Identification of novel mutations in the α-galactosidase A gene in patients with Fabry disease: Pitfalls of mutation analyses in patients with low α-galactosidase A activity

Yoshimitsu, Makoto; Higuchi, Koji; Miyata, Masaaki; Devine, Sean P; Mattman, André; Sirrs, Sandra; Medin, Jeffrey A.; Takenaka, Toshihiro

doi:10.1016/j.jjcc.2010.12.004

Cited by 17 publications

(12 citation statements)

References 23 publications

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“…Family A It was difficult to diagnose FD due to large deletion of GLA in female subjects II-1, II-4, and II-5, as they did not show Some previous studies have shown the effectiveness of MLPA analysis to detect large deletions of the GLA gene in female FD patients (Marziliano et al 2012;Yoshimitsu et al 2011;Schirinzi et al 2008). We found deletion mutations with multiple exons from exon 2-5 elements using MLPA analysis in this family.…”

Section: Discussionmentioning

confidence: 73%

Identification of Cryptic Novel α-Galactosidase A Gene Mutations: Abnormal mRNA Splicing and Large Deletions

et al. 2015

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Anderson-Fabry (FD) disease is an inborn error of metabolism caused by a deficiency of α-galactosidase A (GLA), a lysosomal enzyme. Many male FD patients display a classic FD phenotype; however, some female patients have neither reduced leukocyte GLA enzyme activity level nor FD symptoms. Thus, GLA gene analysis is especially important for diagnosing suspected FD in female subjects. In this study, we revealed 4 novel GLA gene mutations in 5 independent families using GLA cDNA analysis and multiplex ligation-dependent probe amplification (MLPA) analysis. These distinct mutations included a large deletion mutation from intron 1 to exon 5 (c.195-471_c.691del5.5k, corresponding to g.8508_g.14069del5.5k), an insertion mutation of splicing enhancer sequence in intron 4 (c.639+329_c.639+330ins113, corresponding to g.12627_g.12628ins113), an insertion mutation of retrotransposon L1 in exon 4 (c.634_c.635, corresponding to g.12293_g.12294), and a non-SNP deep intronic point mutation in intron 3 (c.547+395G>C, corresponding to g.11727G>C). It is difficult to detect these mutations with direct sequencing of only the exonic element. When exonic mutations are not found in the GLA gene from suspected FD patients, GLA cDNA and MLPA analyses should be performed to detect large deletion/insertion and intronic mutations including transcription abnormalities.

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Section: Discussionmentioning

confidence: 73%

Identification of Cryptic Novel α-Galactosidase A Gene Mutations: Abnormal mRNA Splicing and Large Deletions

et al. 2015

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“…86,87 In females, due to the presence of the wild-type allele, gross GLA gene rearrangements, such as deletion or insertion of entire exons, may be missed, unless specific laboratory technique, such as multiplex ligation-dependent probe amplification analysis and/or quantitative polymerase chain reaction amplification, are used. 88,89 Additional investigations are also necessary in order to assess the pathogenicity of new variants. In silico and mRNA analysis, computational modeling, and functional studies are needed to prove or exclude the effect of the new identified variant as a disease-causing mutation.…”

