A missense mutation, A156T, in the alpha-galactosidase A gene causes typical Fabry disease

Aims: Fabry disease is a rare but important cause of end-stage renal diseas e. Recent molecular investigations on alpha -galactosidase A (alpha -Gal A) have proven the existence of atypical variants in Fabry disease, making ge notype assessment of each phenotype indispensable. We report here a missens e mutation, which causes a typical form of Fabry disease. Material and meth ods: The proband, a 45-year-old man, presented with acroparesthesias, hypoh idrosis, left ventricular hypertrophy, renal involvement (proteinuria and r enal insufficiency) with typical microscopic findings and extremely reduced plasma alpha -Gal A activity, indicating the typical form of the disease. Total RNA was isolated from the proband's cultured fibroblasts, reverse-tra nscribed and amplified for direct sequencing of alpha -Gal A. Genomic. DNA of the proband's mother and 75 controls (50 males and 25 females) living in the same area as the proband was also examined. Results: Sequencing of the cDNA revealed a substitution of G to A in codon 156 of alpha -GalA, result ing in a single amino acid change from alanine to threonine (A156T). The mu tation can be detected with PCR-RFLP with SfaNI digestion. This technique r evealed that the mother was a heterozygote of A156T with no A156T noted in the 100 haplotypes of the controls. With a vigorous search of the same muta tion in the literature, no previous description was found other than one ca se listed in several review papers as a classic phenotype without any other information. In our study, we examined A156T in a pedigree and demonstrate d that the mutation was not a polymorphic variant in our area. Conclusion: Taken together, the present results strongly suggest that the missense muta tion A156T, in the alpha -Gal A gene causes typical Fabry disease.