Alternative titles; symbols
HGNC Approved Gene Symbol: HMBS
SNOMEDCT: 234422006;
Cytogenetic location: 11q23.3 Genomic coordinates (GRCh38): 11:119,084,881-119,093,549 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q23.3 | Encephalopathy, porphyria-related | 620704 | Autosomal recessive | 3 |
| Leukoencephalopathy, porphyria-related | 620711 | Autosomal recessive | 3 | |
| Porphyria, acute intermittent | 176000 | Autosomal dominant | 3 | |
| Porphyria, acute intermittent, nonerythroid variant | 176000 | Autosomal dominant | 3 |
Porphobilinogen deaminase (PBGD; EC 4.3.1.8) is the third enzyme of the biosynthetic pathway leading to the production of heme. It catalyzes the synthesis of hydroxymethylbilane by stepwise condensation of 4 porphobilinogen units. Hydroxymethylbilane is then converted to uroporphyrinogen III by uroporphyrinogen III synthetase (UROS; 606938) (Raich et al., 1986).
Raich et al. (1986) isolated a cDNA clone corresponding to the human erythrocyte porphobilinogen deaminase gene from a human erythrocyte library prepared from human spleen. The deduced 334-amino acid protein has a calculated molecular mass of approximately 37.6 kD. Northern blot analysis identified a single 1.6-kb mRNA transcript.
Grandchamp et al. (1987) determined that there are 2 PBGD isoforms that differ by approximately 2 kD (40 and 42 kD). One is active in all tissues and can be isolated from liver, and the other is restricted to erythrocytes. The nonerythrocyte isoform contains an additional 17 amino acid residues at the N terminus.
Chretien et al. (1988) demonstrated that the PBGD gene undergoes alternative splicing with 2 different promoters to yield 2 mRNAs. The first 'upstream' promoter is active in all tissues and has structural features of a housekeeping promoter, whereas the second promoter, located 3 kb downstream, is active only in erythrocytes and shows structural homology to the beta-globin gene (141900) promoters. The 2 mRNAs differ only in their first exon.
Gubin and Miller (2001) identified 2 alternatively spliced isoforms of erythroid PBGD in CD34+/- (142230) erythroid precursor cells. Complete sequencing showed that the alternatively spliced form, designated PBGD-EA, contained the intron between exons 2 and 3, thus extending the 5-prime untranslated region of the erythroid transcript by 176 bp. Northern blot analysis identified a distinct 1.5-kb mRNA corresponding to the alternatively spliced erythrocyte isoform only in bone marrow and fetal spleen.
Chretien et al. (1988) determined that the HMBS gene contains 15 exons and spans approximately 10 kb of DNA.
The housekeeping HMBS transcript contains exons 1 and 3-15; the erythroid HMBS transcript is encoded by exons 2-15 (Chen et al., 1994).
By study of mouse-human hybrid clones, Meisler et al. (1980, 1981) showed that PBG-deaminase is determined by a gene on chromosome 11; Wang et al. (1981) assigned the locus to the long arm in the segment 11q23-qter. In 3 children with trisomy of 11qter, de Verneuil et al. (1982) studied expression of uroporphyrinogen I synthase. Dosage effect supported assignment to the region 11q23.2-qter.
By in situ hybridization and by gene dosage studies in patients with monosomy or trisomy of the terminal portion of 11q, Namba et al. (1991) refined the assignment of the PBGD gene to 11q24.1-q24.2.
Tunnacliffe and McGuire (1990) constructed a long-range restriction map extending over 1.8 Mb of 11q23.3 using pulsed field gel electrophoresis and concluded that PBGD is situated in the following relation to 5 other genes: cen--CD3E--CD3D--CD3G--PBGD--CBL2--THY1--qter. They determined that the CD3G (186740) gene and PBGD are separated by 750 kb.
By the method of isoelectric focusing, Meisler and Carter (1980) identified structural variants of PBG-deaminase.
Louie et al. (1992) defined the 3-domain structure of PBGD by x-ray analysis. Two of the domains structurally resembled the transferrins (see, e.g., TF; 190000). The x-ray structure and results from site-directed mutagenesis provided evidence for a single catalytic site.
