Complete mitochondrial DNA genome sequence variation of Chinese families with mutation m.3635GA and Leber hereditary optic neuropathy

摘要

Purpose: The majority of Leber hereditary optic neuropathy (LHON) cases are caused by one of three mitochondrial DNA (mtDNA) primary mutations (m.3460GA, m.11778GA, and m.14484TC). In recent studies, we and others have shown that mutation m.3635GA is a primary LHON mutation, particularly in Chinese. The purpose of this study was to perform a thorough analysis for the complete mtDNA genome sequence variation in Chinese patients with m.3635GA and to identify potentially functional variants cosegregated with m.3635GA. Methods: The complete mtDNA genomes of five Chinese patients with LHON carrying m.3635GA were determined. A phylogenetic tree was constructed to distinguish the private and ancestral mtDNA variants in each lineage. Previously unreported variants in each mtDNA were defined with a web-based and database search. mtDNA variants that changed the structure of the membrane-spanning region of the protein were also evaluated, together with evolutionary conservation analysis, to predict their potential pathogenicity. Results: The five patients with LHON sequenced in this study belonged to haplogroups M7b4 (Le131), F1a (Le329 and Le337), B5b (Le569), and M7b6 (Le834), which suggested multiple origins of m.3635GA. Private variants m.12811TC, m.14063TC, m.15237TC, and m.9071CT in these patients were predicted to change the structure of the membrane-spanning region of the respective proteins. Conclusions: Mutation m.3635GA had multiple origins in Chinese patients with LHON. We also identified several potentially functional variants cosegregated with m.3635GA.