Alternative titles; symbols
HGNC Approved Gene Symbol: GLA
SNOMEDCT: 124464003, 16652001; ICD10CM: E75.21;
Cytogenetic location: Xq22.1 Genomic coordinates (GRCh38) : X:101,397,803-101,407,925 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq22.1 | Fabry disease | 301500 | X-linked | 3 |
| Fabry disease, cardiac variant | 301500 | X-linked | 3 |
The GLA gene encodes alpha-galactosidase (GLA; EC 3.2.1.22), a lysosomal hydrolase.
Calhoun et al. (1985) isolated clones corresponding to the GLA gene from a human liver cDNA library. The 370-amino acid protein has a molecular mass of 41.4 kD. The mature active enzyme is a homodimeric protein.
Bishop et al. (1986) isolated GLA cDNA clones and found an open reading frame of 398 residues with a molecular mass of 45.4 kD. RNA transfer hybridization analysis detected a 1.45-kb transcript. Bishop et al. (1988) determined that the GLA gene lacks a 3-prime untranslated sequence, with the polyadenylation signal included in the coding region. Kornreich et al. (1989) presented the complete nucleotide sequence of the GLA gene.
Using RT-PCR amplification of genomic GLA DNA isolated from normal individuals, Novo et al. (1995) found that a subset of RNA molecules had a 1187U-A conversion which differed from the wildtype cDNA sequence. Multiple genes, pseudogenes, or allelic variants were excluded. Novo et al. (1995) proposed RNA editing as a mechanism responsible for this base change in the GLA RNA, similar to that which has been demonstrated for the nuclear encoded RNA for intestinal apoB (107730) and several subunits of brain L-glutamate receptors such as GLUR2 (138247), GLUR5 (138245), and GLUR6 (138244).
Bishop et al. (1988) determined that the GLA gene contains 7 exons and spans about 12 kb.
The GLA gene was localized to the X chromosome using cell hybridization techniques (Grzeschik, 1972).
From study of radiation-induced segregants in which irradiated human cells are rescued by fusion with hamster cells, Goss and Harris (1977) showed that the order of the following 4 loci on Xq is PGK--alpha-GAL--HPRT--G6PD and that the 3 intervals between these 4 loci are, in relative terms, 0.33, 0.30, and 0.23.
Lusis and West (1976) reported X-linked inheritance of the Gla gene in the mouse. Alpha-GAL, HPRT, PGK and G6PD are X-linked in the rabbit, according to mouse-rabbit hybrid cell studies (Cianfriglia et al., 1979; Echard and Gillois, 1979). By comparable methods, Hors-Cayla et al. (1979) found them to be X-linked also in cattle. Francke and Taggart (1979) assigned HPRT and alpha-GAL to the X chromosome in the Chinese hamster by study of mouse-Chinese hamster hybrid cells.
Davies et al. (1993) demonstrated 3 polymorphic variants in the first exon of the GLA gene, which contains 60 bp of 5-prime untranslated sequence before the methionine initiation codon. Such a high level of polymorphism had not previously been reported and was unusual in such a short stretch of DNA.
In a patient with Fabry disease (301500), Bernstein et al. (1989) identified a mutation in the GLA gene (300644.0001). The substitution altered the enzyme's kinetic properties and stability.
Eng et al. (1993) identified 18 different mutations in the GLA gene (see, e.g., 300644.0012; 300644.0013; 300644.0018-300644.0022) in patients with Fabry disease.
Lai et al. (2003) pointed out that most of the mutations in the GLA gene were identified in Fabry disease patients by genomic sequencing only, and therefore some of the splicing mutations were misclassified as missense mutations. To predict splicing events caused by specific mutations, they conducted a literature search for all published GLA mutations located near splice sites, including exonic point mutations, and performed a splice site score (SSS) analysis. They found 13 donor site mutations, 6 acceptor site mutations, and 1 new exon creation. All mutated splice sites, except for the 1 associated with new exon creation, had a lower SSS than their respective natural sites.
Yasuda et al. (2003) noted that the human GLA gene is one of the rare mammalian genes that has its polyadenylation signal in the coding sequence and lacks a 3-prime untranslated region. In 2 unrelated men with classic Fabry disease, they identified 2 novel frameshift mutations, 1277delAA (300644.0060) and 1284delACTT (300644.0061), which occurred in the 3-prime terminus of the coding region and obliterated the termination codon; the 2-bp deletion also altered the polyadenylation signal. Both mutations generated multiple transcripts of various lengths of 3-prime terminal sequences, some elongated by approximately 1 kb. Northern blot analysis suggested that mRNA degradation did not occur.