Autosomal Dominant Acute Intermittent Porphyria
In a large Dutch family with the nonerythroid variant of acute intermittent porphyria (AIP; 176000), Grandchamp et al. (1989) identified a heterozygous splice site mutation in intron 1 of the PBGD gene (609806.0001). The mutation interrupted the sequence coding for the nonerythroid isoform of PBGD; thus, expression of the erythroid isoform was unaffected. In a patient with CRM-positive AIP, Grandchamp et al. (1989) identified a heterozygous mutation in the HMBS gene, resulting in the skipping of exon 12 (609806.0002).
In affected members of 11 different families with either CRM-negative or CRM-positive AIP, Grandchamp et al. (1990) identified 7 different point mutations in the PBGD gene.
In a patient with the nonerythroid variant of AIP, Chen et al. (1994) identified a mutation in the initiation codon of the housekeeping HMBS isoform (M1V; 609806.0044). Puy et al. (1998) identified 3 different mutations in the donor splice site of the HMBS gene in 4 unrelated patients with the nonerythroid variant of AIP. They found that the splice site mutations resulted in activation of a cryptic splice site located 67 nucleotides downstream from the normal splice site, leading to a frameshift and premature stop codon in exon 4.
In 28 Finnish families representing 72% of all AIP families in the Finnish population of 5 million, Kauppinen et al. (1995) found 19 separate mutations in HMBS: 13 novel mutations, including 1 de novo event, and 6 previously characterized mutations.
Whatley et al. (1999) found 39 different mutations in the HMBS gene in 54 of 57 consecutive patients with AIP.
In patients with the nonerythroid variant of AIP, Whatley et al. (2000) identified mutations in the housekeeping promoter (-154delG; 609806.0041) and in exon 3 (41delA; 609806.0042) of the HMBS gene.
Floderus et al. (2002) studied most of the AIP kindreds in Sweden. They identified 27 novel mutations in the HMBS gene, bringing the total number of known mutations in the HMBS gene in Sweden to 39. Most of the mutations were located in exons 10 and 12, with fewer in exon 7. Floderus et al. (2002) used the 3-dimensional structure of the porphobilinogen deaminase enzyme to predict the possible molecular and functional consequences of the novel Swedish missense and nonsense mutations.
Porphyria-Related Encephalopathy
In a Dutch girl with porphyria-related encephalopathy (ENCEP; 620704) originally reported by Beukeveld et al. (1990), Picat et al. (1990) identified compound heterozygous missense mutations in the HMBS gene (R167Q, 609806.0005 and R173Q, 609806.0006). Each parent who had classic AIP was heterozygous for 1 of the mutations. The patient had a severe disease course and died at 8 years of age.
In an English brother and sister with ENCEP, Llewellyn et al. (1992) identified compound heterozygous missense mutations in the HMBS gene (R167Q and R167W, 609806.0013).
Solis et al. (2004) reported a Spanish patient with ENCEP who was homozygous for the R167W substitution. Both parents were heterozygous for the mutation.
In a patient, born of consanguineous Turkish parents, with ENCEP, Hessels et al. (2004) detected a homozygous missense mutation in the HMBS gene (L81P; 609806.0045). Porphobilinogen deaminase activity in red cells was decreased to 2 to 4%. The clinically unaffected parents were heterozygous for the mutation.
Porphyria-Related Leukoencephalopathy
In 3 adult sibs, born of unrelated Dutch parents, with slowly progressive porphyria-related leukoencephalopathy (LENCEP; 620711), Kevelam et al. (2016) identified compound heterozygous missense mutations in the HMBS gene: R167Q and R225Q (609806.0047). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. At least 2 unaffected sibs carried a heterozygous R225Q variant. HMBS erythrocyte activity ranged from 55 to 67% of normal controls in the affected sibs, similar to heterozygous carriers of HMBS mutations. One unaffected sib had 83% activity and the other had 105% activity. Kevelam et al. (2016) noted that both the R225Q and R167Q mutations had been reported in the heterozygous state in patients with autosomal dominant AIP.
In a 45-year-old man (P3), born of unrelated Dutch parents (family 2), with LENCEP, Stutterd et al. (2021) identified compound heterozygosity for the R225Q and R167Q mutations. His mother, who was heterozygous for the R167Q mutation, had latent AIP; his father was unavailable for testing. A measurement of HMBS enzyme activity was not available for P3. Stutterd et al. (2021) noted that the pathogenicity of the R225Q variant had not been conclusively demonstrated and that previous functional studies had yielded conflicting results of the effect of this variant on HMBS enzyme activity. Stutterd et al. (2021) also identified a homozygous missense mutation in the HMBS gene (A84D; 609806.0048) in 2 adult sibs, born of consanguineous Lebanese parents (family 1), with slowly progressive LENCEP. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not present in the gnomAD database. Erythrocyte HMBS enzyme activity in the affected sibs ranged from 13 to 18% of normal control values. Erythrocyte HMBS activity in an unaffected sib who was heterozygous for the mutation was 50% of normal.
