Novel sequence variants of the α-galactosidase A gene in patients with Fabry disease

Erdős, Melinda; Németh, Krisztína; Töth, Beáta; Constantin, T.; Rákóczi, Éva; Ponyi, Andrea; Dajnoki, Angéla; Grubits, János; Pintér, István; Garzuly, Ferencz; Hahn, Katalin; Bencsik, Krisztina; Vécsei, László; Fekete, György; Maródi, László

doi:10.1016/j.ymgme.2008.09.002

Cited by 6 publications

(5 citation statements)

References 20 publications

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“…The D165 amino acid belongs to the group of buried amino acids, so probably it is involved in the preservation of the protein folding, as reported in literature [14,16]. Moreover, we believe that this amino acid and the flanking ones have a key role in the enzyme functionality, as revealed also by the multiple sequence alignment, which shows that they have been highly conserved throughout the evolution (Figure 3).…”

Section: Discussionsupporting

confidence: 63%

“…Moreover, we believe that this amino acid and the flanking ones have a key role in the enzyme functionality, as revealed also by the multiple sequence alignment, which shows that they have been highly conserved throughout the evolution (Figure 3). Our hypothesis is strengthened by the fact that the mutations affecting this amino acid (D165H e D165V) and some of the flanking ones (G163V, L166G e L166V) are responsible for the classic phenotype of Fabry disease [14,17-20]. Moreover, the study of the potential role of this mutation, performed using PolyPhen-2 software, confirms the damaging effect on the enzyme structure.…”

Section: Discussionmentioning

confidence: 64%

“…This mutation results in the replacement of an amino acid (aspartic acid) by a basic one (histidine) at codon 165, thus altering normal α-galactosidase A activity. This genetic alteration was previously described, in a Hungarian family, as associated with the classic form of Fabry disease [14]. …”

Section: Discussionmentioning

confidence: 78%

“…Purified PCR mutated products were sequenced using LI-COR NEN Model 4300 DNA Analyzer, according to the LI-COR protocol. Sequence analysis of the GLA gene in the patient, in comparison with the wild-type sequence (Figure 1), revealed a single nucleotide point mutation in hemizygosis at nucleotide c.493 G > C in exon 3 (D165H in the protein) [14]. The α-galactosidase A activity of the patient was determined by Dried Blood Filter Paper test described by Chamoles et al, with minor modifications [15]: enzyme activity in the whole blood was 0.5 nmol/h/ml (normal range is > 3.0 nmol/h/ml).…”

Section: Case Presentationmentioning

confidence: 99%

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De novo mutation in a male patient with Fabry disease: a case report

et al. 2014

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BackgroundFabry disease is an X-linked inherited metabolic condition where the deficit of the α-galactosidase A enzyme, encoded by the GLA gene, leads to glycosphingolipid storage, mainly globotriaosylceramide. To date, more than 600 mutations have been identified in human GLA gene that are responsible for FD, including missense and nonsense mutations, small and large deletions. Such mutations are usually inherited, and cases of de novo onset occur rarely.Case presentationIn this article we report an interesting case of a 44-year-old male patient suffering from a severe form of Fabry disease, with negative family history. The patient showed signs such as cornea verticillata, angiokeratomas, cardiac and neurological manifestations, an end-stage renal disease and he had low α-galactosidase A activity. We detected, in this subject, the mutation c.493 G > C in the third exon of the GLA gene which causes the amino acid substitution D165H in the protein. This mutation affects the amino acid - belonging to the group of buried residues - involved, probably, in the preservation of the protein folding. Moreover, studies of multiple sequence alignment indicate that this amino acid is highly conserved, thus strengthening the hypothesis that it is a key amino acid to the enzyme functionality.The study of the relatives of the patient showed that, surprisingly, none of the members of his family of origin had this genetic alteration, suggesting a de novo mutation. Only his 11-year-old daughter - showing acroparaesthesias and heat intolerance with reduced enzymatic activity - had the same mutation.ConclusionsWe suggest that a non-inherited mutation of the α-galactosidase A gene is responsible for Fabry disease in the patient who had reduced enzyme activity and classical clinical manifestations of the disease. In a family, it is rare to find only one Fabry disease affected subject with a de novo mutation. These findings emphasize the importance of early diagnosis, genetic counselling, studying the genealogical tree of the patients and starting enzyme replacement therapy to prevent irreversible vital organ damage that occurs during the course of the disease.

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 78%

Section: Case Presentationmentioning

confidence: 99%

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De novo mutation in a male patient with Fabry disease: a case report

et al. 2014

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“…Hence, Fabry disease is marked by multisystemic disease but considerable phenotypic variability exists possibly because of molecular heterogeneity [23]; most families carry a private mutation [24]. …”

Section: Introductionmentioning

confidence: 99%

Prevention of Lysosomal Storage Diseases and Derivation of Mutant Stem Cell Lines by Preimplantation Genetic Diagnosis

Altarescu

Beeri

Eiges

et al. 2012

Molecular Biology International

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Preimplantation genetic diagnosis (PGD) allows birth of unaffected children for couples at risk for a genetic disorder. We present the strategy and outcome of PGD for four lysosomal storage disorders (LSD): Tay-Sachs disease (TSD), Gaucher disease (GD), Fabry disease (FD), and Hunter syndrome (HS), and subsequent development of stem cell lines. For each disease, we developed a family-specific fluorescent multiplex single-cell PCR protocol that included the familial mutation and informative markers surrounding the mutation. Embryo biopsy and PGD analysis were performed on either oocytes (polar bodies one and two) or on single blastomeres from a six-cell embryo. We treated twenty families carrying mutations in these lysosomal storage disorders, including 3 couples requiring simultaneous analysis for two disorders (TSD/GD, TSD/balanced Robertsonian translocation 45XYder(21;14), and HS/oculocutaneus albinism). These analyses led to an overall pregnancy rate/embryo transfer of 38% and the birth of 20 unaffected children from 17 families. We have found that PGD for lysosomal disorders is a safe and effective method to prevent birth of affected children. In addition, by using mutant embryos for the derivation of stem cell lines, we have successfully established GD and HS hESC lines for use as valuable models in LSD research.

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Clinically Relevant Examples of Genotype–Phenotype Correlation

Altarescu

2010

Fabry Disease

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Novel sequence variants of the α-galactosidase A gene in patients with Fabry disease

Cited by 6 publications

References 20 publications

De novo mutation in a male patient with Fabry disease: a case report

De novo mutation in a male patient with Fabry disease: a case report

Prevention of Lysosomal Storage Diseases and Derivation of Mutant Stem Cell Lines by Preimplantation Genetic Diagnosis

Clinically Relevant Examples of Genotype–Phenotype Correlation

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