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

Background: Fabry disease, an X-linked inborn error of glycosphingolipid ca tabolism, results from the deficient activity of the lysosomal exoglycohydr olase alpha-galactosidase A (EC 3.2.1.22; ct-Gal A). The nature of the mole cular lesions in the oc-Gal A gene in 30 unrelated families was determined to provide precise heterozygote detection, prenatal diagnosis, and define g enotype-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 a lpha-Gal A coding region and flanking intronic sequences were analyzed by P CR amplification and automated sequencing. Results: Twenty new mutations were identified, each in a single family: C14 2R, G183D, S235C, W236L, D244H, P259L, M2671, 1289F, Q321E, C378Y, C52X, W2 77X, IVS4(+4), IVS6(+2), IVS6(-1), 35del13, 256del1, 892ins1, 1176del4, and 1188del1. In the remaining 10 unrelated Fabry families, 9 previously repor ted mutations were detected: M42V, R112C, S148R, D165V, N215S (in 2 familie s), Q99X, C142X, R227X, and 1072del3. Haplotype analysis using markers clos ely flanking the ct-Gal A gene indicated that the two patients with the N21 5S lesion were unrelated. The IVS4(+4) mutation was a rare intronic splice site mutation that causes Fabry disease. Conclusions: These studies further define the hererogeneity of mutations in the alpha-Gal A gene causing Fabry disease, permit precise heterozygote de tection and prenatal diagnosis, and help delineate phenotype-genotype corre lations in this disease.