Section: Biochemical Diagnosismentioning

confidence: 99%

Anderson-Fabry, the Histrionic Disease: From Genetics to Clinical Management

Cecchi¹,

Tomberli

Morrone

2013

Cardiogenetics

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Anderson-Fabry disease (AFD) is an Xlinked lysosomal storage disorder of glycosphingolipid catabolism, due to deficiency or absence of a galactosidase A (α-gal A) enzyme. The disease may affect males and females, the latter with an average 10 years delay. Metabolites storage (mostly Gb3 and lyso-Gb3) leads to progressive cellular and multiorgan dysfunction, with either early and late onset variable clinical manifestations that usually reduce quality of life and life expectancy. Heart and kidney failure, stroke and sudden death are the most devastating complications. AFD is always been considered a very rare disease, although new epidemiologic data, based on newborn screening, showed that AFD prevalence is probably underestimated and much higher than previously reported, especially for late-onset atypical phenotypes. Currently, the diagnosis may be easier and simpler by evaluating α-gal A enzyme activity and genetic analysis for GLA gene mutations on dried blood spot. While a marked α-gal A deficiency leads to diagnosis of AFD in hemizygous males, the molecular analysis is mandatory in heterozygous females. However, referral to a center with an expert multidisciplinary team is highly advisable, in order to ensure careful management and treatment of patients, based also on accurate molecular and biochemical data interpretation. While long-term efficacy of enzyme replacement therapy (ERT) in advanced stage is still debated, increasing evidence shows greater efficacy of early treatment initiation. Concomitant, organ-specific therapy is also needed. New treatment approaches, such as chemical chaperone therapy, alone or in combination with ERT, are currently under investigation. The present review illustrates the major features of the disease, focusing also on biochemical and genetic aspects

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“…Fabry disease is a lysosomal storage disorder (LSD) caused by deficient activity of the lysosomal hydrolase α-galactosidase A (α-gal A) (EC 3.2.1.22), encoded by the gene GLA [1,2]. The presence of dysfunctional α-gal A or its absence leads to progressive accumulation of neutral glycosphingolipids with α-D-galactosyl residues, mainly globotriaosylceramide (Gb3), in a variety of cell types, and results in multi-system disease [3].…”

Section: Introductionmentioning

confidence: 99%

Altered dynamics of a lipid raft associated protein in a kidney model of Fabry disease

Labilloy¹,

Youker²,

Bruns³

et al. 2014

Molecular Genetics and Metabolism

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Accumulation of globotriaosylceramide (Gb3) and other neutral glycosphingolipids with galactosyl residues is the hallmark of Fabry disease, a lysosomal storage disorder caused by deficiency of the enzyme alpha-galactosidase A (α-gal A). These lipids are incorporated into the plasma membrane and intracellular membranes, with a preference for lipid rafts. Disruption of raft mediated cell processes is implicated in the pathogenesis of several human diseases, but little is known about the effects of the accumulation of glycosphingolipids on raft dynamics in the context of Fabry disease. Using siRNA technology, we have generated a polarized renal epithelial cell model of Fabry disease in Madin-Darby canine kidney cells. These cells present increased levels of Gb3 and enlarged lysosomes, and progressively accumulate zebra bodies. The polarized delivery of both raft-associated and raft-independent proteins was unaffected by α-gal A knockdown, suggesting that accumulation of Gb3 does not disrupt biosynthetic trafficking pathways. To assess the effect of α-gal A silencing on lipid raft dynamics, we employed number and brightness (N&B) analysis to measure the oligomeric status and mobility of the model glycosylphosphatidylinositol (GPI)-anchored protein GFP-GPI. We observed a significant increase in the oligomeric size of antibody-induced clusters of GFP-GPI at the plasma membrane of α-gal A silenced cells compared with control cells. Our results suggest that the interaction of GFP-GPI with lipid rafts may be altered in the presence of accumulated Gb3. The implications of our results with respect to the pathogenesis of Fabry disease are discussed.

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Identification of novel mutations in the α-galactosidase A gene in patients with Fabry disease: Pitfalls of mutation analyses in patients with low α-galactosidase A activity

Cited by 17 publications

References 23 publications

Identification of Cryptic Novel α-Galactosidase A Gene Mutations: Abnormal mRNA Splicing and Large Deletions

Identification of Cryptic Novel α-Galactosidase A Gene Mutations: Abnormal mRNA Splicing and Large Deletions

Anderson-Fabry, the Histrionic Disease: From Genetics to Clinical Management

Altered dynamics of a lipid raft associated protein in a kidney model of Fabry disease

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