Molecular characterization of two pedigrees with maternally inherited diabetes mellitus

Mutations in mitochondrial DNA (mtDNA), especially in mitochondrial tRNA (mt-tRNAs) genes, play important roles in maternally inherited type 2 diabetes mellitus (T2DM), but the molecular mechanism remains unclear. In this study, two families with maternally transmitted T2DM are underwent clinical, genetic and molecular assessments. The mtDNA mutations are screened by direct sequencing. Furthermore, the phylogenetic conservation analysis and pathogenicity scoring system were used to evaluate the pathogenic status of mt-tRNA mutations. Interestingly, matrilineal relatives exhibit variable severity of DM, in particular, the age at onset of DM varies from 39 to 60 years, with an average of 50 years. Screening for the entire mitochondrial genomes identifies the existence of tRNA(Thr) A15901G and C15926T mutations, as well as 59 variants belonging to mtDNA haplogroups D2 and C4c. Notably, the m.A15901G mutation is located at D-arm of tRNA(Thr), whereas the m.C15926T mutation resides in the anticodon loop of tRNA(Thr), both of these positions are well conserved and critical for tRNA functions. Thus, the m.A15901G and m.C15926T mutations may impair mitochondrial translation and lead to mitochondrial dysfunctions. However, the fail to identify any other functional variants indicate that mitochondrial haplogroup may not play a role in T2DM. Hence, tRNA(Thr) A15901G and C15926T may be the novel mutations associated with T2DM.