Analysis of a polycytosine tract and heteroplasmic length variation in themitochondrial 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 va riation in the control region of mtDNA. Previous reports have suggested tha t this defect may be associated with the development of other pathogenic mt DNA mutations, including the diabetogenic A to G mutation in the tRNA(LEU(U UR)). Recently the 16189 nt variant has also been associated with insulin r esistance 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 rea ction-restriction fragment length polymorphism analysis and automated seque ncing. 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 differenc es in the prevalence of the 16189 nt variant or heteroplasmic length variat ion between patients with the 3243 nt mutation, patients with Type 2 diabet es or race-matched normal controls. Conclusions include that these variants are likely to represent normal poly morphisms and that previously reported associations should be treated with caution unless they can be replicated in other populations.