Mitochondrial gene mutations in the tRNA(Leu(UUR)) region and diabetes: Prevalence and clinical phenotypes in Japan

Background: Mitochondrial gene mutations play a role in the development of diabetes mellitus. We have assessed the frequency of the A3243G and other m itochondrial mutations in Japan and in the relationship to clinical feature s of diabetes. Methods: DNA was obtained from peripheral leukocytes of 240 patients with d iabetes mellitus (39 with type 1; 188 with type 2; 13 with gestational diab etes) and 125 control subjects. We used PCR-restriction fragment length pol ymorphism analysis (ApaI) for A3243G and PCR-single-strand conformation pol ymorphism analysis to determine the mutations in the mitochondrial gene inc luding nucleotide position 3243. Results. The A3243G mutation was found in seven patients, and an inverse re lationship was observed between the degree of heteroplasmy and the age at o nset of diabetes. A3156G, G3357A, C3375A, and T3394C were detected in addit ion. Those who shared the same mutation showed similar clinical characteris tics, thus representing a putative clinical subtype. The patients with A315 6G had a sudden onset of hyperglycemia and showed a rapid progression to an insulin-dependent state with positive anti-glutamic acid decarboxylase ant ibody. Those with T3394C showed a mild defect in glucose-stimulated insulin secretion, and hyperglycemia appeared after adding such factors as aging o r obesity. Conclusions: The identification of mitochondrial gene mutations allows prec linical diagnosis of diabetes and prediction of the age at onset by evaluat ing the degree of heteroplasmy in cases with A3243G. Mutation detection may also be important for patient management and identification of affected fa mily members. (C) 2001 American Association for Clinical Chemistry.