R. F., Bundey, S., Nance, W., Steel, K. P., Brown, S. D. M. A mutation (2314delG) in the Usher syndrome type IIA gene: high prevalence and phenotypic variation. (Letter) Am. J. Hum. Genet. 64: 1221-1225, 1999. [PubMed: 10090909, related citations] [Full Text]

  19. McGee, T. L., Seyedahmadi, B. J., Sweeney, M. O., Dryja, T. P., Berson, E. L. Novel mutations in the long isoform of the USH2A gene in patients with Usher syndrome type II or non-syndromic retinitis pigmentosa. J. Med. Genet. 47: 499-506, 2010. [PubMed: 20507924, related citations] [Full Text]

  20. Ouyang, X. M., Yan, D., Hejtmancik, J. F., Jacobson, S. G., Li, A. R., Du, L. L., Angeli, S., Kaiser, M., Balkany, T., Liu, X. Z. Mutational spectrum in Usher syndrome type II. Clin. Genet. 65: 288-293, 2004. Note: Erratum: Clin. Genet. 65: 433 only, 2004. [PubMed: 15025721, related citations] [Full Text]

  21. Perez-Carro, R., Blanco-Kelly, F., Galbis-Martinez, L., Garcia-Garcia, G., Aller, E., Garcia-Sandoval, B., Minguez, P., Corton, M., Mahillo-Fernandez, I., Martin-Merida, I., Avila-Fernandez, A., Millan, J. M., Ayuso, C. Unravelling the pathogenic role and genotype-phenotype correlation of the USH2A p.(cys759phe) variant among Spanish families. PLoS One 13: e0199048, 2018. Note: Electronic Article. [PubMed: 29912909, related citations] [Full Text]

  22. Pozo, M. G., Bravo-Gil, N., Mendez-Vidal, C., Montero-de-Espinosa, I., Millan, J. M., Dopazo, J., Borrego, S., Antinolo, G. Re-evaluation casts doubt on the pathogenicity of homozygous USH2A p.C759F. Am. J. Med. Genet. 167A: 1597-1600, 2015. [PubMed: 25823529, related citations] [Full Text]

  23. Reiners, J., van Wijk, E., Marker, T., Zimmermann, U., Jurgens, K., Brinke, H., Overlack, N., Roepman, R., Knipper, M., Kremer, H., Wolfrum, U. Scaffold protein harmonin (USH1C) provides molecular links between Usher syndrome type 1 and type 2. Hum. Molec. Genet. 14: 3933-3943, 2005. [PubMed: 16301216, related citations] [Full Text]

  24. Rivolta, C., Berson, E. L., Dryja, T. P. Paternal uniparental heterodisomy with partial isodisomy of chromosome 1 in a patient with retinitis pigmentosa without hearing loss and a missense mutation in the Usher syndrome type II gene USH2A. Arch. Ophthal. 120: 1566-1571, 2002. [PubMed: 12427073, related citations] [Full Text]

  25. Rivolta, C., Sweklo, E. A., Berson, E. L., Dryja, T. P. Missense mutation in the USH2A gene: association with recessive retinitis pigmentosa without hearing loss. Am. J. Hum. Genet. 66: 1975-1978, 2000. [PubMed: 10775529, related citations] [Full Text]

  26. Vache, C., Besnard, T., le Berre, P., Garcia-Garcia, G., Baux, D., Larrieu, L., Abadie, C., Blanchet, C., Bolz, H. J., Millan, J., Hamel, C., Malcolm, S., Claustres, M., Roux, A.-F. Usher syndrome type 2 caused by activation of an USH2A pseudoexon: implications for diagnosis and therapy. Hum. Mutat. 33: 104-108, 2012. [PubMed: 22009552, related citations] [Full Text]

  27. van Wijk, E., Kersten, F. F. J., Kartono, A., Mans, D. A., Brandwijk, K., Letteboer, S. J. F., Peters, T. A., Marker, T., Yan, X., Cremers, C. W. R. J., Cremers, F. P. M., Wolfrum, U., Roepman, R., Kremer, H. Usher syndrome and Leber congenital amaurosis are molecularly linked via a novel isoform of the centrosomal ninein-like protein. Hum. Molec. Genet. 18: 51-64, 2009. [PubMed: 18826961, images, related citations] [Full Text]

  28. van Wijk, E., Pennings, R. J. E., te Brinke, H., Claassen, A., Yntema, H. G., Hoefsloot, L. H., Cremers, F. P. M., Cremers, C. W. R. J., Kremer, H. Identification of 51 novel exons of the Usher syndrome type 2A (USH2A) gene that encode multiple conserved functional domains and that are mutated in patients with Usher syndrome type II. Am. J. Hum. Genet. 74: 738-744, 2004. [PubMed: 15015129, images, related citations] [Full Text]

  29. Weston, M. D., Eudy, J. D., Fujita, S., Yao, S.-F., Usami, S., Cremers, C., Greenburg, J., Ramesar, R., Martini, A., Moller, C., Smith, R. J., Sumegi, J., Kimberling, W. J. Genomic structure and identification of novel mutations in usherin, the gene responsible for Usher syndrome type IIa. Am. J. Hum. Genet. 66: 1199-1210, 2000. Note: Erratum: Am. J. Hum. Genet. 66: 2020 only, 2000. [PubMed: 10729113, related citations] [Full Text]

  30. Yan, D., Ouyang, X., Patterson, D. M., Du, L. L., Jacobson, S. G., Liu, X.-Z. Mutation analysis in the long isoform of USH2A in American patients with Usher syndrome type II. J. Hum. Genet. 54: 732-738, 2009. [PubMed: 19881469, related citations] [Full Text]

  31. Zlotogora, J. Parents of children with autosomal recessive diseases are not always carriers of the respective mutant alleles. Hum. Genet. 114: 521-526, 2004. [PubMed: 15024643, related citations] [Full Text]