During study of the pathogenesis of the neurologic symptoms of AIP, Lindberg et al. (1996) generated Pbgd-deficient mice by gene targeting. These mice exhibited typical biochemical characteristics of human AIP, including decreased hepatic Pbgd activity, increased delta-aminolevulinic acid synthase (ALAS1; 125290) activity, and massively increased urinary excretion of the heme precursor delta-aminolevulinic acid after treatment with drugs such as phenobarbital. Behavioral tests revealed decreased motor function and histopathologic findings, including axonal neuropathy and neurologic muscle atrophy.
Homedan et al. (2015) studied the AIP mouse model generated by Lindberg et al. (1996), in which the mice were compound heterozygous for a null Hmbs allele and a functional Hmbs allele with a mild mutation. They had previously found that Hmbs mutant liver showed deficiencies in mitochondrial complexes I through III. Homedan et al. (2015) found tissue-specific alterations in mitochondrial complexes in Hmbs mutant brain and muscle in the basal state. Phenobarbital-induced AIP was accompanied by a sharp alteration of oxidative metabolism in muscle, with significantly decreased ATP production in Hmbs mutant skeletal muscle due to deficiencies in complexes I and II. In contrast, all 4 respiratory chain complexes were affected in Hmbs mutant brain.
Clavero et al. (2010) described a naturally occurring feline model of AIP in 4 unrelated cat lines that presented phenotypically as congenital erythropoietic porphyria (CEP; 263700). Affected cats had erythrodontia, brownish urine, fluorescent bones, and markedly elevated urinary uroporphyrin and coproporphyrin, consistent with CEP. However, their UROS activities (deficient in CEP) were normal. Notably, affected cats had half-normal HMBS activities and elevated urinary 5-aminolevulinic acid (5-ALA) and PBG. Sequencing the feline Hmbs gene revealed different mutations in each line, including a duplication, an in-frame 3-bp deletion (842delGAG), and 2 missense (A84T and R149W) mutations. The 842delGAG and R149W mutations were identical to mutations reported in human. Prokaryotic expression of the 842delGAG and R149W mutations resulted in mutant enzymes with less than 1% wildtype activity, whereas the A84T mutation expressed a stable enzyme with approximately 35% of wildtype activity. The discolored teeth from the affected cats contained markedly elevated URO I and III, accounting for the CEP-like phenocopy. In 3 lines, the phenotype was an autosomal dominant trait, while affected cats with the A84T mutation were homozygous, a unique recessive form of AIP.
Yasuda et al. (2019) developed 2 separate mouse models with compound heterozygous missense mutations in the Hmbs gene: R167Q (609806.0005) and R173Q (609806.0006). Homozygosity for the R173Q mutation resulted in 1% of normal Hmbs activity and was embryonic lethal, whereas homozygosity for the R167Q mutation resulted in approximately 5% of normal Hmbs activity. Homozygous R167Q mice had elevated plasma and urinary 5-ALA and PBG at baseline, thought to be due to local production rather than transport through the blood brain barrier, and phenotypic features of delayed eye opening, severe early-onset ataxia, delayed motor development, and abnormal rotarod performance at 2 to 3 months of age, which progressively worsened. Brain myelination was delayed and total myelin volume was decreased by approximately 30% compared to wildtype littermates. In comparison to the T1/T2 mouse model of AIP, which has approximately 30% residual Hmbs activity, heme concentrations in liver and brain were similar, whereas 5-ALA and PBG concentrations were elevated in brain and CSF in R167Q mice. This suggests that the 5-ALA and PBG underlie the neurologic phenotype as opposed to reduced heme. Porphyrinogenic stimuli, including fasting and phenobarbital administration, led to no or mild changes in Alas1 mRNA levels and 5-ALA and PBG levels. R167Q homozygous mice had grossly normal brain and spinal cord at age 12 months and normal femoral nerve structures at age 6 months. (In the article by Yasuda et al. (2019), the mutations were also stated as Arg167Glu and Arg173Glu, which would be R167E and R173E, respectively. Yasuda (2020) confirmed that the mutations are Arg167Gln (R167Q) and Arg173Gln (R173Q).)