Splicing Patterns
In the context of examining splice site mutations in the GLA gene, Lai et al. (2003) discussed the 5 major aberrant splicing patterns caused by mutations in general: exon skipping, cryptic site activation, new site creation, intron retention, and disruption of exonic splicing enhancers (Nakai and Sakamoto, 1994; Cooper and Mattox, 1997). The selection of splicing patterns is based on many factors. When no strong cryptic site or newly created site is available, destruction of either the donor or acceptor splice site causes skipping of the neighboring exon. Cryptic splice sites are normally silent consensus sites that are activated when the authentic site is destroyed by mutation. In general, the distance between the authentic site and the cryptic site is about 100 nucleotides long. Mutations also can result in the creation of a new splice site, which may or may not be associated with destruction of the authentic site. If the authentic site is not altered, the new splice site is always in the upstream region of the authentic site. Intron retention occurs infrequently and sometimes simultaneously with other splicing patterns. Cis element exonic splicing enhancers (ESE) also have a role in the regulation of splicing. See the report of Liu et al. (2001) showing that disruption of an exonic splicing enhancer resulted in missplicing of exon 18 in the BRCA1 gene (113705). Similar mechanisms may explain why many exonic missense or nonsense mutations that are not located at splice sites are associated with exon skipping.
Using the x-ray crystal structure of human alpha-galactosidase reported by Garman and Garboczi (2004), Matsuzawa et al. (2005) performed computerized 3-dimensional structural analysis of the mutant enzyme resulting from 161 missense mutations in the GLA gene causing Fabry disease. Mutations resulting in the severe classic phenotype showed a wide distribution in the number of atoms affected by the mutation, but the majority (82%) had 3 or more affected atoms in the main chain of the protein. Nineteen classic mutations affected the active site or the substrate-binding site of the enzyme. By contrast, 85% of mutations resulting in the milder variant phenotype had less than 3 atoms influenced in the main chain, and none of the variant mutations affected the active site. These results suggested that variant Fabry mutations cause small changes that do not affect the whole protein structure.
Matsuzawa et al. (2005) performed further analysis of 11 specific mutations in the GLA gene, which the authors subdivided into 4 groups according to the clinical and biochemical phenotypes of Fabry disease: classic with a completely dysfunctional and ineffective protein; classic with an unstable and ineffective protein; classic with an unstable but moderately effective protein; and variant with an unstable but effective protein. In particular, the G328R (300644.0010) mutation, which results in an unstable, ineffective protein, had 77 and 53 affected atoms in the main and side chains, respectively. The variant mutations Q279E (300644.0008) and M296I (300644.0051) were located apart from the active site and affected less than 3 atoms each in the main chain.
In a Japanese patient with the cardiac variant of Fabry disease, Ishii et al. (1992) identified a mutation in the GLA gene (300644.0008) associated with residual GLA enzyme activity. The patient developed dyspnea and bradycardia for the first time at age 60 years and died of heart failure at age 64. He was found to have complete left bundle branch block associated with hypertrophy of the left ventricular wall and interventricular septum. He had no other signs or symptoms characteristic of Fabry disease except proteinuria, which was found after cardiac failure had developed. Myocardial biopsy had shown inclusion bodies on electron microscopic examination. A 39-year-old nephew was asymptomatic but showed a thick interventricular septum and left ventricular wall by echocardiography and magnetic resonance imaging. The mutation in this case, as in 2 other cases of the cardiac form (300644.0003, 300644.0005), was located in exon 6.
Oliveira et al. (2020) reported 11 symptomatic Portuguese males from 10 families with Fabry disease who had a hemizygous F113L (300644.0063) mutation in the GLA gene. All of the patients had a late-onset form of the disorder, manifesting with a cardiac phenotype invariably including cardiomyopathy/hypertrophic cardiomyopathy, and often including other features such as conduction defects, arrhythmias, and myocardial ischemia. Some patients also had cerebrovascular or kidney involvement, although the association with the GLA mutation was confounded by the presence of other risk factors (e.g., hypertension, diabetes, obesity).
