Non-insulin-dependent (type II) diabetes mellitus (NIDDM) is characterized by hyperglycaemia and insulin resistance, and affects nearly 5% of the general population. Inherited factors are important for its development, but the genes involved are unknown. We have identified a large pedigree in which NIDDM, in combination with a sensorineural hearing loss, is maternally inherited. The maternal inheritance and the observed decrease in mitochondrial enzyme activities of the respiratory chain indicate a genetic defect in the mitochondrial DNA. An A to G transition was identified at nucleotide 3,243, a conserved position in the mitochondrial gene for tRNA(Leu)(UUR). This mutation cosegregates with the disease in this family and is absent in controls, and indicates that a point mutation in mitochondrial DNA is a pathogenetic factor for NIDDM.

Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness.

The inner membranes of mitochondria contain three multi-subunit enzyme complexes that act successively to transfer electrons from NADH to oxygen, which is reduced to water (Fig. I). The first enzyme in the electron transfer chain, NADH:ubiquinone oxidoreductase (or complex I), is the subject of this review. It removes electrons from NADH and passes them via a series of enzyme-bound redox centres (FMN and Fe-S clusters) to the electron acceptor ubiquinone. For each pair of electrons transferred from NADH to ubiquinone it is usually considered that four protons are removed from the matrix (see section 4.1 for further discussion of this point).

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/S003358350000425X

The NADH:ubiquinone oxidoreductase (complex I) of respiratory chains.

Cytoplasts from two unrelated patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) harboring an A----G transition at nucleotide position 3243 in the tRNA(Leu(UUR)) gene of the mitochondrial genome were fused with human cells lacking endogenous mitochondrial DNA (mtDNA) (rho 0 cells). Selected cybrid lines, containing less than 15 or greater than or equal to 95% mutated genomes, were examined for differences in genetic, biochemical, and morphological characteristics. Cybrids containing greater than or equal to 95% mutant mtDNA, but not those containing normal mtDNA, exhibited decreases in the rates of synthesis and in the steady-state levels of the mitochondrial translation products. In addition, NADH dehydrogenase subunit 1 (ND 1) exhibited a slightly altered mobility on polyacrylamide gel electrophoresis. The mutation also correlated with a severe respiratory chain deficiency. A small but consistent increase in the steady-state levels of an RNA transcript corresponding to 16S rRNA + tRNA(Leu(UUR)) + ND 1 genes was detected. However, there was no evidence of major errors in processing of the heavy-strand-encoded transcripts or of altered steady-state levels or ratios of mitochondrial rRNAs or mRNAs. These results provide evidence for a direct relationship between the tRNALeu(UUR) mutation and the pathogenesis of this mitochondrial disease.

Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the tRNA(Leu(UUR)) mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes.

Approximately three years ago, this journal published a review on the clinical and molecular analysis of mitochondrial encephalomyopathies, with emphasis on defects in mitochondrial DNA (mtDNA). At that time, approximately 30 point mutations associated with a variety of maternally-inherited (or rarely, sporadic) disorders had been described. Since that time, almost twenty new pathogenic mtDNA point mutations have been described, and the pace of discovery of such mutations shows no signs of abating. This accumulating body of data has begun to reveal some patterns that may be relevant to pathogenesis.

Mitochondrial DNA mutations and pathogenesis.

Diabetes mellitus associated with a pathogenic point mutation in mitochondrial DNA

We studied 23 patients with clinically defined mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), 25 oligosymptomatic or asymptomatic maternal relatives, and 50 mitochondrial disease control subjects for the presence of a previously reported heteroplasmic point mutation at nt 3,243 in the transfer RNA(Leu(UUR)) gene of mitochondrial DNA. We found a high concordance between clinical diagnosis of MELAS and transfer RNA(Leu(UUR)) mutation, which was present in 21 of the 23 patients with MELAS, all 11 oligosymptomatic and 12 of 14 asymptomatic relatives, but in only five of 50 patients without MELAS. The proportion of mutant genomes in muscle ranged from 56 to 95% and was significantly higher in the patients with MELAS than in their oligosymptomatic or asymptomatic relatives. In subjects in whom both muscle and blood were studied, the percentage of mutations was significantly lower in blood and was not detected in three of 12 asymptomatic relatives. The activities of complexes I + III, II + III, and IV were decreased in muscle biopsies harboring the mutation, but there was no clear correlation between percentage of mutant mitochondrial DNAs and severity of the biochemical defect.

MELAS: Clinical features, biochemistry, and molecular genetics

• Objective. —To study and describe a large family with the tRNA Leu(UUR) point mutation at position 3243 in mitochondrial DNA, which is associated with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes. Design. —Survey; case series. Setting. —University hospital inpatient and outpatient neurology department. Patients. —Twelve patients from three generations in a family carrying the tRNA Leu(UUR) point mutation at position 3243 were studied. Interventions. —Clinical evaluation, muscle biopsy, and mitochondrial DNA point mutation quantitation of the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes in muscle and blood. Main Outcome Measure. —Correlation between clinical, pathologic, and genotypic features. Results. —Family members had various combinations of sensorineural hearing loss, retinal pigmentary degeneration, migraine, hypothalamic hypogonadism, and mild myopathy. Only one member had a strokelike episode at the age of 46 years. This patient had the highest point mutation percentage. Conclusion. —This report suggests that this point mutation may not be associated with stroke in all families and that whether patients develop stroke may depend on the percentage of mutant mitochondrial DNA and its tissue distribution.

R. K. Mosewich

Papers

MELAS: Clinical features, biochemistry, and molecular genetics

The syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes presenting without stroke