Marla J. F. O'Neill - updated : 02/02/2023
Anne M. Lopez - updated : 10/11/2018
Nara Sobreira - updated : 11/10/2015
Marla J. F. O'Neill - updated : 6/11/2015
Cassandra L. Kniffin - updated : 1/9/2012
Marla J. F. O'Neill - updated : 5/3/2011
Cassandra L. Kniffin - updated : 6/14/2010
George E. Tiller - updated : 10/23/2009
George E. Tiller - updated : 7/20/2009
George E. Tiller - updated : 7/6/2009
Cassandra L. Kniffin - updated : 4/2/2009
Jane Kelly - updated : 11/30/2007
Cassandra L. Kniffin - updated : 10/10/2007
Patricia A. Hartz - updated : 4/30/2007
Cassandra L. Kniffin - updated : 12/28/2006
Marla J. F. O'Neill - updated : 3/13/2006
Marla J. F. O'Neill - updated : 6/2/2004
Victor A. McKusick - updated : 5/7/2004
Victor A. McKusick - updated : 4/22/2004
Victor A. McKusick - updated : 4/8/2004
Creation Date:
Cassandra L. Kniffin : 1/15/2004
carol : 04/18/2023
carol : 04/17/2023
alopez : 02/02/2023
carol : 03/15/2021
alopez : 10/11/2018
alopez : 02/19/2016
carol : 11/11/2015
carol : 11/10/2015
alopez : 6/11/2015
alopez : 4/23/2015
mcolton : 4/21/2015
alopez : 3/30/2015
carol : 6/18/2014
terry : 3/14/2013
terry : 8/31/2012
carol : 1/19/2012
carol : 1/19/2012
ckniffin : 1/9/2012
ckniffin : 1/9/2012
carol : 5/5/2011
terry : 5/5/2011
terry : 5/3/2011
terry : 5/3/2011
alopez : 3/15/2011
wwang : 6/21/2010
ckniffin : 6/14/2010
wwang : 11/4/2009
terry : 10/23/2009
alopez : 7/20/2009
alopez : 7/10/2009
terry : 7/6/2009
wwang : 6/23/2009
wwang : 4/17/2009
ckniffin : 4/2/2009
carol : 11/30/2007
carol : 11/29/2007
wwang : 10/17/2007
ckniffin : 10/10/2007
wwang : 4/30/2007
carol : 1/4/2007
ckniffin : 12/28/2006
ckniffin : 12/28/2006
wwang : 3/17/2006
terry : 3/13/2006
carol : 6/8/2004
terry : 6/2/2004
tkritzer : 5/24/2004
terry : 5/7/2004
tkritzer : 4/26/2004
terry : 4/22/2004
tkritzer : 4/16/2004
terry : 4/8/2004
carol : 4/8/2004
tkritzer : 2/20/2004
carol : 1/22/2004
ckniffin : 1/16/2004

* 608400

USHERIN; USH2A


Alternative titles; symbols

USH2A GENE
USH2; US2


HGNC Approved Gene Symbol: USH2A

Cytogenetic location: 1q41     Genomic coordinates (GRCh38): 1:215,622,891-216,423,448 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
1q41 Retinitis pigmentosa 39 613809 Autosomal recessive 3
Usher syndrome, type 2A 276901 Autosomal recessive 3

TEXT

Description

Usherin is a transmembrane protein expressed in various tissues including retinal photoreceptors and cochlear hair cells, with a crucial role in photoreceptor survival and cochlear development (summary by Jung et al., 2023).


Cloning and Expression

From the Usher syndrome type IIa (276901) critical region on chromosome 1 established by linkage studies, Eudy et al. (1998) identified the USH2A gene and isolated the corresponding cDNA from a human retina cDNA library. The USH2A gene encodes a 1,551-amino acid protein with a predicted molecular mass of 171.5 kD. Northern blot analysis identified 3 mRNA transcripts of 6.5, 5.0, and 1.9 kb in the retina. Reverse transcriptase PCR identified expression of USH2A in human fetal cochlea, eye, brain, and kidney. The USH2A protein sequence contains laminin epidermal growth factor and fibronectin type III motifs, which are most commonly observed in proteins comprising components of the basal lamina and extracellular matrices and in cell adhesion molecules. In the eye, both Bruch membrane (a specialized basement membrane underlying the retinal pigment epithelium) and the interphotoreceptor cell matrix are rich in extracellular matrix proteins. Extracellular matrix proteins also play a fundamental role in the cochlea: COL1A2 (120160), COL2A1 (120140), and COL3A1 (120180) are highly expressed in the membranous labyrinth of the cochlea. In addition, both X-linked and autosomal forms of Alport syndrome (see 104200) are caused by mutations in collagen type IV genes.

Weston et al. (2000) found a sequence difference in the USH2A gene, resulting in reduction of the total length of the encoded protein, which they designated usherin, from 1,551 to 1,546 amino acids.

Huang et al. (2002) isolated and characterized the mouse and rat orthologs of human USH2A. Like human USH2A, the mouse and rat genes are expressed primarily in retina and cochlea. Mouse Ush2a encodes a 161-kD protein that shows 68% identity and 9% similarity to the human USH2A protein. The predicted amino acid sequence of the mouse and rat proteins, like their human counterpart, contain a leader sequence, an amino-terminal globular domain, 10 laminin epidermal growth factor domains, and 4 carboxy-terminal fibronectin type III motifs. With in situ hybridization, the authors compared the cellular expression of the USH2A gene in rat, mouse, and human retinas. In all 3 species, Ush2a mRNA was expressed in cells of the outer nuclear layer of the retina, one of the target tissues of the disease. In the developing rat retina, Ush2a mRNA expression appeared in the neuroepithelium at embryonic day 17.