In a population of 150 adults with hypertrophic cardiomyopathy in Guimaraes, Portugal, Azevedo et al. (2020) identified 25 patients with Fabry disease, 21 of whom were hemizygous or heterozygous for the F113L mutation in the GLA gene. Genealogy studies demonstrated a common ancestor in 17 of the 21 patients. Through pedigree analysis in these patients, Azevedo et al. (2020) identified 120 patients, including 47 males and 73 females, with Fabry disease due to the F113L mutation. The mean age at diagnosis was 46 years, which was similar in both genders. Left ventricular hypertrophy (LVH) was identified in 49 patients, with a male predominance, and most patients were diagnosed with LVH at or after 40 years of age. Albuminuria was identified in 36.1% of patients; however, renal insufficiency was rare and no patient progressed to dialysis. Acroparesthesias were more common in females (34.2% of females and 6.4% of males). Sensorineural hearing loss was more common in males (30.8% of females and 64.4% of males). Strokes and angiokeratomas were rare. Azevedo et al. (2020) concluded that the F113L mutation in the Guimaraes region of Portugal was associated with a cardiac-predominant, late-onset form of Fabry disease.
In a patient with Fabry disease (301500), Bernstein et al. (1989) identified a 1066C-T transition in the GLA gene, resulting in an arg356-to-trp (R356W) substitution. The substitution altered the enzyme's kinetic properties and stability.
Fukuhara et al. (1990) reported partial deletion of the GLA gene in a case of Fabry disease (301500). The deletion involved exon 3 and was associated with an A-to-C transversion. The 402-bp deletion was flanked by 6-bp direct repeat sequences. These structures may have promoted 'slipped mispairing' as the origin of the mutation in this family.
In a Japanese patient with Fabry disease following an atypical clinical course characterized by late-onset cardiac involvement and significant residual GLA (see 301500), Sakuraba et al. (1990) identified a G-to-A transition in exon 6 of the GLA gene, resulting in an arg301-to-gln (R301Q) substitution.
Sawada et al. (1996) identified the R301Q substitution in a 45-year-old man who developed moderate proteinuria and was found to have the renal histologic findings of Fabry disease, together with a decrease in activity of alpha-galactosidase A in his plasma, urine, leukocytes, and skin fibroblasts. The mutation was inherited from his mother. The patient was unique in that he demonstrated only renal manifestations, whereas all other patients with atypical Fabry disease, including a case with the identical point mutation (Sakuraba et al., 1990), presented with cardiomyopathy.
Kase et al. (2000) characterized this mutant and another, Q279E (300644.0008), in a patient with the cardiac variant of Fabry disease. In contrast to patients with classic Fabry disease, who have no detectable alpha-galactosidase activity, patients with these variants have residual enzyme activity. Compared to normal control cells, fibroblasts from a patient with the Q279E mutation secreted only small amounts of alpha-galactosidase. The authors concluded that these 2 substitutions do not significantly affect enzymatic activity, but the mutant protein levels are decreased presumably in the endoplasmic reticulum of cells.
In a Japanese patient with classic Fabry disease (301500) and no detectable alpha-galactosidase A activity, Sakuraba et al. (1990) found a G-to-A transition in exon 1 of the GLA gene, resulting in a trp44-to-ter (W44X) substitution.
In a 54-year-old man with the cardiac variant of Fabry disease (see 301500), von Scheidt et al. (1991) identified an 886A-G transition in exon 6 of the GLA gene, resulting in a met296-to-val (M296V) substitution. The patient had 'crescendo angina,' relieved by nitroglycerin, as well as electrocardiographic changes, but normal cardiac chamber size and normal systolic and diastolic function by echocardiogram. Cardiac catheterization showed no stenoses of the extramural coronary arteries. Diagnosis of Fabry disease was made by endomyocardial biopsy. Light-microscopic examination showed that approximately half the myocytes contained a centrally stored foamy material that stained metachromatically. By electron microscopy, typical myelin-figure-like concentric lamellar inclusions in lysosomes were observed. Most remarkably, the endothelial cells of the myocardial capillaries were not involved and no changes were observed in specimens of skeletal muscle, liver, rectum, and skin, including small blood vessels and nerves.
In an 11-year-old boy with Fabry disease (301500), Yokoi et al. (1991) identified a G-to-A transition at the 3-prime consensus sequence (splicing acceptor) of intron 3 of the GLA gene. The mutation resulted in deletion of exon 4 and a frameshift with appearance of a terminating codon in exon 5.
