Identification of a novel nonsense mutation in α-galactosidase A that causes Fabry disease in a Chinese family.

Fabry disease, a lysosomal storage disease, is an uncommon X-linked recessive genetic disorder stemming from abnormalities in the alpha-galactosidase gene () that codes human alpha-Galactosidase A (α-Gal A). To date, over 800 mutations have been found to cause Fabry disease (FD). Continued enhancement of the mutation spectrum will contribute to a deeper recognition and underlying mechanisms of FD. In this study, a 27-year-old male proband exhibited a typical phenotype of Fabry disease. Subsequently, family screening for Fabry disease was conducted, and high-throughput sequencing was employed to identify the mutated gene. The three-level structure of the mutated protein was analyzed, and its subcellular localization and enzymatic activity were determined. Apoptosis was assessed in mutant cell lines to confirm the functional effects. As a result, a new mutation, c.777_778del (p. Gly261Leufs*3), in the gene was identified. The mutation caused a frameshift during translation and the premature appearance of a termination codon, which led to a partial deletion of the domain in C-terminal region and altered the protein's tertiary structure. experiments revealed a significant reduction of the enzymatic activity in mutant cells. The expression was noticeably decreased at the mRNA and protein levels in mutant cell lines. Additionally, the subcellular localization of α-Gal A changed from a homogeneous distribution to punctate aggregation in the cytoplasm. mutant cells exhibited significantly higher levels of apoptosis compared to wild-type cells.