Aims: Fabry disease is a rare but important cause of end-stage renal disease. Recent molecular investigations on alpha-galactosidase A (alpha-Gal A) have proven the existence of atypical variants in Fabry disease, making genotype assessment of each phenotype indispensable. We report here a missense mutation, which causes a typical form of Fabry disease.
Material and methods: The proband, a 45-year-old man, presented with acroparesthesias, hypohidrosis, left ventricular hypertrophy, renal involvement (proteinuria and renal 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-transcribed 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-Gal A, resulting in a single amino acid change from alanine to threonine (A156T). The mutation can be detected with PCR-RFLP with SfaNI digestion. This technique revealed 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 mutation in the literature, no previous description was found other than one case listed in several review papers as a classic phenotype without any other information. In our study, we examined A156T in a pedigree and demonstrated that the mutation was not a polymorphic variant in our area.
Conclusion: Taken together, the present results strongly suggest that the missense mutation, A156T, in the alpha-Gal A gene causes typical Fabry disease.