Analysis of a polycytosine tract and heteroplasmic length variation in the mitochondrial DNA D-loop of patients with diabetes, MELAS syndrome and race-matched controls

Aim The T to C substitution at position 16189 nt of the human mitochondrial genome has been associated with the development of heteroplasmic length variation in the control region of mtDNA. Previous reports have suggested that this defect may be associated with the development of other pathogenic mtDNA mutations, including the diabetogenic A to G mutation in the tRNA(LEU(UUR)). Recently the 16189 nt variant has also been associated with insulin resistance in British adult men. In order to investigate these associations further we studied 23 patients with the 3243 nt mutation, 150 patients with Type 2 diabetes and 149 non-diabetic controls. Methods The region around 16189 nt was investigated by polymerase chain reaction-restriction fragment length polymorphism analysis and automated sequencing. Results We find that the T to C substitution at 16189 nt is associated with heteroplasmic length variation only when the resultant polycytosine tract is not interrupted by a second mutation. There are no significant differences in the prevalence of the 16189 nt variant or heteroplasmic length variation between patients with the 3243 nt mutation, patients with Type 2 diabetes or race-matched normal controls. Conclusions include that these variants are likely to represent normal polymorphisms and that previously reported associations should be treated with caution unless they can be replicated in other populations.