Berger et al. (2020) found that mice homozygous for the R167Q mutation in the Hmbs gene (609806.0005) showed depression-like behavioral abnormalities. RNA-seq analysis of hippocampal tissue from mutant mice showed differentially expressed genes (DEGs) compared to controls. The DEGs were involved in myelination in the CNS and oligodendrocyte development. Mutant mice had fewer hippocampal oligodendrocytes compared to controls and there was evidence of disrupted mitochondrial energy metabolism. Hippocampal neurons in mutant mice showed impaired neuronal cell proliferation and differentiation and aberrant synaptic plasticity. The findings implicated defective myelination as the pathogenic mechanism in the behavioral and neuronal plasticity defects and suggested that mitochondrial dysfunction may play a role.
In affected members of a large Dutch family with the nonerythroid variant of acute intermittent porphyria (AIP; 176000), Grandchamp et al. (1989) identified a heterozygous G-to-A transition in the 5-prime splice donor site of intron 1 of the HMBS gene. The mutation interrupted the sequence coding for the nonerythroid isoform of PBGD; thus, expression of the erythroid isoform was unaffected. Hybridization analysis using oligonucleotide probes after in vitro amplification of genomic DNA offered another possibility of detecting asymptomatic carriers of the mutation in affected families.
Puy et al. (1997, 1998) identified this splice site mutation in patients with nonerythroid variant AIP.
Petrides (1998) identified the G-to-A transition in intron 1 of the HMBS gene in 9 members of a German kindred in which the proband had a life-threatening coma due to the nonerythroid variant of AIP. The newly identified family members were taught how to prevent porphyric attacks.
In a patient with acute intermittent porphyria (AIP; 176000), Grandchamp et al. (1989) identified a heterozygous G-to-A transition in exon 12 of the HMBS gene, resulting in the skipping of exon 12. The resulting aberrant mRNA encoded a truncated protein that was inactive, but stable, and could be detected using antibodies directed against the normal enzyme (CRM-positive).
In a Finnish family with the nonerythroid variant of acute intermittent porphyria (AIP; 176000) Grandchamp et al. (1989) identified a G-to-T transversion in the 5-prime splice donor sequence of intron 1 of the HMBS gene. This is only 1 nucleotide removed from the mutation listed as 609806.0001, in which the change occurred in the first nucleotide of intron 1. Grandchamp et al. (1989) proposed that both of these mutations resulted in an abnormal splicing of primary transcripts initiated at the upstream promoter of the gene without affecting the expression of the PBGD gene in erythroid cells where the downstream promoter is utilized. A similar mutation located at the last position of exon 1 of the beta-globin gene was found by Vidaud et al. (1989) to be responsible for a splicing defect leading to beta-thalassemia.
In affected members of a Swedish family with acute intermittent porphyria (AIP; 176000), Lee et al. (1990) identified a C-to-T transition in exon 8 of the HMBS gene, resulting in an arg116-to-trp (R116W) substitution.
The R116W mutation was found by Gu et al. (1993) in 15 Dutch AIP families and in 1 French AIP family.
Acute Intermittent Porphyria
In patients with acute intermittent porphyria (AIP; 176000), Delfau et al. (1990) identified a heterozygous G-to-A transition in exon 10 of the HMBS gene, resulting in an arg167-to-gln (R167Q) substitution.
Porphyria-Related Encephalopathy
In a Dutch girl with porphyria-related encephalopathy (ENCEP; 620704) originally reported by Beukeveld et al. (1990), Picat et al. (1990) identified compound heterozygous missense mutations in the HMBS gene: R167Q and R173Q (609806.0006). The parents, who had classic AIP, were each heterozygous for 1 of the mutations.
In an English brother and sister with ENCEP, Llewellyn et al. (1992) identified compound heterozygosity for 2 mutations in the HMBS gene: a c.500G-A transition, resulting in an R167Q substitution, and a c.499C-T transition, resulting in an R167W substitution (609806.0013). Erythrocyte HMBS activity ranged from 14 to 17% of controls. Each clinically unaffected parent was heterozygous for 1 of the variants and had about a 50% reduction in HMBS activity.
