MATERNALLY INHERITED DIABETES AND DEAFNESS IS A DISTINCT SUBTYPE OF DIABETES AND ASSOCIATES WITH A SINGLE-POINT MUTATION IN THE MITOCHONDRIAL TRNA(LEU(UUR)) GENE

We have recently reported an A to G transition at nucleotide position 3243 in the mitochondrial DNA (mtDNA) tRNA(Leu(UUR)) gene in a large f amily with non-insulin-dependent diabetes mellitus (NIDDM). Characteri stic was its maternal transmission and an associated sensorineural hea ring loss. In a screening of a Dutch and French NIDDM population for t he presence of the tRNA(Leu(UUR)) mutation we identified two new pedig rees in which NIDDM is present in combination with deafness. The mode of inheritance agrees with a maternal one. This result shows that pati ents with a phenotype of NIDDM and deafness can be identified within g roups of NIDDM patients based on the tRNA(Leu(UUR)) mutation. The same mutation has also been linked to the syndrome of mitochondrial myopat hy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). How the same mutation can give rise to different clinical phenotypes is not clear. We obtained the complete mtDNA sequence from our initial pedigree and identified a number of additional mutations that could c onfer the phenotype of the tRNA(Leu(UUR)) mutation to diabetes. We exa mined the presence of these additional, potentially pathogenic mutatio ns in the mtDNA from the two new pedigrees and from a previously descr ibed British pedigree. The absence of these mutations in all three ped igrees shows that the tRNA(Leu(UUR)) mutation alone associates with th e phenotype of NIDDM and deafness. We conclude that maternally inherit ed diabetes and deafness is a distinct subtype of diabetes that is ass ociated with a single mitochondrial tRNA(Leu(UUR)) mutation. We propos e the abbreviation MIDD for this particular subtype.