Froissart Roseline, Guffon Nathalie, Vanier Marie T, Desnick Robert J, Maire Irene
Laboratoire de Biochimie Pédiatrique, Hôpital Debrousse, Lyon, France.
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.
法布里病是一种X连锁隐性溶酶体贮积病，由外切半乳糖苷酶α-半乳糖苷酶A（α-Gal A）活性不足引起。迄今为止，已鉴定出270多种致病突变；然而，尚未报道编码序列变异。在酶诊断测试过程中，一名正常女性对照的血浆和白细胞α-Gal A活性较低。对她的α-Gal A基因进行测序，发现了D313Y替代（cDNA核苷酸937处的GAT突变为TAT）。对家庭成员进行α-Gal A突变和酶分析，结果显示为X连锁遗传，且女性白细胞α-Gal A酶活性与莱昂化一致。由于在一名患有双重突变D313Y和G411D的典型患病男性中报道了D313Y，因此开展了对这些病变特征的研究。D313Y、G411D以及双重突变体D313Y/G411D的表达，导致α-Gal A水平分别为野生型平均表达活性的76%、2.9%和1.7%。生物合成研究表明，D313Y亚基的加工基本正常，但G411D和D313Y/G411D构建体编码的成熟亚基缺失。因此，G411D是致病突变，而D313Y是在人类α-Gal A基因中鉴定出的首个编码序列变异。
