Retinitis pigmentosa and progressive sensorineural hearing loss caused by a C12258A mutation in the mitochondrial MTTS2 gene

Family ZMK is a large Irish kindred that segregates progressive sensorineural hearing loss and retinitis pigmentosa. The symptoms in the family are almost identical to those observed in Usher syndrome type III. Unlike that in Usher syndrome type III, the inheritance pattern in this family is compatible with dominant, X-linked dominant, or maternal inheritance. Prior linkage studies had resulted in exclusion of most candidate loci and >90% of the genome. A tentative location for a causative nuclear gene had been established on 9q; however, it is notable that 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-->A transversion at position 12258 in the gene encoding the second mitochondrial serine tRNA, MTTS2, 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 probably disrupts the amino acid-acceptor stem of the tRNA molecule, affecting aminoacylation of the tRNA and thereby reducing the efficiency and accuracy of mitochondrial translation. In summary, the data presented provide substantial evidence that the C12258A mtDNA mutation is causative of the disease phenotype in family ZMK.