Abstract
BACKGROUND: Mitochondrial dysfunctions caused by mitochondrial DNA (mtDNA) pathogenic mutations play putative roles in type 2 diabetes mellitus (T2DM) progression. But the underlying mechanism remains poorly understood. METHODS: A large Chinese family with maternally inherited diabetes and deafness (MIDD) underwent clinical, genetic, and molecular assessment. PCR and sequence analysis are carried out to detect mtDNA variants in affected family members, in addition, phylogenetic conservation analysis, haplogroup classification, and pathogenicity scoring system are performed. Moreover, the GJB2, GJB3, GJB6, and TRMU genes mutations are screened by PCR-Sanger sequencing. RESULTS: Six of 18 matrilineal subjects manifested different clinical phenotypes of diabetes. The average age at onset of diabetic patients is 52 years. Screening for the entire mitochondrial genomes suggests the co-existence of two possibly pathogenic mutations: tRNA(Trp) A5514G and tRNA(Ser(AGY)) C12237T, which belongs to East Asia haplogroup G2a. By molecular level, m.A5514G mutation resides at acceptor stem of tRNA(Trp) (position 3), which is critical for steady-state level of tRNA(Trp) . Conversely, m.C12237T mutation occurs in the variable region of tRNA(Ser(AGY)) (position 31), which creates a novel base-pairing (11A-31T). Thus, the mitochondrial dysfunctions caused by tRNA(Trp) A5514G and tRNA(Ser(AGY)) C12237T mutations, may be associated with T2DM in this pedigree. But we do not find any functional mutations in those nuclear genes. CONCLUSION: Our findings suggest that m.A5514G and m.C12337T mutations are associated with T2DM, screening for mt-tRNA mutations is useful for molecular diagnosis and prevention of mitochondrial diabetes.