Porphyria-Related Leukoencephalopathy
For discussion of the R167Q mutation (c.500G-A, NM_000190.3) in the HMBS gene that was found in compound heterozygous state with R225Q (609806.0047) in 2 Dutch families with porphyria-related leukoencephalopathy (LENCEP; 620711) by Kevelam et al. (2016) and Stutterd et al. (2021), see 609806.0047.
Variant Function
In in vitro studies, Solis et al. (2004) found that the R167Q variant had about 1% residual HMBS activity.
Acute Intermittent Porphyria
In patients with acute intermittent porphyria (AIP; 176000), Delfau et al. (1990) identified a heterozygous G-to-A transition in exon 10 of the HMBS gene, resulting in an arg173-to-gln (R173Q) substitution.
Kauppinen et al. (1992) identified the R173Q substitution in 3 out of 7 Finnish families with CRM-positive AIP.
Porphyria-Related Encephalopathy
In a Dutch patient with porphyria-related encephalopathy (ENCEP; 620704) originally reported by Beukeveld et al. (1990), Picat et al. (1990) identified compound heterozygous missense mutations in the HMBS gene: R173Q and R167Q (609806.0005). The parents, who had symptomatic AIP (the mother) or latent AIP (the father), were each heterozygous for 1 of the mutations and had about 50% decreased erythrocyte HMBS activity.
In 1 of 43 unrelated patients with acute intermittent porphyria (AIP; 176000), Scobie et al. (1990) identified a C-to-T transition in the HMBS gene, resulting in a gln155-to-ter (Q155X) substitution.
In a patient with acute intermittent porphyria (AIP; 176000), Delfau et al. (1991) identified a c.446G-A transition in exon 9 of the HMBS gene, resulting in an arg149-to-gln (R159Q) substitution.
In a patient with acute intermittent porphyria (AIP; 176000), Delfau et al. (1991) identified a c.734T-G transversion in exon 12 of the HMBS gene, resulting in a leu245-to-arg (L245R) substitution.
In a patient with CRM-positive acute intermittent porphyria (AIP; 176000), Delfau et al. (1991) identified a 1-bp deletion (c.900delT) in exon 1 of the HMBS gene, resulting in a stop codon located 15 codons downstream from the deletion.
In a patient with CRM-positive acute intermittent porphyria (AIP; 176000), Delfau et al. (1991) identified a deletion of the last 9 bp of exon 10. This resulted from abnormal splicing of intron 10 which was a consequence of a G-to-T substitution of the last base of exon 10.
In affected members of a northern Swedish (Lappland) family with acute intermittent porphyria (AIP; 176000), Lee and Anvret (1991) identified a G-to-A transition in exon 10 of the HMBS gene, resulting in a trp198-to-ter (W198X) substitution. The same mutation was found in 15 of 33 Swedish AIP families. Genealogic data showed that 12 of the 15 were related, indicating a founder effect.
Acute Intermittent Porphyria
The seemingly high frequency of mutations in exon 10 of the PBGD gene (Delfau et al., 1990) prompted Gu et al. (1992) to screen this exon in 41 unrelated patients with autosomal dominant AIP (AIP; 176000) by use of denaturing gradient gel electrophoresis (DGGE) after PCR amplification. In about one-fourth of the patients, they distinguished 3 abnormal migration patterns, indicating the presence of mutation in heterozygous state. Sequencing demonstrated the presence of 3 different single-base substitutions: R167Q (609806.0005), R173Q (609806.0006), and R167W.
In Finland, Kauppinen et al. (1992) found an R167W mutation in 3 out of 7 families with CRM-positive AIP. DNA analyses of family members demonstrated that conventional assays of erythrocyte PBGD activity identified correctly only 72% of the carriers of the mutation.
Porphyria-Related Encephalopathy
In an English brother and sister with porphyria-related encephalopathy (ENCEP; 620704), Llewellyn et al. (1992) identified compound heterozygosity for 2 mutations in the PBGD gene: a c.499C-T transition, resulting in an arg167-to-trp (R167W) substitution, and an adjacent c.500G-A transition, resulting in an R167Q (609806.0005) substitution. Erythrocyte HMBS activity was 14 to 17% of normal controls.
Solis et al. (2004) reported a Spanish patient with ENCEP who was homozygous for the R167W substitution. Both parents were heterozygous for the mutation. The patient had 1% residual HMBS activity. The clinically asymptomatic parents were heterozygous for the mutation and had about 50% HMBS activity. The proband had a severe disease course with psychomotor delay, dystonic movements, axial hypotonia, delayed myelination, and death at age 40 months.