Van Wijk et al. (2004) identified novel exons in the USH2A gene and obtained evidence for alternative splicing. The putative 5,202-residue protein encoded by the longest open reading frame harbors, in addition to the known functional domains, 2 laminin G and 28 fibronectin type III repeats, as well as a transmembrane region followed by an intracellular domain with a PDZ-binding domain at its C-terminal end. Semiquantitative expression profile analysis suggested a low level of expression for both the long and the short isoform(s) and partial overlap in spatial and temporal expression patterns.

Using immunofluorescence microscopy in mouse retina, Liu et al. (2007) localized usherin to the apical inner segment recess that wraps around the connecting cilia, which links the inner and outer photoreceptor segments. Usherin also associated transiently with hair bundles in hair cells of the cochlea during early postnatal mouse development.


Gene Structure

Weston et al. (2000) determined that the usherin gene contains 21 exons.

Van Wijk et al. (2004) identified 51 additional exons at the 3-prime end of the USH2A gene, bringing the total number of exons to 72, and Adato et al. (2005) described a new alternatively spliced exon 71.


Mapping

By fluorescence in situ hybridization, Huang et al. (2002) mapped the mouse Ush2a gene to chromosome 1 in a region syntenic to human chromosome 1q41. Rat Ush2a was localized by radiation hybrid analysis to rat chromosome 13.


Gene Function

Adato et al. (2005) described usherin alternative transcripts in the murine inner ear encoding several predicted transmembrane usherin isoforms with modular ectodomains of different lengths. They identified a 24-amino acid peptide, encoded by a novel exon, within the cytoplasmic region and found it to be predominantly expressed in the inner ear but not in the retina. In mouse and rat inner ears, a transmembrane usherin was present at the base of the differentiating stereocilia, which make up the mechanosensitive hair bundles receptive to sound. Usherin immunolabeling was transient in the hair bundles of cochlear hair cells (HCs), but persisted in mature hair bundles of vestibular HCs. Coimmunoprecipitation and in vitro binding assays demonstrated that the usherin cytodomain can bind to whirlin (WHRN; 607928) and harmonin (USH1C; 605242), 2 PDZ domain-containing proteins that are defective in genetic forms of isolated deafness (see 607084) and Usher type IC (276904), respectively. These PDZ proteins are suitable to provide the anchoring of interstereocilia lateral links to the F-actin core of stereocilia. The authors suggested that congenital deafness in Usher types I and II (see 276901) shares similar pathogenic mechanisms, i.e., the disruption of hair bundle links-mediated adhesion forces that are essential for the proper organization of growing hair bundles.

Reiners et al. (2005) demonstrated a molecular interaction between the scaffold protein harmonin, the USH2A protein usherin, VLGR1 (USH2C; 602851), and NBC3 (SLC4A7; 603353). The authors pinpointed these interactions to the PDZ1 domain of harmonin and the PDZ-binding motifs at the C termini of the USH2 proteins and NBC3. USH2A, VLGR1, and NBC3 are coexpressed with the USH1 protein harmonin in the synaptic terminals of both retinal photoreceptors and inner ear hair cells. In hair cells, these USH proteins are also localized in the signal uptaking stereocilia. The authors concluded that the USH2 proteins and NBC3 are partners in the supramolecular USH protein network in the retina and inner ear.

By yeast 2-hybrid analysis using deletion constructs of lebercilin (611408) and the intracellular region of USH2A isoform B, van Wijk et al. (2009) showed that the intermediate filament region of NLP(isoB) (NINL; 609580) interacts with lebercilin and USH2A(isoB), whereas no interaction was detected for NLP(isoA). Coimmunoprecipitation and GST pull-down assays confirmed interaction between NLP(isoB) and lebercilin and USH2A. Recombinant NLP(isoB), lebercilin, and USH2A(isoB) were all found to colocalize at the centrosomes in human retinal pigment epithelial (ARPE-19) cells. Staining of adult rat retinal sections with specific antibodies against all 3 proteins revealed their colocalization at the basal bodies of the photoreceptor-connecting cilia. A truncation mutation (611408.0003) in lebercilin reduced interaction and colocalization with NLP(isoB); however, RNAi knockdown of both endogenous NLP and lebercilin in ciliated ARPE-19 cells did not result in altered protein localization of NLP or lebercilin.

In coimmunoprecipitation studies, Ebermann et al. (2010) demonstrated interaction of USH2A with the first and second PDZ domains of PDZD7 (612971); a truncated version of USH2A without the C-terminal PDZ-binding motif showed reduced interaction.


Molecular Genetics

Usher Syndrome Type IIA

Among 96 patients with Usher syndrome type IIa (276901), Eudy et al. (1998) identified 3 mutations in the USH2A gene (608400.0001-608400.0003), all of which resulted in frameshifts and premature terminations. A 2299delG mutation (608400.0001), originally reported as 2314delG, was the most frequent mutant allele, occurring in 21 cases.

In a mutation search of 57 independent USH2A probands, Weston et al. (2000) identified 15 mutations in the USH2A gene. Of 114 independent USH2A alleles, 58 harbored probable pathologic mutations. Ten cases were true homozygotes and 10 were compound heterozygotes; 18 heterozygotes with only 1 identifiable mutation were observed. The 2299delG allele was the most frequent mutant allele, observed in 31 of 192 alleles (16%).

Dreyer et al. (2000) screened the USH2A gene for mutations in 31 unrelated patients from Denmark and Norway with Usher syndrome type II. The 2299delG mutation accounted for 44% of disease alleles. They found 16 novel putative disease-causing mutations, of which 12 were private and 4 were shared by unrelated patients.

