ArticleGenetics in medicine : official journal of the American College of Medical Genetics2023
Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder.
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Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed, 11 citations in OpenAlex.
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- A CpG Epigenetic Switch Reverts PFAS ToxicityAn In Vitro Study.Environment & health (Washington, D.C.) · 2025Article
- Neurogenetic Disorders with Hearing Loss: Mechanisms, Classifications, and Emerging Insights.Current neurology and neuroscience reports · 2025Review
- Neonatal diabetes mellitus is a significant feature of COXPD-24 caused by recessive NARS2 variants.Diabetic medicine : a journal of the British Diabetic Association · 2025Article
- Morpholino Knockdown in Zebrafish: A Tool to Investigate the Functional Impact of Variants of Unknown Significance in Mitochondrial Diseases.Neuromolecular medicine · 2025Review
- A homozygous TARS2 variant is a novel cause of syndromic neonatal diabetes.Diabetic medicine : a journal of the British Diabetic Association · 2025Article
- Article
- TARS2 c.470 C > G is a chinese-specific founder mutation in three unrelated families with mitochondrial encephalomyopathy.Orphanet journal of rare diseases · 2024Article
- Expanding the Phenotypic Spectrum: Chronic Kidney Disease in a Patient with Combined Oxidative Phosphorylation Defect 21.Balkan journal of medical genetics : BJMG · 2023Article
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Authors and funding
59 authors at 20 institutions in 12 countries.
Andrea AccogliDivision of Medical Genetics, Department of Specialized Medicine, Montreal Children's Hospital, McGill University Health Centre (MUHC), Montreal, Canada; Department of Human Genetics, McGill University, Montreal, QC, Canada.
Sheng-Jia LinGenes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK.
Mariasavina SeverinoNeuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Sung-Hoon KimGoodman Cancer Institute, McGill University, Montreal, Canada; Department of Biochemistry, McGill University, Montreal, Canada.
Kevin HuangGenes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK.
Clarissa RoccaDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom.
Megan LandsverkUniversity of South Dakota Sanford School of Medicine Sioux Falls, SD; Sanford Research, Pediatrics and Rare Diseases Group, Sioux Falls, SD.
Maha S ZakiHuman Genetics and Genome Research Institute, Clinical Genetics Department, National Research Centre, Cairo, Egypt.
Almundher Al-MaawaliDepartment of Genetics, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman; Genetic and Developmental Medicine Clinic, Sultan Qaboos University Hospital, Muscat, Oman.
Varunvenkat M SrinivasanIndira Gandhi Institute of Child Health, Bangalore, India.
Khalid Al-ThihliDepartment of Genetics, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman; Genetic and Developmental Medicine Clinic, Sultan Qaboos University Hospital, Muscat, Oman.
G Bradly SchaeferDepartment of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR.
Monica DavisDepartment of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR.
Davide TondutiUnit of Pediatric Neurology, COALA (Center for Diagnosis and Treatment of Leukodystrophies), V. Buzzi Children's Hospital, Milan, Italy; Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
Chiara DonedaPediatric Radiology and Neuroradiology Department, Children's Hospital Vittore Buzzi, Milan, Italy.
Lara M MartenDepartment of Pediatrics and Adolescent Medicine, University Medical Center Göttingen, Germany.
Chris MühlhausenDepartment of Pediatrics and Adolescent Medicine, University Medical Center Göttingen, Germany.
Maria GomezCentro de Obsetricia y Ginecologia & Centro Medico Moderno, Santo Domingo, Dominican Republic.
Eleonora LamanteaUnit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
Rafael MenaDivision of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Centro de Obsetricia y Ginecologia, Santo Domingo, Dominican Republic.
Mathilde NizonService de Génétique Médicale, CHU de Nantes, Nantes Université, Nantes, France; Nantes Université, CNRS, INSERM, l'Institut du Thorax, Nantes, France.
Vincent ProcaccioUniversity of Angers, MitoLab Team, Unité MitoVasc, UMR CNRS 6015, INSERM U1083, SFR ICAT, Angers, France; Department of Genetics, CHU Angers, Angers, France.
Amber BegtrupGeneDx, Gaithersburg, MD.
Aida TelegrafiGeneDx, Gaithersburg, MD.
Hong CuiGeneDx, Gaithersburg, MD.
Heidi L SchulzHuman Genetic center Tübingen, Baden-Württemberg, Germany.
Julia MohrHuman Genetic center Tübingen, Baden-Württemberg, Germany.
Saskia BiskupHuman Genetic center Tübingen, Baden-Württemberg, Germany; CeGaT GmbH, Germany.
Mariana Amina LoosDepartment of Neurology, Hospital de Pediatría Juan P. Garrahan, Buenos Aires, Argentina.
Hilda Verónica AráozGenomics Laboratory, Hospital de Pediatría Juan P. Garrahan, Buenos Aires, Argentina.
Vincenzo SalpietroDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom; Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
Laura Davis KeppenUniversity of South Dakota Sanford School of Medicine Sioux Falls, SD; Sanford Research, Pediatrics and Rare Diseases Group, Sioux Falls, SD.
Manali ChitreCambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
Cassidy PetreeGenes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK.