Variant Function
Solis et al. (2004) noted that the R167W, R173Q, and R167Q mutations all occur at CpG dinucleotides within exon 10, and can thus be considered mutation hotspots. All 3 substitutions alter highly conserved arginines in the enzyme's active site, which interact with the precursor porphobilinogen and the acidic side chains of the enzyme's dipyrromethane cofactor. Functional expression studies showed that all 3 substitutions resulted in less than 2% normal HMBS activity.
Using site-directed mutagenesis, Lander et al. (1991) demonstrated that an arg167-to-leu (R167L) substitution in the HMBS protein resulted in a profound decrease of PBGD activity, consistent with acute intermittent porphyria (AIP; 176000). It is noteworthy that substitution of arg167 by glutamine (R167Q; 609806.0005) and by tryptophan (R167W; 609806.0013) resulted in loss of enzyme activity.
In a patient with CRM-positive acute intermittent porphyria (AIP; 176000), Llewellyn et al. (1993) identified a c.77G-A transition in exon 3 of the HMBS gene, resulting in an arg26-to-his (R26H) substitution.
In a patient with CRM-positive acute intermittent porphyria (AIP; 176000), Gu et al. (1994) identified a c.91G-A transition in exon 4 of the HMBS gene, leading to an ala31-to-thr (A31T) substitution.
In a patient with CRM-negative acute intermittent porphyria (AIP; 176000), Mgone et al. (1992) identified a c.100C-A transversion in exon 4 of the HMBS gene, resulting in a gln34-to-lys (Q34K) substitution.
In a patient with CRM-positive acute intermittent porphyria (AIP; 176000), Gu et al. (1994) identified a c.163G-T transversion in exon 5 of the HMBS gene, resulting in an ala55-to-ser (A55S) substitution.
In a patient with CRM-negative acute intermittent porphyria (AIP; 176000), Gu et al. (1994) identified a 1-bp deletion (c.174delC) in exon 5 of the HMBS gene. This frameshift mutation leads to a premature termination 40 codons downstream and a truncated protein.
In a patient with CRM-negative acute intermittent porphyria (AIP; 176000), Gu et al. (1994) identified a 1-bp insertion (c.182insG) in exon 5 of the HMBS gene. This frameshift mutation leads to a premature termination 5 codons downstream and a truncated protein.
In a patient with CRM-negative acute intermittent porphyria (AIP; 176000), Gu et al. (1994) identified a c.210G-A substitution in the first nucleotide of the donor splice site of intron 5 of the HMBS gene, resulting in abnormal splicing.
In a patient with CRM-negative acute intermittent porphyria (AIP; 176000), Gu et al. (1994) identified a 2-bp deletion (c.218delAG) in exon 6 of the HMBS gene. This frameshift mutation leads to a premature termination 9 codons downstream and a truncated protein.
In a patient with CRM-negative acute intermittent porphyria (AIP; 176000), Gu et al. (1994) identified a c.331G-A transition in exon 7 of the HMBS gene, resulting in a gly111-to-arg (G111R) substitution.
In Argentina, De Siervi et al. (1999) found that the G111R mutation was present in 12 of 26 (46%) presumably unrelated propositi with AIP; haplotype analysis with intragenic and flanking markers indicated an ancestral founder.
In a patient with acute intermittent porphyria (AIP; 176000), Lundin et al. (1994) identified a c.499G-A transition in the first nucleotide of the acceptor splice site of intron 9 of the HMBS gene, resulting in abnormal splicing.
In affected members of several unrelated Finnish and Dutch families with acute intermittent porphyria (AIP; 176000), Mgone et al. (1992) identified a c.530T-G transversion in exon 10 of the HMBS gene, resulting in a leu177-to-arg (L177R) substitution.
In a patient with acute intermittent porphyria (AIP; 176000), Lundin et al. (1994) identified a c.601C-T transition in exon 10 of the HMBS gene, resulting in an arg201-to-trp (R201W) substitution.
In a patient with CRM-negative acute intermittent porphyria (AIP; 176000), Gu et al. (1994) identified a c.667G-A transition in exon 12 of the HMBS gene, resulting in a glu223-to-lys (E223K) substitution.
In a patient with CRM-negative acute intermittent porphyria (AIP; 176000), Mgone et al. (1993) and Gu et al. (1994) identified a 2-bp deletion (c.730delCT) exon 12 of the HMBS gene. This frameshift mutation leads to a premature termination 6 codons downstream and a truncated protein.
