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

Mol Genet Metab. 2003 Nov;80(3):307-14. doi: 10.1016/S1096-7192(03)00136-7.


Fabry disease, an X-linked recessive lysosomal storage disease, results from the deficient activity of the exogalactosidase, alpha-galactosidase A (alpha-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 alpha-Gal A activities. Sequencing her alpha-Gal A gene revealed the D313Y substitution (GAT to TAT at cDNA nucleotide 937). alpha-Gal A mutation and enzyme analyses of family members revealed X-linked transmission and leukocyte alpha-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 alpha-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 alpha-Gal A gene.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Animals
  • Blotting, Southern
  • COS Cells
  • Chlorocebus aethiops
  • DNA Primers
  • Dosage Compensation, Genetic
  • Fabry Disease / genetics*
  • Fabry Disease / metabolism
  • Female
  • Gene Expression*
  • Glycosphingolipids / urine
  • Haplotypes / genetics
  • Humans
  • Male
  • Middle Aged
  • Mutagenesis, Site-Directed
  • Mutation, Missense / genetics*
  • Pedigree
  • Precipitin Tests
  • Sequence Analysis, DNA
  • Transfection
  • alpha-Galactosidase / blood
  • alpha-Galactosidase / genetics*


  • DNA Primers
  • Glycosphingolipids
  • alpha-Galactosidase