In 3 affected brothers from a Japanese family with Fabry disease (301500), Sakuraba et al. (1992) identified deletion of exon 6 due to a G-to-T transversion at the first nucleotide of the 5-prime splice site of intron 6 of the GLA gene. Sakuraba et al. (1992) stated that this was the first G-to-T transversion of a mammalian 5-prime splice site that consistently eliminated the preceding exon. Sakuraba et al. (1992) gave a tabulation of various mammalian 5-prime consensus splice site mutations that lead to exon skipping and in most cases use of cryptic splice sites. They pointed out that glycophorin B (GYPB; 617923) of the Ss blood group (111740) differs from glycophorin A (GYPA; 617922) of the MN blood group (111300) by 2 changes at the 5-prime splice site of intron 3 which presumably took place after duplication of the progenitor gene. As indicated in their Table 1, the gene for growth hormone-like (GH2; 139240) differs from that for growth hormone (GH1; 139250) by a G-to-A transition at position +1 of intron 2 in the duplicated gene (Chen et al., 1989).
Ishii et al. (1992) identified an 835C-G transversion in the GLA gene, resulting in a gln279-to-glu (Q279E) substitution, in a Japanese patient with the cardiac variant of Fabry disease (see 301500). The patient developed dyspnea and bradycardia for the first time at age 60 years and died of heart failure at age 64. He was found to have complete left bundle branch block associated with hypertrophy of the left ventricular wall and interventricular septum. He had no other signs or symptoms characteristic of Fabry disease except proteinuria, which was found after cardiac failure had developed. Myocardial biopsy had shown inclusion bodies on electron microscopic examination. A 39-year-old nephew was asymptomatic but showed a thick interventricular septum and left ventricular wall by echocardiography and magnetic resonance imaging. Both men had some residual alpha-galactosidase A activity. The mutation in this case, as in 2 other cases of the cardiac form (300644.0003, 300644.0005), was located in exon 6. On the other hand, the gly328-to-arg mutation, located at the 3-prime end of exon 6 was associated with classic features of Fabry disease (see 300644.0010).
Koide et al. (1990) described a pro40-to-ser (P40S) mutation in exon 1 of the GLA gene in a patient with Fabry disease (301500) and no detectable alpha-galactosidase A activity.
In a 34-year-old man with typical Fabry disease (301500), Ishii et al. (1992) identified a 982G-A transition in exon 6 of the GLA gene, resulting in a gly328-to-arg (G328R) substitution. This mutation was located at the 3-prime end of exon 6; mutations located at the central or 5-prime end of the exon were associated with the predominantly cardiac form of the disease.
In a 14-year-old boy with classic Fabry disease (301500), Ishii et al. (1992) found 2 point mutations in exon 2 of the GLA gene: a GAG-to-CAG change causing a glu66-to-gln (E66Q) substitution, and a CGC-to-TGC change causing an arg112-to-cys (R112C) substitution.
Lee et al. (2010) presented evidence that the E66Q variant is a functional polymorphism and not disease causing. Substantial residual GLA activity was shown both in the leukocytes of individuals carrying E66Q (19.0 to 30.3% of normal activity) and in transiently overexpressed COS-7 cells (43.8% of normal activity). Although the E66Q-variant GLA was unstable at neutral pH, the enzyme was efficiently expressed in the lysosomes of COS-7 cells. The allele frequency of E66Q determined in 833 unrelated Korean individuals was considered to be high at 1.046%. The variant was found in 5 individuals from 4 Korean families during a screen of patients with Fabry disease. Of the 5 patients carrying E66Q, only 1 patient had proteinuria, and 2 had hypertrophic cardiomyopathy without other signs of the disorder. Lee et al. (2010) suggested that either these patients had a different etiology for their features or that they had a very mild atypical variant of the disease with other genetic or environmental factors contributing to the phenotype.
In a patient with classic Fabry disease (301500), Eng et al. (1993) found an A-to-G transition in exon 1 of the GLA gene, resulting in an asn34-to-ser (N34S) substitution.
In an English patient with classic Fabry disease (301500), Eng et al. (1993) found a T-to-G transversion in exon 1 of the GLA gene, resulting in a cys56-to-gly (C56G) substitution.
In a Dutch patient with mild Fabry disease (301500), deJong et al. (1993) found a C-to-T transition in exon 3 of the GLA gene, resulting in a pro146-to-ser (P146S) substitution.
In a Danish patient with classic Fabry disease (301500), Madsen et al. (1993) found a G-to-A transition in exon 3 of the GLA gene, resulting in an ala156-to-thr (A156T) substitution.
In an Italian patient with classic Fabry disease (301500), Eng et al. (1993) found a T-to-C transition in exon 3 of the GLA gene, resulting in a trp162-to-arg (W162R) substitution.
