CLINICAL MANIFESTATIONS DUE TO A POINT MUTATION OF THE MITOCHONDRIAL TRNA(LEU(UUR)) GENE IN 5 FAMILIES WITH DIABETES-MELLITUS

It has been shown that an adenine (A) to guanine (G) transition at pos ition 3243 of the mitochondrial transfer RNA(tRNA)(leu(UUR)) gene is a ssociated with a subgroup of diabetes mellitus, Therefore, we screened for this transition in 86 patients with non-insulin-dependent diabete s mellitus (NIDDM) in which two or three generations were affected wit h diabetes, in 14 patients with insulin-dependent diabetes mellitus, a nd in 9 families with diabetes mellitus and/or associated disorders su ggesting mitochondrial gene abnormalities. We failed to identify the m utation in 100 diabetic patients, 86 NIDDM and 14 insulin-dependent di abetes mellitus (IDDM). Out of the latter 9 families, we identified an A to G transition in 14 individuals in 5 families. Diabetes mellitus was shown to be maternally inherited in one family. In 9 of 14 patient s with the mutation, insulin was required to treat diabetes mellitus, indicating impaired insulin secretion. A hyperglycemic clamp test perf ormed in one subject revealed significant impairment of insulin secret ion, whereas euglycemic clamp test showed normal insulin sensitivity i n this patient. The heteroplasmy of the mutant mitochondrial DNA (mtDN A) in leukocytes does not appear to correlate with the severity of dia betes in terms of the insulin therapy required, Body mass index of the affected individuals was less than 23.3, In one family, in addition t o diabetes mellitus and hearing loss, hypoparathyroidism was associate d with the mutation, suggesting that hypoparathyroidism is caused by t he impaired processing and/or secretion of proparathyroid hormone due to the mutation, In addition, the affected subjects presented with pro teinuria at the time of diagnosis of diabetes mellitus which appeared not to be related with diabetic nephropathy.