Molecular basis of Fabry disease: mutations and polymorphisms in the human alpha-galactosidase A gene.

Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from mutations in the alpha-galactosidase A gene at Xq22.1. Studies of the mutations in unrelated Fabry families have identified a variety of lesions indicating the molecular genetic heterogeneity underlying the disease. Forty-nine different mutations have been described including five partial gene deletions, one partial gene duplication, nine small deletions and insertions, three splice junction consensus site alterations, and 31 coding region single base substitutions. Most mutations resulted in the classical disease phenotype; however, five missense mutations were detected in atypical hemizygotes who were asymptomatic or had symptoms confined to the heart, including N215S, which was described in three unrelated atypical males. Most mutations were confined to a single pedigree with the exception of N215S, R227Q, R227X, R342Q, and R342X, which were each found in several unrelated families. Five of the 14 coding region CpG dinucleotides were sites of point mutations including the CpGs in codons 227 and 342, which were each mutated in both orientations. The identification of the mutation in a given Fabry family permits precise prenatal diagnosis and heterozygote detection of other family members with this X-linked recessive disease. Studies of additional Fabry families will provide information on the nature and frequency of the mutations causing this disease as well as potential insights into the structure/function relationships of this lysosomal hydrolase.