Identification of point mutations in the α-galactosidase A gene in classical and atypical hemizygotes with Fabry disease

Efforts were directed to identify the specific mutations in the α-galactosidase A (α-Gal A) gene which cause Fabry disease in families of Japanese origin. By polymerase-chain-reaction-amplification of DNA from reverse-transcribed mRNA and genomic DNA, different point mutations were found in two unrelated Fabry hemizygotes. A hemizygote with classic disease manifestations and no detectable α-Gal A activity had a G-to-A transition in exon 1 (codon 44) which substituted a termination codon (TAG) for a tryptophan codon (TGG) and created an NheI restriction site. This point mutation would predict a truncated α-Gal A polypeptide, consistent with the observed absence of enzymatic activity and a classic Fabry phenotype. In an unrelated Japanese hemizygote who had an atypical clinical course characterized by lateonset cardiac involvement and significant residual α-Gal activity, a G-to-A transition in exon 6 (codon 301) resulted in the replacement of a glutamine for an arginine residue. This amino acid substitution apparently altered the properties of the enzyme such that sufficient enzymatic activity was retained to markedly alter the disease course. Identification of these mutations permitted accurate molecular heterozygote diagnosis in these families.