Fabry disease: D313Y is an α-galactosidase A sequence variant that causes pseudodeficient activity in plasma

Fabry disease, an X-linked recessive lysosomal storage disease, results from the deficient activity of the exogalactosidase, α-galactosidase A (α-Gal A). To date, over 270 disease-causing mutations have been identified; however, no coding sequence variants have been reported. In the course of enzyme diagnostic testing, a normal female control had low plasma and leukocyte α-Gal A activities. Sequencing her α-Gal A gene revealed the D313Y substitution (GAT to TAT at cDNA nucleotide 937). α-Gal A mutation and enzyme analyses of family members revealed X-linked transmission and leukocyte α-Gal A enzymatic activities in females, consistent with Lyonization. Since D313Y was reported in a classically affected male who had the double mutation, D313Y and G411D, efforts were undertaken to characterize these lesions. Expression of D313Y, G411D, and the doubly mutated construct, D313Y/G411D, resulted in α-Gal A levels of 76, 2.9, and 1.7% of mean expressed wild-type activity, respectively. Biosynthetic studies revealed essentially normal processing of the D313Y subunit, but the absence of the mature subunit encoded by the G411D and D313Y/G411D constructs. Thus, G411D is the disease-causing mutation, while D313Y is the first coding sequence variant identified in the human α-Gal A gene.