FABRY-DISEASE - 23 MUTATIONS INCLUDING SENSE AND ANTISENSE CPG ALTERATIONS AND IDENTIFICATION OF A DELETIONAL HOT-SPOT IN THE ALPHA-GALACTOSIDASE-A GENE

Fabry disease, an X-linked inborn error of glycosphingolipid catabolis m, results from mutations in the alpha-galactosidase A gene at Xq22.1. To determine the nature and frequency of the molecular lesions causin g the classical and milder variant Fabry phenotypes, and for precise c arrier detection in Fabry families, the cr-galactosidase A coding and flanking intronic sequences from 23 unrelated Fabry hemizygotes were a nalyzed. In patients with the classic phenotype, 16 new missense and n onsense mutations and four small exonic gene rearrangements were ident ified: C52S, C56F, E59K, L89R, R100K, R112H, L131P, A143P, G144V, C172 Y, D244N, N272K, A288D, W81X, Q99X, Q157X, R301X, 25del1, 333del18, 35 8del6, and 1020del1. The R112H mutation at a CpG dinucleotide resulted in residual activity and a mild variant phenotype while the R112C les ion caused the classic disease manifestations, defining a genotype/phe notype correlation for sense and antisense mutations at the same CpG d inucleotide. In addition, two complex rearrangements, each involving t wo mutational events, occurred in classic hemizygotes. Both rearrangem ents resulted in missense mutations that did not change the reading fr ame. Notably, three of the deletions occurred within 11 codons in exon 2, thereby defining a 'hot-spot' for deletions. These studies reveale d that most mutations in the alpha-galactosidase A gene causing Fabry disease were private, that codons 111 - 122 defined a deletion hot-spo t, and that different substitutions of the same codon resulted in mark edly different disease phenotypes.