Lucy RaymondCambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
Julie VogtWest Midlands Regional Genetics Service, Birmingham Women and Children's Hospital NHS Foundation Trust, Birmingham, United Kingdom.
Lindsey B SawyerChildren's Hospital of the King's Daughters, Norfolk, Virginia, VA.
Alice A BasingerChildren's Hospital of the King's Daughters, Norfolk, Virginia, VA.
Signe Vandal PedersenDepartment of Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
Toni S PearsonDepartment of Neurology, Washington University School of Medicine, St. Louis, MO.
Dorothy K GrangeDivision of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO; Center for the Investigation of Membrane Excitability Diseases (CIMED), St. Louis, MO.
Lokesh LingappaRainbow Children Hospital, Hyderabad, India.
Paige McDunnahDivision of Medical Genetics, Nemours/A I duPont Hospital for Children, Wilmington, DE.
Rita HorvathDepartment of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
Benjamin CognèService de Génétique Médicale, CHU de Nantes, Nantes Université, Nantes, France; Nantes Université, CNRS, INSERM, l'Institut du Thorax, Nantes, France.
Bertrand IsidorService de Génétique Médicale, CHU de Nantes, Nantes Université, Nantes, France.
Andreas HahnDepartment of Child Neurology, University Hospital, Gießen, Germany.
Karen W GrippDivision of Medical Genetics, Nemours/A I duPont Hospital for Children, Wilmington, DE.
Seyed Mehdi JafarnejadPatrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, United Kingdom.
Elsebet ØstergaardDepartment of Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
Carlos E PradaDivision of Genetics, Genomics, and Metabolism, Ann & Robert Lurie Children's Hospital of Chicago, Chicago; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago; Fundacion Cardiovascular de Colombia, Floridablanca, Colombia.
Daniele GhezziUnit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
Vykuntaraju K GowdaIndira Gandhi Institute of Child Health, Bangalore, India.
Robert W TaylorWellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom; NHS Highly Specialized Service for Rare Mitochondrial Disorders of Adults and Children, Newcastle University, Newcastle upon Tyne, United Kingdom.
Nahum SonenbergGoodman Cancer Institute, McGill University, Montreal, Canada; Department of Biochemistry, McGill University, Montreal, Canada.
Henry HouldenDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom.
Marie SisslerARNA - UMR5320 CNRS - U1212 INSERM, Université de Bordeaux, IECB, Pessac, France.
Gaurav K VarshneyGenes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK. Electronic address: gauravvarshney@omrf.org.
Reza MaroofianDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom. Electronic address: r.maroofian@ucl.ac.uk.
Centre National de la Recherche Scientifique · FROklahoma Medical Research Foundation · USBernstein Center for Computational Neuroscience Tübingen · DECambridge University Hospitals NHS Foundation Trust · GBChildren's Hospital of The King's Daughters · USCommunity Health Systems - Dupont Hospital · USCopenhagen University Hospital · DKFondazione IRCCS Istituto Neurologico Carlo Besta · ITGarrahan Hospital · ARIndira Gandhi Institute of Child Health · INMcGill University · CANational Hospital for Neurology and Neurosurgery · GBSanford Research · USSultan Qaboos University Hospital · OMUniversitätsmedizin Göttingen · DEUniversity of Arkansas for Medical Sciences · USWashington University in St. Louis · USBirmingham Women’s and Children’s NHS Foundation Trust · GBCeGaT (Germany) · DECentre Hospitalier Universitaire de Nantes · FR
Funding
Department of Health BRC-1215-20014Medical Research Council MR/S005021/1Medical Research Council MR/V009346/1Wellcome Trust 109915/Z/15/ZWellcome Trust 203105/Z/16/Z
Abstract
purposeBiallelic variants in TARS2, encoding the mitochondrial threonyl-tRNA-synthetase, have been reported in a small group of individuals displaying a neurodevelopmental phenotype but with limited neuroradiological data and insufficient evidence for causality of the variants.
methodsExome or genome sequencing was carried out in 15 families. Clinical and neuroradiological evaluation was performed for all affected individuals, including review of 10 previously reported individuals. The pathogenicity of TARS2 variants was evaluated using in vitro assays and a zebrafish model.
resultsWe report 18 new individuals harboring biallelic TARS2 variants. Phenotypically, these individuals show developmental delay/intellectual disability, regression, cerebellar and cerebral atrophy, basal ganglia signal alterations, hypotonia, cerebellar signs, and increased blood lactate. In vitro studies showed that variants within the TARS2
conclusionWe define the clinico-radiological spectrum of TARS2-related mitochondrial disease, unveil the likely involvement of the mTORC1 signaling pathway as a distinct molecular mechanism, and establish a TARS2 zebrafish model as an important tool to study variant pathogenicity.
Indexed as
RNA, TransferZebrafishAnimalsHumansLigasesMechanistic Target of Rapamycin Complex 1MutationPhenotypeLigasesMechanistic Target of Rapamycin Complex 1RNA, TransferCerebellar atrophyMitochondrial dysfunctionMitochondrial threonyl-tRNA-synthetasemTORC1 signalingTARS2
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