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PLoS Genet. 2015 Mar 25;11(3):e1005097. doi: 10.1371/journal.pgen.1005097. eCollection 2015 Mar.

Mutations of human NARS2, encoding the mitochondrial asparaginyl-tRNA synthetase, cause nonsyndromic deafness and Leigh syndrome.

Author information

1
Department of Developmental and Cellular Biology, School of Biological Sciences, University of California, Irvine, Irvine, California, United States of America; CHOC Childrens', Division of Metabolics, Orange, California, United States of America.
2
Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, United States of America.
3
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
4
National Center for Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
5
Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
6
Division of Pediatric Otolaryngology Head & Neck Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
7
Smilow Center for Translational Research, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
8
Trovagene, San Diego, California, United States of America.
9
Marshall B Ketchum University, Fullerton, California, United States of America.
10
Department of Physiology and Biophysics, University of California, Irvine, Irvine, California, United States of America.
11
CHOC Childrens', Division of Metabolics, Orange, California, United States of America.
12
Manchester Centre for Genomic Medicine, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre (MAHSC), Manchester, United Kingdom.
13
Department of Neurology and Neurobiology, University of California, Irvine, Irvine, California, United States of America.
14
Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
15
Swiss Epilepsy Center, Zurich, Switzerland.
16
Institute of Molecular Biology, Mainz, Germany.
17
Department of Developmental and Cellular Biology, School of Biological Sciences, University of California, Irvine, Irvine, California, United States of America.
18
Institute for Genomics and Bioinformatics, University of California, Irvine, Irvine, California, United States of America.
19
Architecture et Réactivité de l'ARN, CNRS, University of Strasbourg, IBMC, Strasbourg, France.
20
Parkinson's Institute and Clinical Center, Sunnyvale, California, United States of America.
21
Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, United States of America.
22
Section on Sensory Cell Regeneration and Development, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, United States of America.
23
Biochemistry and Genetics Department, UMR CNRS 6214-INSERM U1083, CHU Angers, Angers, France.
24
Jinnah Hospital Complex, Allama Iqbal Medical College, University of Health Sciences, Lahore, Pakistan; University of Lahore, Lahore, Pakistan; Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan.

Abstract

Here we demonstrate association of variants in the mitochondrial asparaginyl-tRNA synthetase NARS2 with human hearing loss and Leigh syndrome. A homozygous missense mutation ([c.637G>T; p.Val213Phe]) is the underlying cause of nonsyndromic hearing loss (DFNB94) and compound heterozygous mutations ([c.969T>A; p.Tyr323*] + [c.1142A>G; p.Asn381Ser]) result in mitochondrial respiratory chain deficiency and Leigh syndrome, which is a neurodegenerative disease characterized by symmetric, bilateral lesions in the basal ganglia, thalamus, and brain stem. The severity of the genetic lesions and their effects on NARS2 protein structure cosegregate with the phenotype. A hypothetical truncated NARS2 protein, secondary to the Leigh syndrome mutation p.Tyr323* is not detectable and p.Asn381Ser further decreases NARS2 protein levels in patient fibroblasts. p.Asn381Ser also disrupts dimerization of NARS2, while the hearing loss p.Val213Phe variant has no effect on NARS2 oligomerization. Additionally we demonstrate decreased steady-state levels of mt-tRNAAsn in fibroblasts from the Leigh syndrome patients. In these cells we show that a decrease in oxygen consumption rates (OCR) and electron transport chain (ETC) activity can be rescued by overexpression of wild type NARS2. However, overexpression of the hearing loss associated p.Val213Phe mutant protein in these fibroblasts cannot complement the OCR and ETC defects. Our findings establish lesions in NARS2 as a new cause for nonsyndromic hearing loss and Leigh syndrome.

PMID:
25807530
PMCID:
PMC4373692
DOI:
10.1371/journal.pgen.1005097
[Indexed for MEDLINE]
Free PMC Article

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