Twenty novel mutations in the alpha-galactosidase A gene causing Fabry disease

• Published in: Molecular medicine (Cambridge, Mass.) Mass.), 1999-12, Vol.5 (12), p.806-811
• Main Authors: Topaloglu, A K, Ashley, G A, Tong, B, Shabbeer, J, Astrin, K H, Eng, C M, Desnick, R J
• Format: Article
• Language: English
• Subjects: alpha-Galactosidase - genetics; Alternative Splicing - genetics; Chromosome Mapping; Exons - genetics; Fabry Disease - enzymology; Fabry Disease - genetics; Female; Genetic Carrier Screening; Genetic Markers; Humans; Introns - genetics; Lipid Metabolism, Inborn Errors - enzymology; Lipid Metabolism, Inborn Errors - genetics; Male; Mutation - genetics; Mutation, Missense - genetics; X Chromosome - genetics
• ISSN: 1076-1551; 1528-3658
• DOI: 10.1007/bf03401993

Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from the deficient activity of the lysosomal exoglycohydrolase alpha-galactosidase A (EC 3.2.1.22; alpha-Gal A). The nature of the molecular lesions in the alpha-Gal A gene in 30 unrelated families was determined to provide precise heterozygote detection, prenatal diagnosis, and define genotype-phenotype correlations. Genomic DNA was isolated from affected males and/or carrier females from 30 unrelated families with Fabry disease. The entire alpha-Gal A coding region and flanking intronic sequences were analyzed by PCR amplification and automated sequencing. 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 alpha-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. These studies further define the heterogeneity of mutations in the alpha-Gal A gene causing Fabry disease, permit precise heterozygote detection and prenatal diagnosis, and help delineate phenotype-genotype correlations in this disease.