Abstract
Background
Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from the deficient activity of the lysosomal exoglycohydrolase α-galactosidase A (EC 3.2.1.22; α-Gal A). The nature of the molecular lesions in the α-Gal A gene in 30 unrelated families was determined to provide precise heterozygote detection, prenatal diagnosis, and define genotype-phenotype correlations.
Materials and Methods
Genomic DNA was isolated from affected males and/or carrier females from 30 unrelated families with Fabry disease. The entire α-Gal A coding region and flanking intronic sequences were analyzed by PCR amplification and automated sequencing.
Results
Twenty new mutations were identified, each in a single family: C142R, G183D, S235C, W236L, D244H, P259L, M267I, I289F, Q321E, C378Y, C52X, W277X, IVS4+4, IVS6+2, IVS6−1, 35del13, 256del1, 892ins1, 1176del4, and 1188del1. In the remaining 10 unrelated Fabry families, 9 previously reported mutations were detected: M42V, R112C, S148R, D165V, N215S (in 2 families), Q99X, C142X, R227X, and 1072del3. Haplotype analysis using markers closely flanking the α-Gal A gene indicated that the two patients with the N215S lesion were unrelated. The IVS4+4 mutation was a rare intronic splice site mutation that causes Fabry disease.
Conclusions
These studies further define the heterogeneity of mutations in the α-Gal A gene causing Fabry disease, permit precise heterozygote detection and prenatal diagnosis, and help delineate phenotype-genotype correlations in this disease.
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Acknowledgments
We thank the following physicians for referral of patients and/or diagnostic specimens: Drs. G. Appel, D. Barfield, S. Cederbaum, M. C. Clarke, J. Daven, H. Goldman, G. M. Grasso, B. Kornhall, T. W. Kurczynski, M. Kushigemachi, R. Lee, A. Linder, V. Moore, J. Murphy, L. Olson, R. Pyeritz, S. Phadke, L. Shapiro, J. Sloand, and D. Suhrbier. This work was supported in part by grants from the National Institutes of Health, including a Merit Award (5 R37 DK34045), a grant (5 MOI RR00071) for the Mount Sinai General Clinical Research Center, and a grant (5 P30 HD28822) for the Mount Sinai Child Health Research Center.
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Topaloglu, A.K., Ashley, G.A., Tong, B. et al. Twenty Novel Mutations in the α-Galactosidase A Gene Causing Fabry Disease. Mol Med 5, 806–811 (1999). https://doi.org/10.1007/BF03401993
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DOI: https://doi.org/10.1007/BF03401993