Mitochondrial Diabetes and Wolfram Syndrome

Mitochondria contain their own genetic information in the form of a circular DNA molecule of l6 569 base pairs that encodes l3 subunits of the oxidative phosphorylation complex, 2 ribosomal RNAs and 22 transfer RNAs (tRNA) needed for mitochondrial protein synthesis. Several mitochondrial cytopathies and syndromes caused by point mutations, deletions or duplications of mitochondrial DNA (mtDNA) and characterized by decreased oxidative phosphorylation are associated with diabetes (64,65). Moreover, about 40 point mutations of mtDNA have been now identified in subjects and families having maternally inherited diabetes as the main phenotypic trait (66). Only one of these mutations, an A to G transition in the mitochondrial tRNALeu(UUR) gene at base-pair 3243, has been systematically tested and phenotypically characterized in several populations (4,67-72). It co-segregates in families with diabetes and sensorineural deafness of maternal transmission, a syndrome known as maternally inherited diabetes and deafness (MIDD). In some populations, MIDD might represent 1-3% of all cases of Type 2 diabetes. The same mutation was also observed in patients with MELAS, a syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, which is often accompanied by diabetes and deafness (73). The mechanisms underlying the different phenotypic expression (MIDD or MELAS) are unknown, but might be related to the variable degree of heteroplasmy in different tissues.

Subjects with the 3243 mutation may present with variable clinical features, ranging from normal glucose tolerance to insulin-requiring diabetes. However, abnormalities in insulin secretion were found in all MIDD subjects that were tested, including those with normal glucose tolerance (74). The pathophysiological mechanisms leading to hyperglycemia and often to insulin-requiring diabetes in this syndrome are probably complex and multifactorial, and might include defects in insulin production, glucose toxicity, as well as insulin resistance. However, a defect of glucose-regulated insulin secretion is an early, possible primary abnormality in carriers of the mutation (74). This defect probably results from the progressive reduction of oxidative phosphory-lation in beta-cells caused by the accumulation of mutant mitochondrial DNA in the cells (64,68).

Wolfram syndrome or the acronym DID-MOAD describe patients with diabetes insipidus, diabetes mellitus, optical atrophy and deafness. Other endocrine and neurological abnormalities are often associated in this genetically and clinically heterogeneous syndrome. Wolfram syn drome is frequently transmitted as an autosomal recessive disorder by a locus mapped to the short arm chromosome 4. This gene, named WFS1, was recently identified (75,76). It encodes wolframin, a protein showing no perceptible homology to known DNA or protein sequence (77). The physiological function of wolframin and its link to diabetes remain totally unclear. In contrast with this autosomal recessive transmission, a few cases of Wolfram syndrome were found to be associated with mitochondrial DNA mutations (78,79).

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