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

Mariella Simon; Elodie M Richard; Xinjian Wang; Mohsin Shahzad; Vincent H Huang; Tanveer A Qaiser; Prasanth Potluri; Sarah E Mahl; Antonio Davila; Sabiha Nazli; Saege Hancock; Margret Yu; Jay Gargus; Richard Chang; Nada Al-Sheqaih; William G Newman; Jose Abdenur; Arnold Starr; Rashmi Hegde; Thomas Dorn; Anke Busch; Eddie Park; Jie Wu; Hagen Schwenzer; Adrian Flierl; Catherine Florentz; Marie Sissler; Shaheen N Khan; Ronghua Li; Min-Xin Guan; Thomas B Friedman; Doris K Wu; Vincent Procaccio; Sheikh Riazuddin; Douglas C Wallace; Zubair M Ahmed; Taosheng Huang; Saima Riazuddin

doi:10.1371/journal.pgen.1005097

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

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

Mariella Simon, Elodie M Richard, Xinjian Wang, Mohsin Shahzad, Vincent H Huang, Tanveer A Qaiser, Prasanth Potluri, Sarah E Mahl, Antonio Davila, Sabiha Nazli, …

PLoS genetics, Vol.11(3), pp.e1005097-e1005097

01/03/2015

DOI: https://doi.org/10.1371/journal.pgen.1005097

PMID: 25807530

Résumé

Adult

Amino Acid Sequence - genetics

Animals

Aspartate-tRNA Ligase - biosynthesis

Aspartate-tRNA Ligase - genetics

Deafness - genetics

Deafness - pathology

Ear, Inner - metabolism

Ear, Inner - pathology

Female

Fibroblasts

Gene Expression - genetics

Genetic Predisposition to Disease

Humans

Leigh Disease - genetics

Leigh Disease - pathology

Male

Mice

Middle Aged

Mitochondria - genetics

Mitochondria - pathology

Mutation, Missense - genetics

Oxygen Consumption - genetics

Pedigree

RNA, Transfer, Amino Acyl - genetics

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.

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Titre: Mutations of human NARS2, encoding the mitochondrial asparaginyl-tRNA synthetase, cause nonsyndromic deafness and Leigh syndrome
Créateurs - sans rôle: Mariella Simon
Elodie M Richard - Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, United States of America
Xinjian Wang - Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America
Mohsin Shahzad - Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, United States of America
Vincent H Huang - Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America
Tanveer A Qaiser - National Center for Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
Prasanth Potluri - 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
Sarah E Mahl - Division of Pediatric Otolaryngology Head & Neck Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America
Antonio Davila - Smilow Center for Translational Research, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
Sabiha Nazli - National Center for Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
Saege Hancock - Trovagene, San Diego, California, United States of America
Margret Yu - Marshall B Ketchum University, Fullerton, California, United States of America
Jay Gargus - Department of Physiology and Biophysics, University of California, Irvine, Irvine, California, United States of America
Richard Chang - CHOC Childrens', Division of Metabolics, Orange, California, United States of America
Nada Al-Sheqaih - 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
William G Newman - 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
Jose Abdenur - CHOC Childrens', Division of Metabolics, Orange, California, United States of America
Arnold Starr - Department of Neurology and Neurobiology, University of California, Irvine, Irvine, California, United States of America
Rashmi Hegde - Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America
Thomas Dorn - Swiss Epilepsy Center, Zurich, Switzerland
Anke Busch - Institute of Molecular Biology, Mainz, Germany
Eddie Park - Department of Developmental and Cellular Biology, School of Biological Sciences, University of California, Irvine, Irvine, California, United States of America
Jie Wu - Institute for Genomics and Bioinformatics, University of California, Irvine, Irvine, California, United States of America
Hagen Schwenzer - Architecture et Réactivité de l'ARN, CNRS, University of Strasbourg, IBMC, Strasbourg, France
Adrian Flierl - Parkinson's Institute and Clinical Center, Sunnyvale, California, United States of America
Catherine Florentz - Architecture et Réactivité de l'ARN, CNRS, University of Strasbourg, IBMC, Strasbourg, France
Marie Sissler - Architecture et Réactivité de l'ARN, CNRS, University of Strasbourg, IBMC, Strasbourg, France
Shaheen N Khan - National Center for Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
Ronghua Li - Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America
Min-Xin Guan - Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America
Thomas B Friedman - Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, United States of America
Doris K Wu - 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
Vincent Procaccio - Centre Hospitalier Universitaire d'Angers
Sheikh Riazuddin
Douglas C Wallace - University of Pennsylvania
Zubair M Ahmed - Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, United States of America
Taosheng Huang - Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America
Saima Riazuddin - Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, United States of America
Détails de publication: PLoS genetics, Vol.11(3), pp.e1005097-e1005097
Note de subvention: R01 DC011803 / NIDCD NIH HHS T32 DC000039 / NIDCD NIH HHS R01 EY022917 / NEI NIH HHS UL1 TR001414 / NCATS NIH HHS NS21328 / NINDS NIH HHS R01 DC012564 / NIDCD NIH HHS R01DC011748 / NIDCD NIH HHS NIDCD DC000039-17 / PHS HHS R01 NS021328 / NINDS NIH HHS Z01 DC000039 / Intramural NIH HHS
Identifiants: 99148063709311
Unité académique: Mécanismes Moléculaires dans les Démences Neurodégénératives - MMDN
Langue: English
Type de ressource: Journal article