In 12 unrelated patients with Usher syndrome, each with 1 mutation in exons 1 to 21 of the USH2A gene, van Wijk et al. (2004) identified a second pathogenic USH2A mutation in the 51 additional USH2A exons that they identified. The novel mutations included 3 different truncating mutations and 2 missense mutations (see, .e.g., 608400.0007-608400.0009). The presence of pathogenic mutations in the novel exons indicated that at least 1 of the putative long isoforms of the USH2A protein plays a role in both hearing and vision.

Aller et al. (2006) identified mutations in the USH2A gene in 14 of 32 unrelated Spanish patients with Usher syndrome, nonsyndromic retinal degeneration, or nonsyndromic deafness in whom 2 disease-causing mutations could not be found after screening the first 21 exons of the USH2A gene. Analysis of the 51 new exons identified by van Wijk et al. (2004) and the 1 new exon identified by Adato et al. (2005) yielded 14 novel mutations, including 7 missense, 5 frameshift, 1 duplication, and 1 putative splice site mutation. Most of the patients had previously been reported by Aller et al. (2004). All of the individuals with 2 mutations were clinically diagnosed with Usher syndrome type IIa.

Baux et al. (2007) identified 34 distinct mutations in the USH2A gene in affected individuals from 25 families with Usher syndrome. Two of the alleles were complex with 3 and 2 mutations in cis, respectively. Only 5 families carried both mutations in the first 21 exons, indicating that screening of the entire gene is necessary for accurate and complete mutational analysis.

To explore the spectrum of USH2A disease-causing mutations among Scandinavian USH2 cases, Dreyer et al. (2008) performed extensive DNA sequence analysis of the full-size USH2A gene in patients from 118 unrelated families, of which 27 had previously been found to carry mutations in exons 1 to 21. In all, 122 USH2A DNA sequence alterations were identified, of which 57 were predicted to be pathogenic, 7 were considered to be of uncertain pathogenicity, and 58 were predicted to be benign variants. Of 36 novel pathogenic USH2A mutations, 31 were located in exons 22 to 73, specific to the long isoform (see, e.g., 608400.0013). USH2A mutations were identified in 89 (75.4%) of 118 families. In 79 (88.8%) of these 89 families, 2 pathogenic mutations were identified, whereas in 10 families (11.2%) the second mutation remained unidentified. In 5 (4.2%) of the 118 families the USH phenotype could be explained by mutations in the CLRN1 gene (606397).

Yan et al. (2009) identified mutant USH2A alleles in 12 (60%) of 20 American patients of European ancestry with Usher syndrome type IIa. Seven (35%) patients had only 1 pathogenic mutation, and 8 patients did not have USH2A mutations. There were 5 novel mutations and 5 previously reported mutations, consisting of 3 missense, 3 frameshift, and 4 nonsense. The 2299delG mutation was the most common, accounting for 38.9% of mutant alleles.

McGee et al. (2010) screened the long isoform of USH2A in 108 patients diagnosed with Usher syndrome type IIa and identified at least 1 deleterious mutation in at least 57% of cases.

Retinitis Pigmentosa 39

Rivolta et al. (2002) identified autosomal recessive retinitis pigmentosa (RP39; 613809) without hearing loss due to mutation in the USH2A gene inherited by uniparental paternal disomy (C759F; 608400.0006). Zlotogora (2004) reviewed examples in which uniparental disomy had been established as the cause of an autosomal recessive disorder. One of 6 such disorders listed for chromosome 1, the most for any single chromosome, was autosomal recessive retinitis pigmentosa without hearing loss due to mutation in the USH2A gene.

McGee et al. (2010) screened the long isoform of USH2A in 80 patients with nonsyndromic autosomal recessive RP and identified at least 1 deleterious mutation in 19% of cases. The authors stated that their findings supported USH2A as the most common known cause of RP in the United States.

In a cohort of 94 Korean probands with RP, Jung et al. (2023) analyzed the USH2A gene and identified 10 probands who were compound heterozygous for mutations in the USH2A gene (e.g., 608400.0016-608400.0018). Hearing tests were not performed because no hearing problems were reported by any of the probands.

Cosegregation of Usher Syndrome and Retinitis Pigmentosa

In a consanguineous family of Iraqi Jewish origin in which some members had USH2 and others had nonsyndromic retinitis pigmentosa, Kaiserman et al. (2007) identified 3 pathogenic mutations in the USH2A gene. Patients with USH2A were compound heterozygous for 2 null mutations (608400.0010-608400.0011), whereas patients with nonsyndromic RP were compound heterozygous for 1 of the null mutations and a novel missense mutation (608400.0012).


Genotype/Phenotype Correlations

To investigate genotype/phenotype correlations, Aller et al. (2004) screened 191 unrelated Spanish patients with syndromic or nonsyndromic retinal diseases, or with nonsyndromic hearing impairment, for the 2299delG (608400.0001) and C759F (608400.0006) mutations in the USH2A gene. They found that the 2299delG mutation was present in patients with clinical signs of Usher syndrome type II or of atypical Usher syndrome, whereas the C759F mutation, whether or not it was associated with the 2299delG mutation, was identified in cases with nonsyndromic retinitis pigmentosa (RP). Aller et al. (2004) concluded that sensorineural hearing loss in patients with RP may depend on the nature and association of the USH2A allelic variants present.

Bernal et al. (2005) studied 28 Spanish patients with Usher syndrome type II, identifying 10 different pathogenic mutations and 17 polymorphisms in the USH2A gene. They observed discordant phenotypes in sib pairs from 2 unrelated families and noted that Liu et al. (1999) had reported clinical differences in monozygotic twins with Usher syndrome type II and had suggested that variation in the expression of the USH2A gene is not determined simply by genetic factors.


Animal Model

Liu et al. (2007) found that Ush2a knockout in mice led to progressive photoreceptor degeneration and a moderate but nonprogressive hearing impairment, mimicking the visual and hearing defects in USH2A patients.