In a Dutch patient with classic Fabry disease (301500), deJong et al. (1993) found a T-to-G transversion in exon 4 of the GLA gene, resulting in a cys202-to-trp (C202W) substitution.
Eng et al. (1993) and Davies et al. (1993) described an A-to-G transition in exon 5 of the GLA gene, resulting in an asn215-to-ser (N215S) substitution. The patients had mild forms of Fabry disease (301500) and residual enzyme activity.
In a patient with classic Fabry disease (301500), Eng et al. (1993) described an G-to-A transition in exon 5 of the GLA gene, resulting in an arg227-to-gln (R227Q) substitution. This mutation conforms to the CG-to-TG mutation 'hotspot' rule. In the complementary, antisense strand, 5-prime--xxxCGAxxx--3-prime is read as 3-prime--xxxGCTxxx--5-prime. Methylation of the cytosine in the CpG of the antisense codon with subsequent deamidation converts the antisense codon to GTT, which corresponds to the sense codon CAA. Read 5-prime to 3-prime, the CG in the sense strand has been changed to TG in the antisense strand; hence, the designation CG-to-TG 'hotspot' rule.
In patients with Fabry disease (301500), Eng et al. (1993) and Davies et al. (1993) identified a C-to-T transition in exon 5 of the GLA gene, resulting in an arg227-to-ter (R227X) substitution. The mutation conforms to the CG-to-TG rule and has been found in more than 1 unrelated patient.
In a Scottish/English patient with classic Fabry disease (301500), Eng et al. (1993) found an A-to-T transversion in exon 5 of the GLA gene, resulting in an asp264-to-val (D264V) substitution.
In an African American patient with classic Fabry disease (301500), Eng et al. (1993) found an A-to-T transversion in exon 5 of the GLA gene, resulting in an asp266-to-val (D266V) substitution.
In an English patient with classic Fabry disease (301500), Davies et al. (1993) found a GTG-to-GCG mutation in exon 6 of the GLA gene, resulting in a val269-to-ala (V269A) substitution.
In an English patient with classic Fabry disease (301500), Davies et al. (1993) found a TGG-to-TGA mutation in exon 6 of the GLA gene, resulting in a trp287-to-ter (W287X) substitution.
In an Italian patient with classic Fabry disease (301500), Eng et al. (1993) found a TCT-to-TTT mutation in exon 6 of the GLA gene, resulting in a ser297-to-phe (S297F) substitution.
This variant, formerly titled FABRY DISEASE, has been reclassified based on the findings of Yasuda et al. (2003).
In a German patient with classic Fabry disease (301500), Eng et al. (1993) found a GAT-to-TAT mutation in exon 6 of the GLA gene, resulting in an asp313-to-tyr (D313Y) substitution.
Yasuda et al. (2003) found that expression of the D313Y variant in COS-7 cells resulted in 60% residual enzyme activity and that the enzyme was localized to lysosomes. In addition, the D313Y variant was found in 0.45% of 883 normal X chromosomes. Molecular homology modeling showed that the D313Y variant did not markedly disrupt enzyme structure. The variant enzyme was stable at lysosomal pH (4.5), but had decreased activity at neutral pH (7.4). Overall, the findings suggested that the D313Y variant is a functional polymorphism rather than a disease-causing variant.
Lenders et al. (2013) noted that the possible pathogenicity of the D313Y variant is controversial. They reported a large family in which 9 females and 1 male carried a heterozygous D313Y mutation; one of the females with the variant was deceased. Seven of the 8 who underwent brain imaging had multifocal white matter lesions, including several young individuals without cardiovascular risk factors. The white matter lesions were primarily subcortical and punctate, but some also were confluent with a periventricular localization. Brain MRI in 2 family members who did not carry the D313Y variant showed no white matter lesions. GLA enzyme activities were normal in carrier leukocytes, but were decreased in plasma. Lyso-Gb3 levels in plasma, which are increased in patients with Fabry disease, were normal. The proband, who carried the D313Y variant, had a peripheral small-fiber neuropathy with decreased intraepithelial nerve fiber density on nerve biopsy. None of the variant carriers had other evidence of Fabry disease, but Lenders et al. (2013) postulated that the D313Y variant may act as a predisposing factor for neurologic manifestations.
