Fabry disease: D313Y is an alpha-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, 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.
Froissart
Roseline
R
Laboratoire de Biochimie Pédiatrique, Hôpital Debrousse, Lyon, France.
Guffon
Nathalie
N
Vanier
Marie T
MT
Desnick
Robert J
RJ
Maire
Irene
I
D000328:Adult; D000818:Animals; D015139:Blotting, Southern; D019556:COS Cells; D002522:Chlorocebus aethiops; D017931:DNA Primers; D004303:Dosage Compensation, Genetic; D000795:Fabry Disease / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006028:Glycosphingolipids / Q000652:urine; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D011233:Precipitin Tests; D017422:Sequence Analysis, DNA; D014162:Transfection; D000519:alpha-Galactosidase / Q000097:blood / Q000235:genetics*
D017931:DNA Primers; D006028:Glycosphingolipids; D000519:alpha-Galactosidase