Clinical and molecular features of two diabetes families carrying mitochondrial ND1 T3394C mutation.

Background: Mutations in mitochondrial DNA (mtDNA) are found to be associated with type 2 diabetes mellitus (T2DM). However, the molecular pathogenesis of these mutations in T2DM is still poorly understood.

Methods: In this study, we report here the molecular features of two Han Chinese families with maternally transmitted T2DM. The matrilineal relatives are undergoing clinical, biochemical, genetic evaluations, and molecular analysis. Furthermore, the entire mitochondrial genomes of these matrilineal relatives are screened by PCR-Sanger sequencing.

Results: The age at onset of T2DM of these participants varies from 28 to 71 years, with an average of 43 years. Molecular analysis of mitochondrial genomes identifies the existence of ND1 T3394C mutation in both families, together with sets of variants belonging to mitochondrial haplogroup Y2 and M9a. The m.T3394C mutation is localized at very conserved tyrosine at position 30 of ND1, may result the failure in ND1 mRNA metabolism, and lead to mitochondrial dysfunction. Moreover, sequence analysis of matrilineal relatives in Family 1 identifies the m.A14693G mutation which occurs in the TΨC-loop of tRNA (position 54), and is critical to the structural formation and stabilization of this tRNA. Thus, m.A14693G mutation may cause the impairment in tRNA metabolism, thereby worsens the mitochondrial dysfunction caused by ND1 T3394C mutation. However, no functional mtDNA variants are identified in Family 2 which suggest that mitochondrial haplogroup may not play an important role in diabetes expression.

Conclusions: Our study indicates that mitochondrial ND1 T3394C mutation is involved in the pathogenesis of maternally inherited T2DM in these families.