Mutations of Human , Encoding the Mitochondrial Asparaginyl-tRNA Synthetase, Cause Nonsyndromic Deafness and Leigh Syndrome

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Mitochondrial respiratory chain (MRC) disease represents a large and heterogeneous group of energy deficiency disorders. Here we report three mutations in NARS2, a mitochondrial asparaginyl-tRNA synthetase, associated with non-syndromic hearing loss (NSHL) and Leigh syndrome in two independent families. Located in the predicted catalytic domain of the protein, missense mutation p.(Val213Phe) results in NSHL (DFNB94) while compound heterozygous mutation (p.Tyr323*; p.Asn381Ser) is leading to Leigh syndrome with auditory neuropathy. In vivo analysis deemed p.Tyr323* mutant protein to be unstable. Co-immunoprecipitation assays show that p.Asn381Ser mutant disrupts the dimerization ability of NARS2. Leigh syndrome patient fibroblasts exhibit a decreased steady-state level of mt-tRNAAsn. In addition, in these cells, the mitochondrial respiratory chain is deficient, including significantly decreased oxygen consumption rates and electron transport chain activities. These functions can be partially restored with over-expression of wild-type NARS2 but not with p.Val213Phe mutant protein. Our study provides new insights into the genes that are necessary for the function of brain and inner ear sensory cells in humans.

Vyšlo v časopise: Mutations of Human , Encoding the Mitochondrial Asparaginyl-tRNA Synthetase, Cause Nonsyndromic Deafness and Leigh Syndrome. PLoS Genet 11(3): e32767. doi:10.1371/journal.pgen.1005097
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005097

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