MITOCHONDRIAL MUTATION ASSOCIATED WITH NONSYNDROMIC DEAFNESS

Purpose: The first mutation associated with nonsyndromic deafness has recently been identified in pedigrees with susceptibility to aminoglyc oside ototoxicity and in a large Arab-Israeli pedigree. The mutation i s maternally transmitted, and is a nucleotide substitution in the mito chondrial 12S ribosomal RNA gene. A different sequence change, in the mitochondrial tRNA(Ser(UCN))/COI gene, has been proposed as a candidat e mutation in a Scottish nonsyndromic deafness pedigree. We have now i dentified a family in New Zealand with maternally inherited nonsyndrom ic sensorineural deafness, and the purpose of the current study is to identify the molecular basis of deafness in this family. Materials and Methods: A family tree was established by history and chart review, a nd audiological and clinical data were obtained. Blood was sampled fro m 10 family members, and lymphoblastoid cell lines were established fo r 4 of them. The DNA of these individuals was extracted, and the mitoc hondrial genome was analyzed by Southern blot analysis for gross rearr angements. Subsequently, the entire coding sequence of the mitochondri al genome was sequenced, compared to the normal sequence, and all sequ ence variations were analyzed by allele-specific oligonucleotide hybri dization or restriction enzyme analysis. Results: Several candidate mu tations were identified, one of them being the nucleotide 7445 A --> G mutation in the mitochondrial tRNA(Ser(UCN))/COI gene. This mutation was heteroplasmic and identical to the one previously identified in th e Scottish pedigree. Conclusions: The finding of the same heteroplasmi c mutation in two independent pedigrees with the same phenotype and tr ansmission pattern, establishes this sequence change as the most likel y determinant of the deafness phenotype in these families. This implie s that nonsyndromic deafness can be caused by mutations in generalized cell processes, such as oxidative phosphorylation, rather than in hea ring specific molecules. Copyright (C) 1995 by W.B. Saunders Company