In a patient with acute intermittent porphyria (AIP; 176000), Mgone et al. (1993) identified a c.739T-C transition in exon 12 of the HMBS gene, resulting in a cys247-to-arg (C247R) substitution.
In a patient with CRM-negative acute intermittent porphyria (AIP; 176000), Gu et al. (1994) identified an 8-bp insertion at position c.742 of the coding sequence in exon 12 of the HMBS gene. This frameshift mutation leads to a premature termination 10 codons downstream and a truncated protein.
In a patient with CRM-negative acute intermittent porphyria (AIP; 176000), Gu et al. (1994) identified a c.748G-A transition in exon 12 of the HMBS gene, resulting in a glu250-to-lys (E250K) substitution.
In a patient with acute intermittent porphyria (AIP; 176000), Mgone et al. (1993) identified a c.754G-A transition in exon 12 of the HMBS gene, resulting in an ala252-to-thr (A252T) substitution.
In a patient with acute intermittent porphyria (AIP; 176000), Mgone et al. (1993) identified a c.755C-T transition in exon 12 of the HMBS gene, resulting in an ala252-to-val (A252V) substitution.
In a patient with acute intermittent porphyria (AIP; 176000), Mgone et al. (1993) identified a c.766C-A transversion in exon 12 of the HMBS gene, resulting in a his256-to-asn (H256N) substitution.
In a Japanese patient with acute intermittent porphyria (AIP; 176000), Daimon et al. (1993) identified a c.771G-C transversion in the first nucleotide of the donor site of intron 12 of the HMBS gene, resulting in aberrant splicing and the skipping of exon 12.
In a patient with CRM-negative acute intermittent porphyria (AIP; 176000), Gu et al. (1993) identified a c.912G-A transition in the first nucleotide of the donor splice site of intron 14 of the HMBS gene, resulting in abnormal splicing and the skipping of exon 14.
In affected members of 28 Swedish families with CRM-negative acute intermittent porphyria (AIP; 176000), Lundin et al. (1997) identified a G-to-C transversion at the splice donor site of intron 6 of the HMBS gene.
In affected members of a Swedish family with CRM-negative acute intermittent porphyria (AIP; 176000), Lundin et al. (1997) identified a c.646G-A transition in exon 11 of the HMBS gene, resulting in a gly216-to-asp (G216D) substitution.
In affected members of a Swedish family with acute intermittent porphyria (AIP; 176000), Lundin et al. (1997) identified a 2-bp deletion (c.847delTG) in exon 14 of the HMBS gene, resulting in an mRNA translational frameshift.
Mustajoki et al. (1999) reported a large Finnish family in which an Alu element interfered with the coding region of the PBGD gene, resulting in acute intermittent porphyria (AIP; 176000). A 333-bp Alu sequence was directly inserted into exon 5 in antisense orientation. Mustajoki et al. (1999) noted that this Alu cassette belongs to a Ya5 subfamily, one of the evolutionarily youngest and at that time most active Alu subfamilies.
Whatley et al. (2000) identified a 1-bp deletion (-154delG) in the promoter region of the HMBS gene as the cause of the nonerythroid variant of acute intermittent porphyria (AIP; 176000). Reporter gene and electromobility shift assays showed that the G nucleotide at position -154, the most 5-prime of several transcription initiation sites in the ubiquitous HMBS promoter, which lies immediately 3-prime to a transcription factor IIB binding motif, is essential for normal transcription.
Whatley et al. (2000) identified a 1-bp deletion (c.41delA) in exon 3 of the HMBS gene as the cause of the nonerythroid variant of acute intermittent porphyria (AIP; 176000). The frameshift mutation introduced a stop codon into mRNA for the ubiquitous isoform only.
In a patient with acute intermittent porphyria (AIP; 176000), Chen et al. (1994) identified a heterozygous c.848G-A transition in exon 14 of the HMBS gene, resulting in a trp283-to-ter (W283X) substitution.
Nearly 60% of all Swiss AIP patients carry the W283X mutation. In France, the prevalence of W283X is less than 5% (Schneider-Yin et al., 2002). In 12 of 25 AIP families of Swiss and French origin, Schneider-Yin et al. (2002) identified a common haplotype containing the W283X HMBS mutation. The authors suggested that a single mutational event took place approximately 40 generations ago (i.e., 1,000 years ago).
