title: Mutations of human NARS2, encoding the mitochondrial asparaginyl-tRNA synthetase, cause nonsyndromic deafness and Leigh syndrome.
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.
authors: 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.
authors: Mariella
authors: M
authors: Simon
authors: Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, United States of America.
authors: Elodie M
authors: EM
authors: Richard
authors: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors: Xinjian
authors: X
authors: Wang
authors: Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, United States of America.
authors: Mohsin
authors: M
authors: Shahzad
authors: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors: Vincent H
authors: VH
authors: Huang
authors: National Center for Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
authors: Tanveer A
authors: TA
authors: Qaiser
authors: 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.
authors: Prasanth
authors: P
authors: Potluri
authors: Division of Pediatric Otolaryngology Head & Neck Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors: Sarah E
authors: SE
authors: Mahl
authors: Smilow Center for Translational Research, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors: Antonio
authors: A
authors: Davila
authors: National Center for Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
authors: Sabiha
authors: S
authors: Nazli
authors: Trovagene, San Diego, California, United States of America.
authors: Saege
authors: S
authors: Hancock
authors: Marshall B Ketchum University, Fullerton, California, United States of America.
authors: Margret
authors: M
authors: Yu
authors: Department of Physiology and Biophysics, University of California, Irvine, Irvine, California, United States of America.
authors: Jay
authors: J
authors: Gargus
authors: CHOC Childrens', Division of Metabolics, Orange, California, United States of America.
authors: Richard
authors: R
authors: Chang
authors: 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.
authors: Nada
authors: N
authors: Al-Sheqaih
authors: 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.
authors: William G
authors: WG
authors: Newman
authors: CHOC Childrens', Division of Metabolics, Orange, California, United States of America.
authors: Jose
authors: J
authors: Abdenur
authors: Department of Neurology and Neurobiology, University of California, Irvine, Irvine, California, United States of America.
authors: Arnold
authors: A
authors: Starr
authors: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors: Rashmi
authors: R
authors: Hegde
authors: Swiss Epilepsy Center, Zurich, Switzerland.
authors: Thomas
authors: T
authors: Dorn
authors: Institute of Molecular Biology, Mainz, Germany.
authors: Anke
authors: A
authors: Busch
authors: Department of Developmental and Cellular Biology, School of Biological Sciences, University of California, Irvine, Irvine, California, United States of America.
authors: Eddie
authors: E
authors: Park
authors: Institute for Genomics and Bioinformatics, University of California, Irvine, Irvine, California, United States of America.
authors: Jie
authors: J
authors: Wu
authors: Architecture et Réactivité de l'ARN, CNRS, University of Strasbourg, IBMC, Strasbourg, France.
authors: Hagen
authors: H
authors: Schwenzer
authors: Parkinson's Institute and Clinical Center, Sunnyvale, California, United States of America.
authors: Adrian
authors: A
authors: Flierl
authors: Architecture et Réactivité de l'ARN, CNRS, University of Strasbourg, IBMC, Strasbourg, France.
authors: Catherine
authors: C
authors: Florentz
authors: Architecture et Réactivité de l'ARN, CNRS, University of Strasbourg, IBMC, Strasbourg, France.
authors: Marie
authors: M
authors: Sissler
authors: National Center for Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
authors: Shaheen N
authors: SN
authors: Khan
authors: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors: Ronghua
authors: R
authors: Li
authors: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors: Min-Xin
authors: MX
authors: Guan
authors: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: Thomas B
authors: TB
authors: Friedman
authors: 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.
authors: Doris K
authors: DK
authors: Wu
authors: Biochemistry and Genetics Department, UMR CNRS 6214-INSERM U1083, CHU Angers, Angers, France.
authors: Vincent
authors: V
authors: Procaccio
authors: 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.
authors: Sheikh
authors: S
authors: Riazuddin
authors: 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.
authors: Douglas C
authors: DC
authors: Wallace
authors: Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, United States of America.
authors: Zubair M
authors: ZM
authors: Ahmed
authors: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors: Taosheng
authors: T
authors: Huang
authors: Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, United States of America.
authors: Saima
authors: S
authors: Riazuddin
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D001226:Aspartate-tRNA Ligase / Q000096:biosynthesis / Q000235:genetics*; D003638:Deafness / Q000235:genetics / Q000473:pathology; D007758:Ear, Inner / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts; D015870:Gene Expression / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D007888:Leigh Disease / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics / Q000473:pathology; D020125:Mutation, Missense / Q000235:genetics; D010101:Oxygen Consumption / Q000235:genetics; D010375:Pedigree; D012346:RNA, Transfer, Amino Acyl / Q000235:genetics*
chemical_list: D012346:RNA, Transfer, Amino Acyl; D001226:Aspartate-tRNA Ligase; C000601756:NARS2 protein, human; C029194:asparaginyl-tRNA synthetase