期刊
MOLECULAR GENETICS AND METABOLISM
卷 80, 期 3, 页码 307-314出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/S1096-7192(03)00136-7
关键词
Fabry disease; alpha-galactosidase A deficiency; mutations; sequence variant
资金
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT [P30HD028822] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [M01RR000071] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R37DK034045] Funding Source: NIH RePORTER
- NCRR NIH HHS [5 M01 RR00071] Funding Source: Medline
- NICHD NIH HHS [5 P30 HD28822] Funding Source: Medline
- NIDDK NIH HHS [5 R37 DK34045] Funding Source: Medline
Fabry disease, an X-linked recessive lysosomal storage disease, results from the deficient activity of the exogalactosidase, a-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. (C) 2003 Elsevier Inc. All rights reserved.
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