In a patient with the nonerythroid variant of acute intermittent porphyria (AIP; 176000), Chen et al. (1994) identified a heterozygous c.3G-A transition in exon 1 of the HMBS gene, resulting in a met1-to-val (M1V) substitution in the initiation of translation codon for the housekeeping transcript. Thus, translation of the erythrocyte transcript was unaffected.
In a 7-year-old boy, born of consanguineous Turkish parents, with porphyria-related encephalopathy (ENCEP; 620704), Hessels et al. (2004) identified a homozygous leu81-to-pro (L81P) substitution in exon 6 of the HMBS gene. Porphobilinogen activity in red cells was decreased to 2 to 4%. Both parents were heterozygous and asymptomatic. Leu81 in PBG deaminase is an evolutionarily conserved residue in the second alpha helix, suggesting its structural importance for preservation of enzyme activity.
In affected members of 2 Finnish families with acute intermittent porphyria (AIP; 176000), Kauppinen et al. (1995) identified a heterozygous c.445C-T transition in exon 9 of the HMBS gene, resulting in an arg149-to-ter (R149X) substitution.
Poblete-Gutierrez et al. (2006) identified a heterozygous R149X substitution in affected members of the original family with so-called 'Chester type porphyria' (McColl et al., 1985) (see 176000). The mutation was not found in 200 control chromosomes. The family had originally been reported as having features of both AIP and variegated porphyria (VP; 176200), but no mutations in the PPOX gene (600923) were identified. The mutation occurred at a hypermutable CpG dinucleotide. The findings confirmed that Chester type porphyria is a variant of AIP. Poblete-Gutierrez et al. (2006) suggested that the original biochemical studies indicating PPOX deficiency may have been erroneous or misinterpreted. A different mutation in this codon has also been associated with AIP (R149Q; 609806.0008).
In 3 adult sibs, born of unrelated Dutch parents, with slowly progressive porphyria-related leukoencephalopathy (LENCEP; 620711), Kevelam et al. (2016) identified compound heterozygous missense mutations in the HMBS gene: a c.674G-A transition in exon 12, resulting in an arg225-to-gln (R225Q) substitution, and R167Q (609806.0005). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. HMBS erythrocyte activity ranged from 55 to 67% of normal controls in the affected sibs, similar to heterozygous carriers of HMBS mutations. At least 2 unaffected sibs carried a heterozygous R225Q variant; HMBS activity was 83% of controls in 1 and 105% of controls in the other. Urine and plasma PBG were mildly elevated (2- to 4-fold increase in urine) in the affected sibs, but not in the unaffected carrier sibs. Plasma ALA levels were borderline elevated in both affected and unaffected sibs. Kevelam et al. (2016) noted that both the R225Q and R167Q mutations had been reported in the heterozygous state in patients with autosomal dominant acute intermittent porphyria (AIP; 176000). The authors concluded that either the mildly reduced enzyme activity with mildly elevated ALA and PBG did not cause the chronic leukoencephalopathy observed in the 3 sibs with biallelic variants, or that the enzyme activity in erythrocytes does not reflect enzyme activity in the brain.
In a 45-year-old man (P3), born of unrelated Dutch parents (family 2), with LENCEP, Stutterd et al. (2021) identified compound heterozygosity for the R225Q (c.674G-A, NM_000190.3) and R167Q mutations. His mother, who was heterozygous for the R167Q mutation, had latent AIP; his father was unavailable for testing. A measurement of HMBS enzyme activity was not available for P3. Stutterd et al. (2021) noted that the pathogenicity of the R225Q variant has not been conclusively demonstrated and that previous functional studies have yielded conflicting results of the effect of this variant on HMBS enzyme activity.
In 2 adult sibs, born of consanguineous Lebanese parents (family 1), with slowly progressive porphyria-related leukoencephalopathy (LENCEP; 620711), Stutterd et al. (2021) identified a homozygous c.251C-A transversion (c.251C-A, NM_000190.3) in the HMBS gene, resulting in an ala84-to-asp (A84D) substitution at a conserved residue in the second alpha-helix. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not present in the gnomAD database. Erythrocyte HMBS enzyme activity ranged from 13 to 18% of normal control values in the sibs. HMBS erythrocyte activity in an unaffected sib who was heterozygous for the mutation was 50% of normal. The patients had onset of progressive neurologic symptoms in the first decade.
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