ALLELIC VARIANTS 18 Selected Examples):

.0001   USHER SYNDROME, TYPE IIA

USH2A, 1-BP DEL, 2299G
SNP: rs80338903, gnomAD: rs80338903, ClinVar: RCV000002445, RCV000032524, RCV000191141, RCV000210326, RCV000254870, RCV000504641, RCV000623326, RCV000678639, RCV000735362, RCV000787895, RCV000787897, RCV000787899, RCV000824793, RCV001000453, RCV001095692, RCV002504737, RCV003398418

By heteroduplex analysis, Eudy et al. (1998) identified a 2299delG mutation (originally reported by them as 2314delG) in the USH2A gene in 21 of 96 probands with Usher syndrome type IIa (USH2A; 276901); 8 of them were homozygous and 13 heterozygous. All but 2 were of northern European ancestry (Swedish, Dutch, German, or English). The 2 non-northern European patients were both homozygous for the 2299G deletion; one was from Spain and the other was an African American from Nebraska, U.S. Examination of various haplotypes failed to reveal any substantial disequilibrium with the 2299delG mutation, suggesting that the mutation did not arise in a common ancestor. The 2299delG mutation caused a frameshift at codon 772, after which the open reading frame continued for 20 codons and ended as TAG.

Liu et al. (1999) performed a mutation analysis of the USH2A gene in 23 families with Usher syndrome, 10 of which had a diagnosis of atypical Usher syndrome, from the United Kingdom and China. They found that most of the families with USH2 carried the 2299delG mutation. Of 12 families with the 2299delG mutation, 8 families had the typical USH2 phenotype (congenital moderate to severe hearing impairment, normal vestibular function, and postpubertal onset of retinitis pigmentosa). However, 5 affected individuals from the remaining 4 families carrying the 2299delG mutation showed atypical Usher syndrome features, with progressive hearing impairment, variable vestibular function, and RP. An isolated patient with the mutation was typical of USH2 in all aspects, including nonprogressive hearing loss, but had absent vestibular function, which is a critical discriminator in clinical classification.

Weston et al. (2000) revised numbering for the sequence of the USH2A gene, taking into account a significant sequence difference. The 2299delG mutation reported by Eudy et al. (1998) is correctly referred to as 2299delG. The sequence difference reduces the length of the usherin protein from 1551 to 1546 amino acids.

Weston et al. (2000) found the 2299delG mutation to be the most frequent, having a frequency of 31 in 192 alleles (16%) in their series.

Dreyer et al. (2001) presented data indicating that the widespread geographic distribution of the 2299delG mutation is the result of an ancestral mutation that spread throughout Europe and into the New World as a result of migration. Various studies had reported a range of frequencies (from 0.16 to 0.44) among patients with Usher syndrome, depending on the geographic origin of the patients. Dreyer et al. (2001) performed haplotype analysis on DNA samples from 116 unrelated patients with Usher syndrome type IIa; the patients were from 14 countries and represented 148 2299delG alleles. On the basis of 6 single-nucleotide polymorphisms (SNPs) within the USH2A gene, 12 core haplotypes were observed in a panel of normal chromosomes. However, in their patient analysis, only 1 core haplotype was associated with the 2299delG mutation.

Ouyang et al. (2004) confirmed that 2299delG is the most common mutation in USH2A, accounting for 77.5% of the pathologic alleles. In 5 of the 24 patients, the 2299delG mutation was present in homozygous state; in 3 it was present in compound heterozygous state with other mutations; and in 16 it was present in heterozygous state.

Baux et al. (2007) identified the 2299delG mutation, which results in a frameshift at codon 767, in 22% of mutated alleles in their study of 25 affected families.

Yan et al. (2009) identified the 2299delG mutation in 38.9% of mutant alleles among 12 American probands of European descent with Usher syndrome type IIa.


.0002   USHER SYNDROME, TYPE IIA

USH2A, 1-BP DEL, 2898G
SNP: rs397518008, ClinVar: RCV000002446, RCV000671576, RCV000824792, RCV001851582, RCV003450613

In patients with Usher syndrome type IIa (USH2A; 276901), Eudy et al. (1998) found a 1-bp deletion, reported by them as 2913delG, in the USH2A gene. This mutation is correctly referred to as 2898delG (T967FS) (Weston et al., 2000).


.0003   USHER SYNDROME, TYPE IIA

USH2A, 2-BP DEL, 4338CT
SNP: rs111033367, gnomAD: rs111033367, ClinVar: RCV000002447, RCV000310917, RCV000710335, RCV000793722, RCV000984013, RCV001073308, RCV002482816

In the Louisiana Acadian population with Usher syndrome type IIa (USH2A; 276901), Eudy et al. (1998) found heterozygosity for a dinucleotide deletion that they reported as 4353-4delCT. This mutation is correctly referred to as 4338-9delCT (C1447FS) (Weston et al., 2000).

Ebermann et al. (2009) identified the homozygous 4338delCT mutation in 4 of 9 French Canadian families with Usher syndrome type IIa from Quebec and New Brunswick, the former Acadia. Affected individuals from 2 additional families carried the mutation in heterozygosity. Altogether, the 4338delCT mutation accounted for 10 (55.6%) of 18 disease alleles. Haplotype analysis indicated a founder effect. The findings indicated that the Acadian and Quebec populations share common ancestors.

Ebermann et al. (2010) studied 2 French Canadian sisters with USH2A who were homozygous for the 4338delCT mutation in the USH2A gene, and identified an additional de novo heterozygous frameshift mutation in the PDZD7 gene (612971.0001) in 1 of the sisters, who had earlier-onset and more severe retinal disease. The PDZD7 mutation was not present in the other sister, who had a much milder retinal phenotype. Ebermann et al. (2010) concluded that PDZD7 is a retinal disease modifier in patients with USH2A.


