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Fabry Disease: Twenty Novel α-Galactosidase A Mutations and Genotype-Phenotype Correlations in Classical and Variant Phenotypes

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Abstract

Background

Fabry disease (OMIM 301500) is an X-linked inborn error of glycosphingolipid metabolism resulting from mutations in the α-galactosidase A (α-Gal A) gene. The disease is phenotypically heterogeneous with classic and variant phenotypes. To assess the molecular heterogeneity, define genotype/phenotype correlations, and for precise carrier identification, the nature of the molecular lesions in the α-Gal A gene was determined in 40 unrelated families with Fabry disease.

Materials and Methods

Genomic DNA was isolated from affected males or obligate carrier females and the entire α-Gal A coding region and flanking sequences were amplified by PCR and analyzed by automated sequencing. Haplotype analyses were performed with polymorphisms within and flanking the α-Gal A gene.

Results

Twenty new mutations were identified (G43R, R49G, M72I, G138E, W236X, L243F, W245X, S247C, D266E, W287C, S297C, N355K, E358G, P409S, g1237del15, g10274insG, g10679insG, g10702delA, g11018insA, g11185-delT), each in a single family. In the remaining 20 Fabry families, 18 previously reported mutations were detected (R49P, D92N, C94Y, R112C [two families], F113S, W162X, G183D, R220X, R227X, R227Q, Q250X, R301X, R301Q, G328R, R342Q, E358K, P409A, g10208delAA [two families]). Haplotype analyses indicated that the families with the R112C or g10208delAA mutations were not related. The proband with the D266E lesion had a severe classic phenotype, having developed renal failure at 15 years. In contrast, the patient with the S247C mutation had a variant phenotype, lacking the classic manifestations and having mild renal involvement at 64 years.

Conclusions

These results further define the heterogeneity of α-Gal A mutations causing Fabry disease, permit precise heterozygote detection and prenatal diagnosis in these families, and provide additional genotype/phenotype correlations in this lysosomal storage disease.

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Acknowledgments

We are indebted to the patients, their families, and our nursing staff for their help with this study. D.P.G. was supported by Vaincre les Maladies Lysosomales (VML). This work also was supported in part by grants from the National Institutes of Health including a research grant (R37 DK 34045 Merit Award), a grant (5 MO1 RR00071) for the Mount Sinai General Clinical Research Center from the National Center of Research Resources, and a grant (5 P30 HD28822) for the Mount Sinai Child Health Research Center.

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Authors and Affiliations

  1. Department of Genetics, Hôpital Européen Georges Pompidou, 20, rue Leblanc, 75015, Paris, France

    Dominique P. Germain MD, PhD & Sylvie Cotigny

  2. Department of Human Genetics, Mount Sinai School of Medicine of New York University, New York, New York, USA

    Junaid Shabbeer & Robert J. Desnick

Authors
  1. Dominique P. Germain MD, PhD
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  2. Junaid Shabbeer
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  3. Sylvie Cotigny
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  4. Robert J. Desnick
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Correspondence to Dominique P. Germain MD, PhD.

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Contributed by: R. Desnick

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Germain, D.P., Shabbeer, J., Cotigny, S. et al. Fabry Disease: Twenty Novel α-Galactosidase A Mutations and Genotype-Phenotype Correlations in Classical and Variant Phenotypes. Mol Med 8, 306–312 (2002). https://doi.org/10.1007/BF03402156

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