Niemann et al. (2013) reported a father and daughter with the D313Y variant. The daughter presented with diffuse skin lesions and nonspecific arm pain. Plasma GLA enzyme activity was mildly decreased. Skin biopsy showed keratosis pilaris rubra atrophicans, but no Fabry angioma. Her 53-year-old father had no clinical manifestations of Fabry disease, although his plasma GLA enzyme activity was also decreased. Lyso-Gb3 was below normal in the daughter and undetectable in the father. Niemann et al. (2013) concluded that the D313Y variant is not clinically relevant for Fabry disease. The authors also suggested that pure assessment of GLA activity and even genetic testing is not sufficient for diagnosing Fabry disease.
In an English patient with classic Fabry disease (301500), Davies et al. (1993) found a CAA-to-AAA mutation in exon 6 of the GLA gene, resulting in a gln327-to-lys (Q327K) substitution.
In a Scottish/Irish patient with classic Fabry disease (301500), Eng et al. (1993) found a GGG-to-GCG mutation in exon 6 of the GLA gene, resulting in a gly328-to-ala (G328A) substitution. A different mutation has also been described in the same codon (see 300644.0010).
In an African American patient with classic Fabry disease (301500), Eng et al. (1993) found a nonsense TGG-to-TGA mutation in exon 7 of the GLA gene, resulting in a trp340-to-ter (W340X) substitution.
In a Dutch patient with classic Fabry disease (301500), deJong et al. (1993) found a CGA-to-CAA mutation in exon 7 of the GLA gene, resulting in an arg342-to-gln (R342Q) substitution. This mutation conforms to the CG-to-TG 'hotspot' rule.
Germain (2001) described a patient with Fabry disease due to the R342Q mutation who also had Klippel-Trenaunay-Weber syndrome (149000). The 30-year-old man had a complex vascular and cutaneous malformation. Skin examination showed numerous angiokeratomas, which had developed only on the right part of the body, with a sharp delineation in the midline of the trunk. The R342Q mutation was demonstrated in DNA extracted from fibroblast cultures established from both affected and unaffected skin areas, thus excluding the hypothesis of somatic mosaicism or revertant mosaicism. The patient had hypertrophy of the right leg, with dilated and varicose superficial veins.
In a Greek/English patient with classic Fabry disease (301500), Davies et al. (1993) found a CGA-to-TGA mutation in exon 7 of the GLA gene, resulting in an arg342-to-ter (R342X) substitution.
In an English patient with classic Fabry disease (301500), Davies et al. (1993) found a GGA-to-CGA mutation in exon 7 of the GLA gene, resulting in a gly361-to-arg (G361R) substitution.
In a Hispanic patient with classic Fabry disease (301500), Eng et al. (1993) found a nonsense GAA-to-TAA mutation in exon 7 of the GLA gene, resulting in a glu398-to-ter (E398X) substitution.
In a Sephardic Jewish patient with classic Fabry disease (301500), Eng et al. (1993) found a T-to-G mutation at nucleotide +2 of the donor splice site of intron 2 of the GLA gene.
In an Irish patient with classic Fabry disease (301500), Eng et al. (1993) found a deletion of 2 nucleotides (-2 and -3) of the acceptor splice site of intron 5 of the GLA gene. The mutation is therefore tcag/exon 6 to tg/exon 6.
In a 34-year-old man with Fabry disease (301500), Nance et al. (2006) identified a G-to-A transition in the GLA gene, resulting in an ala143-to-thr (A143T) substitution. The patient had a 5-year history of progressive activity-induced leg and foot cramps and fasciculations with pain. No other stigmata of Fabry disease was present. His mother, who also carried the mutation, had a similar phenotype.
In a Japanese patient with severe Fabry disease (301500), Ishii et al. (1991) identified a 13-bp deletion in exon 1 of the GLA gene. The deletion is flanked by a TGGG direct repeat.
In an English patient with severe Fabry disease (301500), Davies et al. (1993) found a 1-bp deletion at nucleotide 716 in exon 5 of the GLA gene.
In a Portuguese patient with severe Fabry disease (301500), Eng et al. (1993) found a 2-bp deletion at nucleotide 773 in exon 5 of the GLA gene.
In a German patient with severe Fabry disease (301500), Eng et al. (1993) found a 5-bp insertion starting at nucleotide 954 of exon 6 of the GLA gene.
In a German patient with severe Fabry disease (301500), Eng et al. (1993) found an 11-bp deletion starting at nucleotide 1016 of exon 7 of the GLA gene.
In a Dutch patient with severe Fabry disease (301500), deJong et al. (1993) found a 1-bp insertion at nucleotide 1040 of exon 7 of the GLA gene.
In a Dutch patient with severe Fabry disease (301500), Eng et al. (1993) found a 53-bp deletion starting at nucleotide 1123 of exon 7 of the GLA gene.
