A new mitochondrial DNA mutation at 14577 T/C is probably a major pathogenic mutation for maternally inherited type 2 diabetes

From a family of 16 diabetic patients with typical maternal inheritance, we investigated a 69-year-old woman with type 2 diabetes. The proband showed no major deletions in the mitochondrial DNA (mtDNA). Direct sequencing reve aled 7 missense and 5 ribosomal RNA homoplasmic nucleotide substitutions wh en compared with the Cambridge Sequence and its recent revision. When compa red with the control cybrid cells, the proband cybrid cells showed 6 nucleo tide substitutions. Among these, 14577 T/C, which turned out to be 98.9% he teroplasmic, is a new missense substitution in the NADH dehydrogenase 6 gen e. We also observed 2 other patients with 14577 T/C substitution from anoth er group of 252 unrelated diabetic patients, whereas no individual from a g roup of 529 control subjects had 14577 T/C substitution. Furthermore, these 6 substitutions were in linkage disequilibrium. Mitochondrial respiratory chain complex I activity and O-2 consumption rates of the proband cybrid ce lls, which were obtained by the fusion of mtDNA-deleted (rho(0)) HeLa cells and mtDNA from the proband, showed 64.5 and 61.5% reductions, respectively , compared with control cybrid cells. The present study strongly indicates that the new mtDNA mutation at 14577 T/C is probably a major pathogenic mut ation for type 2 diabetes in this family.