A 3243G-A mutation in the mitochondrial gene encoding tRNA for leucine(UUR) (590050.0001) is a frequently encountered change associated with diabetes mellitus. Lynn et al. (1998) described a family with extensive maternal transmission of cerebellar ataxia, cataracts, and diabetes, together with a mutation in the MTTS2 gene: 12258C-A. The index case was a 61-year-old woman who developed cataracts at 30 years of age, deafness at 39 years of age, and cerebellar ataxia at 57 years of age. Diabetes was diagnosed at 60 years of age and at the time of report was treated with gliclazide orally. She was lean, with a body mass index of 18 kg/m2. Her daughter was 30 years old at the time of report and developed deafness and cataracts in her early twenties. She was found to have impaired glucose tolerance. The 12258C-A mutation was heteroplasmic in both the mother and the daughter. Mutant mtDNA was highest in the muscle of the daughter (85%) compared with that of the mother (68.4%). Using the mismatch PCR technique, Lynn et al. (1998) found that the mutation accounted for 19.4% of the MTTS2 gene in the blood of the mother and 45% in the daughter. The mutation was not detected in 100 unrelated nondiabetic control subjects. The mutation was considered pathogenic for 3 reasons. It was heteroplasmic and had higher levels in muscle than in blood. The C-to-A transversion altered a highly conserved basepair in the acceptor stem of tRNA(ser) and would be expected to effect both secondary and tertiary structure as well as the function of this tRNA. The mutated DNA was at much higher levels in the COX-negative compared with the COX-positive fibers. This evidence confirmed that the mutation causes the observed biochemical defect in the muscle and presumably in the pancreatic beta cells, since insulin secretion is heavily dependent on oxidative metabolism, and mitochondrial dysfunction will impair insulin secretion.

Mansergh et al. (1999) described a large Irish kindred that segregated progressive sensorineural hearing loss and retinitis pigmentosa (500004). The symptoms in this family were almost identical to those observed in Usher syndrome type III (USH3; 276902). Unlike that in USH3, however, the inheritance pattern in the Irish family was compatible with autosomal dominant, X-linked dominant, or maternal inheritance. Prior linkage studies had resulted in exclusion of most candidate loci and more than 90% of the genome. A tentative location for a causative nuclear gene had been established on 9q; however, no markers were found at zero recombination with respect to the disease gene. The marked variability in symptoms, together with the observation of subclinical muscle abnormalities in a single muscle biopsy, stimulated sequencing of the entire mtDNA in affected and unaffected individuals. This revealed a number of previously reported polymorphisms and/or silent substitutions. However, a C-to-A transversion at position 12258 in the MTTS2 gene was heteroplasmic and was found in family members only. This sequence change was not present in 270 normal individuals from the same ethnic background. The consensus C at this position is highly conserved and is present in species as divergent from Homo sapiens as vulture and platypus. The mutation was thought to disrupt the amino acid-receptor stem of the tRNA molecule, affecting aminoacylation of the tRNA and thereby reducing the efficiency and accuracy of mitochondrial translation.

Wong et al. (2006) identified a heteroplasmic 12207G-A transition in the MTTS2 gene in a girl with clinical features of both MERRF (545000) and MELAS (540000) syndromes. Skeletal muscle studies showed ragged red fibers, significant pleomorphic mitochondrial proliferation, complex I deficiency (see 252010), and 92% mutation load. The 12207G-A mutation occurs at the first nucleotide of the 5-prime end of the molecule, which is involved in the formation of the stem region of the amino acid acceptor arm. The mutation was not found in the unaffected mother's peripheral blood or hair follicles nor in 200 controls. Wong et al. (2006) suggested that the mutation likely affects proper processing of the precursor MTTS2 mRNA and may also affect neighboring genes. Clinically, the patient showed severe developmental delay, feeding difficulties, recurrent infections, basal ganglia lesions, cerebral atrophy, proximal muscle weakness, increased serum lactate, and liver dysfunction.