In a Dutch patient with severe Fabry disease (301500), deJong et al. (1993) found a 2-bp deletion at nucleotide 1176 of exon 7 of the GLA gene. The deletion had a 6-bp inverted repeat at the breakpoint junction.
In an English patient with moderate Fabry disease (301500), Eng et al. (1993) found a 3-bp deletion (1208delAAG) in exon 7 of the GLA gene, resulting in the deletion of arg405.
In a Slavic patient with severe Fabry disease (301500), Kornreich et al. (1990) found a 4.6-kb deletion that included exons 1 and 2 of the GLA gene. The deletion breakpoints had a CCA direct repeat suggesting a possible functional role of this short sequence in illegitimate recombination.
In affected members of a Hispanic family with severe Fabry disease (301500), Kornreich et al. (1990) found a 3.2-kb deletion in the GLA gene that included exons 3 and 4. The 2 breakpoints occurred in Alu repetitive elements and Alu-Alu recombination is the probable mechanism of this deletion.
In an English patient with severe Fabry disease (301500), Kornreich et al. (1990) found a 4.5-kb deletion in the GLA gene that included exons 3 to 6 and a portion of exon 7. The deletion breakpoints had an AAG direct repeat suggesting a possible functional role of this short sequence in illegitimate recombination.
In an Irish/German patient with severe Fabry disease (301500), Kornreich et al. (1990) found a deletion of 1.7 kb in the GLA gene that included exons 6 and 7.
In an English patient with severe Fabry disease (301500), Kornreich et al. (1990) found a duplication of 8.1 kb that included exons 2 to 5 and part of exon 6 of the GLA gene. The duplicated area was flanked by a TAGACA direct repeat.
In a study of left ventricular hypertrophy in Japan, Nakao et al. (1995) found 7 of 230 males (3%) with low plasma alpha-galactosidase activity but none of the typical manifestations of Fabry disease (see 301500), namely, angiokeratoma, acroparesthesias, hypohidrosis, or corneal opacities. One of the patients had a met296-to-ile (M296I) mutation in exon 6 of the GLA gene, whereas a second had an ala20-to-pro (A20P) mutation in exon 1 (300644.0052).
See 300644.0051 and Nakao et al. (1995).
Cariolou et al. (1996) described a novel trinucleotide deletion in the GLA gene in a Greek patient with Fabry disease (301500). This deletion led to loss of phenylalanine-383. The phenotype in this patient was unusual in that diffuse facial telangiectasia was present.
In 2 unrelated Chinese patients with Fabry disease (301500), living in Taiwan, Chen et al. (1998) identified a G-to-C transversion in the last nucleotide of exon 1 of the GLA gene, which not only resulted in a ser65-to-thr (S65T) substitution but probably also caused a splicing defect.
Lai et al. (2003) demonstrated that the S65T mutation does not affect enzyme function. Instead it results in activation of a weak cryptic site 14 nucleotides downstream and results in an insertion of 14 bp and a frameshift stop at codon 106. This splicing abnormality was thought to be more consistent with the clinical presentation of the patient with classic Fabry disease.
In affected members of a family with Fabry disease (301500), Miyamura et al. (1996) identified a mutation in the GLA gene, resulting in a tyr365-to-ter (Y365X) substitution and truncation of the C terminus by 65 amino acid residues. In a heterozygote of this family, although the mutant and normal alleles were equally transcribed in cultured fibroblasts, lymphocyte alpha-galactosidase A activity was approximately 30% of the normal control, and severe clinical symptoms were apparent. COS-1 cells transfected with this mutant cDNA showed a complete loss of its enzymatic activity. Furthermore, cells cotransfected with mutant and wildtype cDNAs showed approximately 30% of the enzyme activity of those with wildtype alone, which suggested a dominant-negative effect of this mutation and implied the importance of the C terminus for its activity. Generating mutant cDNAs with various deletions of the C terminus, Miyamura et al. (1996) found that enzyme activity was enhanced up to 6-fold compared with wildtype when 2 to 10 amino acid residues were deleted. In contrast, deletion of 12 or more amino acid residues resulted in a complete loss of enzyme activity. These data suggested that the C-terminal region of the GLA protein plays an important role in the regulation its enzyme activity.
This variant, previously titled FABRY DISEASE, CARDIAC VARIANT, has been reclassified based on the findings of Chiang et al. (2017).