.0004   USHER SYNDROME, TYPE IIA

USH2A, LEU260TER
SNP: rs121912598, gnomAD: rs121912598, ClinVar: RCV000002448

In members of a Swedish family with type IIa Usher syndrome (USH2A; 276901), Weston et al. (2000) identified a 779T-G transversion in the USH2A gene, resulting in a leu260-to-ter (L260X) change. The mutation was present in compound heterozygous state with the 2299delG mutation (608400.0001).


.0005   USHER SYNDROME, TYPE IIA

USH2A, CYS319TYR
SNP: rs121912599, gnomAD: rs121912599, ClinVar: RCV000002449, RCV000303941, RCV000824798, RCV001004780, RCV001074393, RCV003460406

Weston et al. (2000) found homozygosity for a cys319-to-tyr (C319Y) mutation in the USH2A gene in a proband with Usher syndrome type IIa (USH2A; 276901) from a Hispanic American family.


.0006   RETINITIS PIGMENTOSA 39

USH2A, CYS759PHE ({dbSNP rs80338902})
SNP: rs80338902, gnomAD: rs80338902, ClinVar: RCV000002450, RCV000032523, RCV000174625, RCV000239000, RCV000404009, RCV000504814, RCV000505146, RCV000623925, RCV001257905, RCV001535506, RCV001813938, RCV002251859, RCV003398419

Rivolta et al. (2000) described a cys759-to-phe (C759F) missense mutation caused by a G-T change in the USH2A gene that was associated with autosomal recessive retinitis pigmentosa without hearing loss (RP39; 613809). The amino acid at this position is within the fifth laminin-epidermal growth factor-like domain and participates in a presumed disulfide bridge. The mutation was found in 4.5% of 224 patients with recessive RP.

Rivolta et al. (2002) reported a patient with RP without hearing loss caused by a homozygous C759F mutation in the USH2A gene. Her father was heterozygous for this change, and her mother was a noncarrier. Further evaluation with microsatellite markers revealed that the patient had inherited 2 copies of chromosome 1 from her father and none from her mother. The 2 paternally derived copies of chromosome 1 were heteroallelic from the centromere to the proximal short and long arms. The distal regions of the short and long arms of chromosome 1 were homoallelic, including the region of 1q with the mutant USH2A allele. This genetic pattern is compatible with uniparental primary heterodisomy with regions of homozygosity arising through a nondisjunction event during paternal meiosis I and subsequent trisomy rescue or gamete complementation. A paternal second cousin of the patient also had RP and had an identical heterozygous mutation in the USH2A gene in the same codon. However, the analysis of an isocoding polymorphism 20 bp away and closely linked microsatellite markers in the patient and family members indicated that the 2 mutant alleles were unlikely to be identical by descent and that the 2 relatives fortuitously had RP and a mutation in the same codon of the USH2A gene.

Pozo et al. (2015) noted that 15 families with RP had been reported to have a homozygous C759F variant (rs80338902) in the USH2A gene. In all reviewed cases, the segregation data either were not shown or were inconclusive. Pozo et al. (2015) restudied a Spanish family (S23) in which Bernal et al. (2003) had identified homozygosity for C759F in 2 affected and 2 unaffected sibs. By next-generation sequencing, they identified homozygosity for an R560C mutation in the PDE6B gene (180072.0008) that segregated with the disorder in the family and was absent in 200 control individuals. Pozo et al. (2015) suggested that the C759F variant might not be pathogenic and proposed genetic reevaluation of other reported families with the C759F variant.

In a discovery cohort of 186 unrelated probands with autosomal recessive retinal degeneration without childhood hearing loss, Lenassi et al. (2015) found the c.2276G-T transversion in USH2A gene, resulting in a C759F substitution, in 11 alleles (once in homozygosity). In the replication cohort of 84 unrelated probands with autosomal recessive retinal degeneration, the allele was found 5 times, once in homozygosity; and in a third panel of 187 patients with nonsyndromic adult-onset autosomal recessive retinitis pigmentosa, it was found 5 times, once in homozygosity. Lenassi et al. (2015) noted that the C759F mutation is often considered to be the most common disease-causing variant in patients with nonsyndromic retinitis pigmentosa.

To assess the role of the C759F mutation in autosomal recessive retinitis pigmentosa and Usher syndrome type 2, Perez-Carro et al. (2018) performed a comprehensive genetic and clinical study of 57 families with affected members who carried the C759F mutation on at least 1 allele. Of the 57 probands, 11 were homozygous for the mutation, 42 were compound heterozygous with another mutation in the USH2A gene, and the remaining 4 also carried mutations in RP1 (603937), PROM1 (604365), or CNGB1 (600724). The 2 patients with PROM1 and CNGB1 mutations, and 1 patient with mutated RP1, were homozygous for those mutations in addition to the C759F mutation in USH2A; the second patient with mutation in RP1 was heterozygous for that mutation. The authors noted that although the C759F variant is enriched in the Spanish population, no homozygous individuals had been identified in control populations, even in Spanish population databases. Perez-Carro et al. (2018) stated that the C759F mutation alters a highly conserved residue in a domain that enhances USH2A stability in the basement membrane by prompting its interaction with collagen IV (see 120070). The mutation was also predicted to disrupt a disulfide bridge, leading to erroneous protein folding and instability. While Pozo et al. (2015) had questioned the pathogenicity of the C759F variant, at least in homozygosity, Perez-Carro et al. (2018) pointed out that no other candidate variants in the USH2A or any other RP genes that could explain the phenotypes were found in their patients by next-generation sequencing. They concluded that C759F homozygosity is associated with a later diagnosis of RP and slower progression of visual field loss, with a very late hypoacusis diagnosis (around the seventh decade).


.0007   USHER SYNDROME, TYPE IIA

USH2A, TRP3955TER
SNP: rs111033364, gnomAD: rs111033364, ClinVar: RCV000002451, RCV000412373, RCV000414231, RCV000414867, RCV000415089, RCV000504922, RCV000824781, RCV001003260, RCV001074873, RCV001806999, RCV001813732, RCV002476913, RCV003114173, RCV003314546, RCV003904796

In 2 patients with Usher syndrome type IIa (USH2A; 276901), van Wijk et al. (2004) found compound heterozygosity for a trp3955-to-ter (W3955X) mutation in the USH2A gene and 2 different mutations: a 949C-A transversion in one patient, resulting in an arg317-to-arg mutation (R317R; 608400.0008), which was predicted to create an additional 5-prime splice site in exon 5; and a 1256G-T transversion, resulting in a cys419-to-phe substitution (C419F; 608400.0009) in the second patient.


.0008   USHER SYNDROME, TYPE IIA

USH2A, 949C-A, ARG317ARG
SNP: rs111033272, gnomAD: rs111033272, ClinVar: RCV000002452, RCV000412796, RCV000627017, RCV000763297, RCV000824799, RCV000984234, RCV001075725, RCV001199595

For discussion of the arg317-to-arg (R317R) mutation in the USH2A gene that was found in compound heterozygous state in patients with Usher syndrome type IIa (USH2A; 276901) by van Wijk et al. (2004), see 608400.0007.


.0009   USHER SYNDROME, TYPE IIA

USH2A, CYS419PHE
SNP: rs121912600, gnomAD: rs121912600, ClinVar: RCV000002453, RCV000224697, RCV000504809, RCV000778222, RCV000824795, RCV000984315, RCV001074823, RCV002482817

For discussion of the cys419-to-phe (C419F) mutation in the USH2A gene that was found in compound heterozygous state in patients with Usher syndrome type IIa (USH2A; 276901) by van Wijk et al. (2004), see 608400.0007.


.0010   USHER SYNDROME, TYPE IIA

RETINITIS PIGMENTOSA 39, INCLUDED
USH2A, 4-BP INS, NT239
SNP: rs587776538, ClinVar: RCV000002454, RCV000002455

In a consanguineous family of Iraqi Jewish origin in which some members had Usher syndrome type IIa (USH2A; 276901) and others had nonsyndromic retinitis pigmentosa (RP39; 613809), Kaiserman et al. (2007) identified compound heterozygosity for 2 null mutations in the USH2A gene in those affected with USH2A: a 4-bp insertion (239_242insCGAT) resulting in a frameshift at position 80 (Thr80fs), and a 2209C-T transition resulting in an arg737-to-ter (R737X; 608400.0011) substitution. In those affected with nonsyndromic RP, they identified compound heterozygosity for one of the null mutations and a 14021A-G transition resulting in an arg4674-to-gly substitution (R4674G; 608400.0012).


.0011   USHER SYNDROME, TYPE IIA

RETINITIS PIGMENTOSA 39, INCLUDED
USH2A, ARG737TER
SNP: rs111033334, gnomAD: rs111033334, ClinVar: RCV000002456, RCV000002457, RCV000725261, RCV000824794, RCV001003279

For discussion of the arg737-to-ter (R737X) mutation in the USH2A gene that was found in compound heterozygous state in a family in which some members had Usher syndrome type IIa (USH2A; 276901) and others had nonsyndromic retinitis pigmentosa (RP39; 613809) by Kaiserman et al. (2007), see 608400.0010.


.0012   RETINITIS PIGMENTOSA 39

USH2A, ARG4674GLY
SNP: rs80338904, gnomAD: rs80338904, ClinVar: RCV000002458, RCV000032522, RCV001379272

For discussion of the arg4674-to-gly (R4674G) mutation in the USH2A gene that was found in compound heterozygous state in a family in which some members had Usher syndrome type IIa (USH2A; 276901) and others had nonsyndromic retinitis pigmentosa (RP39; 613809) by Kaiserman et al. (2007), see 608400.0010.


.0013   USHER SYNDROME, TYPE IIA

USH2A, IVS40AS, A-G, -2144
SNP: rs786200928, gnomAD: rs786200928, ClinVar: RCV000023700, RCV000505092, RCV000664608, RCV000787740, RCV000814767, RCV001003267, RCV001074209, RCV001376510, RCV001824575

In a French patient with Usher syndrome type IIa (USH2A; 276901), Vache et al. (2012) identified compound heterozygosity for 2 mutations in the USH2A gene: a heterozygous A-to-G transition deep within intron 40 (c.7595-2144) and a 1-bp duplication (3129dupT; 608400.0014), resulting in a frameshift. Two other individuals in a different branch of the family had the intron 41 mutation and a different heterozygous frameshift mutation, 8890dupT (608400.0015). The intron 41 mutation was found only after RT-PCR amplification of RNA from nasal cells in 1 patient showed an aberrant USH2A out-of-frame transcript predicted to result in a truncated protein that would not be anchored to the cell membrane. DNA studies showed that the A-to-G transition resulted in activation of a pseudoexon between exons 40 and 41, causing a 153-bp insertion and a frameshift. The nomenclature used for this insertion was r.7594_7595ins7595-2296_7595-2143. This mutation was not found in 338 alleles. However, this mutation was found in 4 of 20 USH2A patients with no identified mutation or only a single pathogenic mutation, as well as in 4 of 18 Spanish patients with incomplete USH2A genotypes. Vache et al. (2012) noted that the identification of a deep intronic mutation in a pseudoexon raised the possibility of a new therapeutic strategy using antisense oligonucleotide chemistry to restore normal splicing via exon skipping.