During the course of mutation analysis of a patient with the cardiac form of Fabry disease (see 301500) who had residual enzyme activity 9.1% of normal, Ishii et al. (2002) were unable to identify any mutation in the exonic or flanking intronic regions of the GLA gene. By RT-PCR of the RNA and direct sequencing of the RT-PCR product, they found an insertion between exons 4 and 5. To characterize further the abnormal splicing, they sequenced intron 4 (nucleotides 8413-10130) of the GLA gene and identified a G-to-A transition at nucleotide 9331 (IVS4+919G-A). This change was not found in 100 unaffected Japanese males. The mutation in the middle of the intron increased the recognition of a normally weak splice site, resulting in the insertion of an additional sequence into the GLA transcript and leading to the cardiac phenotype of Fabry disease.
Chiang et al. (2017) screened for the IVS4+919G-A variant in the Taiwanese population, including 3,268 controls, 3,949 patients from a type 2 diabetes cohort, and 649 patients from heart disease cohorts (heart failure, atrial fibrillation, ventricular tachycardia, and coronary artery disease). In the control sample, 4 males and 2 females carried the variant and only 1 male, who reportedly had a history of heavy smoking and drinking, had heart disease; none of 80 controls who reportedly had cardiomyopathy carried the variant. In the diabetes cohort, 1 of 11 patients who carried the variant had overt heart disease. Among the heart disease cohorts, only 1 patient carried the variant. The authors found that the incidence of the variant in their population was 1/409.
In 4 unrelated patients of Nova Scotian ancestry with Fabry disease (301500), Branton et al. (2002) found an ala143-to-pro (A143P) missense mutation in exon 3 of the GLA gene. Three of the patients were French Acadian; the fourth had a Greek surname but may also have been of French Acadian ancestry (Kopp, 2002).
In affected members of a Chinese family with Fabry disease (301500), Yang et al. (2003) identified a nonsense mutation in the GLA gene, a C-to-A transversion resulting in a tyr222-to-ter (Y222X) substitution. The genotype was associated with classic Fabry disease, with unexpectedly rapid deterioration of visual acuity.
In affected members of a Chinese family with Fabry disease (301500), Yang et al. (2003) identified an A-to-G transition in the GLA gene, resulting in a thr410-to-ala (T410A) substitution. The T410A mutation was associated with a milder form of Fabry disease, with ventricular hypertrophy and neuropathic pain.
In a patient with classic Fabry disease (301500), Yasuda et al. (2003) identified a 2-bp deletion, 1277delAA, causing a frameshift, in the GLA gene. The patient was a 51-year-old Swedish man who had onset of acroparesthesias at 10 years of age and subsequently had gastrointestinal manifestations, including abdominal pain and chronic diarrhea. He developed hypertrophic cardiomyopathy and, because of atrial ventricular block, required a pacemaker. His renal function was normal, with only a trace of urinary protein.
In a patient with classic Fabry disease (301500), Yasuda et al. (2003) identified a 4-bp deletion, 1284delACTT, in the GLA gene. The patient was a 51-year-old Brazilian man who had childhood onset of acroparesthesias, angiokeratoma, hypohidrosis, and corneal opacities. He had microalbuminuria, which may have been secondary to his diabetes mellitus, but retained normal renal function. He had no evidence of cardiac or cerebral involvement.
In affected members of a Slovenian family with Fabry disease (301500), Verovnik et al. (2004) identified a 10523A-G transition in exon 6 of the GLA gene, resulting in an asn272-to-ser (N272S) substitution. The 7 affected males, including a set of twins, showed decreased to absent alpha-galactosidase activity and had symptoms of classic Fabry disease, but there was considerable variability in their organ involvement, particularly renal: 3 were on dialysis, but 4 had only mild to moderate proteinuria. The 10 affected females had much milder symptoms, with no renal failure, severe cardiac disease, or stroke. Verovnik et al. (2004) stated that this was the first reported Slovenian family with Fabry disease.
In 11 symptomatic Portuguese males from 10 families and in 2 Italian males identified by newborn screening with Fabry disease (301500), Oliveira et al. (2020) identified hemizygosity for a c.337T-C transition (c.337T-C, NM_000169.2) in the GLA gene, resulting in a phe113-to-leu (F113L) substitution. The mutation was identified by Sanger sequencing of the GLA gene or by next-generation sequencing of a multigene panel testing for hypertrophic cardiomyopathy. The symptomatic men had a late-onset cardiac phenotype. Microsatellite analysis showed that all of the alleles were on the same GLA haplotype, suggesting inheritance from a common ancestor.
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