.0014   USHER SYNDROME, TYPE IIA

USH2A, 1-BP DUP, 3129T
SNP: rs786205115, gnomAD: rs786205115, ClinVar: RCV000023701

For discussion of the 1-bp duplication in the USH2A gene (3129dupT) that was found in compound heterozygous state in a patient with Usher syndrome type IIa (USH2A; 276901) by Vache et al. (2012), see 608400.0013.


.0015   USHER SYNDROME, TYPE IIA

USH2A, 1-BP DUP, 8890T
SNP: rs786205116, gnomAD: rs786205116, ClinVar: RCV000023702, RCV002513202

For discussion of the 1-bp duplication in the USH2A gene (8890dupT) that was found in compound heterozygous state in patients with Usher syndrome type IIa (USH2A; 276901) by Vache et al. (2012), see 608400.0013.


.0016   RETINITIS PIGMENTOSA 39

USH2A, CYS934TRP
SNP: rs201527662, gnomAD: rs201527662, ClinVar: RCV000132710, RCV000576637, RCV000595137, RCV000986542, RCV001003277, RCV001074347, RCV002469023

In 5 Korean probands with retinitis pigmentosa (RP39; 613809), Jung et al. (2023) identified compound heterozygosity for a c.2802T-G transversion in exon 13 of the USH2A gene, resulting in a cys934-to-trp (C934W) substitution within the LamE 8 domain, and another missense or truncating mutation in the USH2A gene (e.g., 608400.0017 and 608400.0018). Hearing tests were not performed, but no hearing problems were reported by any of the probands.


.0017   RETINITIS PIGMENTOSA 39

USH2A, 4-BP DEL, 13112AAAT
SNP: rs768161313, gnomAD: rs768161313, ClinVar: RCV000674880, RCV000734827, RCV000985058, RCV003223665, RCV003411586, RCV003889966

In 2 Korean probands with retinitis pigmentosa (RP39; 613809), Jung et al. (2023) identified compound heterozygosity for a 4-bp deletion (c.13112_13115delAAAT) in exon 63 of the USH2A gene, causing a frameshift predicted to result in a premature termination codon (Gln4371fs), and another missense or truncating mutation in the USH2A gene (e.g., 608400.0016). Hearing tests were not performed, but no hearing problems were reported by the probands.


.0018   RETINITIS PIGMENTOSA 39

USH2A, ARG1578CYS
SNP: rs201529124, gnomAD: rs201529124, ClinVar: RCV001067861, RCV001376322, RCV002282450, RCV003455294

In 2 Korean probands with retinitis pigmentosa (RP39; 613809), Jung et al. (2023) identified compound heterozygosity for a c.4732C-T transition in exon 22 of the USH2A gene, resulting in an arg1578-to-cys (R1578C) substitution within the LamG 1 domain, and another missense or truncating mutation in the USH2A gene (e.g., 608400.0016). Hearing tests were not performed, but no hearing problems were reported by the probands.


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Contributors:
Marla J. F. O'Neill - updated : 02/02/2023
Anne M. Lopez - updated : 10/11/2018
Nara Sobreira - updated : 11/10/2015
Marla J. F. O'Neill - updated : 6/11/2015
Cassandra L. Kniffin - updated : 1/9/2012
Marla J. F. O'Neill - updated : 5/3/2011
Cassandra L. Kniffin - updated : 6/14/2010
George E. Tiller - updated : 10/23/2009
George E. Tiller - updated : 7/20/2009
George E. Tiller - updated : 7/6/2009
Cassandra L. Kniffin - updated : 4/2/2009
Jane Kelly - updated : 11/30/2007
Cassandra L. Kniffin - updated : 10/10/2007
Patricia A. Hartz - updated : 4/30/2007
Cassandra L. Kniffin - updated : 12/28/2006
Marla J. F. O'Neill - updated : 3/13/2006
Marla J. F. O'Neill - updated : 6/2/2004
Victor A. McKusick - updated : 5/7/2004
Victor A. McKusick - updated : 4/22/2004
Victor A. McKusick - updated : 4/8/2004

Creation Date:
Cassandra L. Kniffin : 1/15/2004

Edit History:
carol : 04/18/2023
carol : 04/17/2023
alopez : 02/02/2023
carol : 03/15/2021
alopez : 10/11/2018
alopez : 02/19/2016
carol : 11/11/2015
carol : 11/10/2015
alopez : 6/11/2015
alopez : 4/23/2015
mcolton : 4/21/2015
alopez : 3/30/2015
carol : 6/18/2014
terry : 3/14/2013
terry : 8/31/2012
carol : 1/19/2012
carol : 1/19/2012
ckniffin : 1/9/2012
ckniffin : 1/9/2012
carol : 5/5/2011
terry : 5/5/2011
terry : 5/3/2011
terry : 5/3/2011
alopez : 3/15/2011
wwang : 6/21/2010
ckniffin : 6/14/2010
wwang : 11/4/2009
terry : 10/23/2009
alopez : 7/20/2009
alopez : 7/10/2009
terry : 7/6/2009
wwang : 6/23/2009
wwang : 4/17/2009
ckniffin : 4/2/2009
carol : 11/30/2007
carol : 11/29/2007
wwang : 10/17/2007
ckniffin : 10/10/2007
wwang : 4/30/2007
carol : 1/4/2007
ckniffin : 12/28/2006
ckniffin : 12/28/2006
wwang : 3/17/2006
terry : 3/13/2006
carol : 6/8/2004
terry : 6/2/2004
tkritzer : 5/24/2004
terry : 5/7/2004
tkritzer : 4/26/2004
terry : 4/22/2004
tkritzer : 4/16/2004
terry : 4/8/2004
carol : 4/8/2004
tkritzer : 2/20/2004
carol : 1/22/2004
ckniffin : 1/16/2004