De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects.

Autor:	Manole A; Department of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK., Efthymiou S; Department of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK., O'Connor E; Department of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK., Mendes MI; Metabolic Unit, Department of Clinical Chemistry, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam Gastroenterology and Metabolism, Amsterdam, 1081 the Netherlands., Jennings M; Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0QQ UK., Maroofian R; Department of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK., Davagnanam I; Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK., Mankad K; Department of Neuroradiology, Great Ormond Street Hospital for Children, London, WC1N 3JH, UK., Lopez MR; Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London (UCL), London, WC1E 6BT, UK., Salpietro V; Department of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK., Harripaul R; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, ON, M5T 1R8, Canada; Institute of Medical Science and Department of Psychiatry, University of Toronto, Toronto, ON, M5T 1R8, Canada., Badalato L; Department of Pediatrics, Queen's University, Kingston, ON, K7L 2V7, Canada., Walia J; Department of Pediatrics, Queen's University, Kingston, ON, K7L 2V7, Canada., Francklyn CS; Department of Biochemistry, University of Vermont College of Medicine, Burlington, VT 05405, USA., Athanasiou-Fragkouli A; Department of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK., Sullivan R; Department of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK., Desai S; Department of Neurology and Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Baranano K; Department of Neurology and Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Zafar F; Department of Pediatrics, Multan Hospital, Multan, 60000, Pakistan., Rana N; Department of Pediatrics, Multan Hospital, Multan, 60000, Pakistan., Ilyas M; University of Islamabad, Islamabad, 45320, Pakistan., Horga A; Department of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK., Kara M; Department of Pediatrics, Tripoli Children's Hospital, Tripoli, Libya., Mattioli F; Institute for Genetics and Molecular and Cellular Biology (IGBMC), University of Strasbourg, CNRS UMR7104, INSERM U1258, Illkirch, 67404, France., Goldenberg A; Département de Génétique, centre de référence anomalies du développement et syndromes malformatifs, CHU de Rouen, Inserm U1245, UNIROUEN, Normandie Université, Centre Normand de Génomique et de Médecine Personnalisée, Rouen, 76031, France., Griffin H; Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0QQ UK., Piton A; Institute for Genetics and Molecular and Cellular Biology (IGBMC), University of Strasbourg, CNRS UMR7104, INSERM U1258, Illkirch, 67404, France., Henderson LB; GeneDx, 207 Perry Parkway Gaithersburg, MD 20877, USA., Kara B; Bezmiâlem Vakıf Üniversitesi, Istanbul, 34093, Turkey., Aslanger AD; Bezmiâlem Vakıf Üniversitesi, Istanbul, 34093, Turkey., Raaphorst J; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500HB Nijmegen, the Netherlands; Department of Neurology, Amsterdam Neuroscience Institute, Amsterdam University Medical Center, 1105AZ Amsterdam, the Netherlands., Pfundt R; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500HB Nijmegen, the Netherlands., Portier R; Department of Neurology, Medisch Spectrum Twente, 7512KZ Enschede, the Netherlands., Shinawi M; Department of Pediatrics, Divisions of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA., Kirby A; Division of Medical Genetics, SSM Health Cardinal Glennon Children's Hospital, Saint Louis University School of Medicine, St. Louis, MO 63104, USA., Christensen KM; Division of Medical Genetics, SSM Health Cardinal Glennon Children's Hospital, Saint Louis University School of Medicine, St. Louis, MO 63104, USA., Wang L; Howard Hughes Medical Institute, University of California San Diego and Rady Children's Hospital, La Jolla, CA 92130, USA., Rosti RO; Howard Hughes Medical Institute, University of California San Diego and Rady Children's Hospital, La Jolla, CA 92130, USA., Paracha SA; Institute of Basic Medical Sciences, Khyber Medical University, 25100 Peshawar, Pakistan., Sarwar MT; Institute of Basic Medical Sciences, Khyber Medical University, 25100 Peshawar, Pakistan., Jenkins D; Institute of Child Health, Guilford Street and Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children, London, WC1N 3JH, UK., Ahmed J; Institute of Basic Medical Sciences, Khyber Medical University, 25100 Peshawar, Pakistan., Santoni FA; Department of Genetic Medicine and Development, University of Geneva, 1206 Geneva, Switzerland; Department of Endocrinology, Diabetes, and Metabolism, University Hospital of Lausanne, 1011 Lausanne, Switzerland., Ranza E; Department of Genetic Medicine and Development, University of Geneva, 1206 Geneva, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland; Medigenome, The Swiss Institute of Genomic Medicine, Geneva, CH-1207, Switzerland., Iwaszkiewicz J; Swiss Institute of Bioinformatics, Molecular Modeling Group, Batiment Genopode, Unil Sorge, Lausanne, CH-1015, Switzerland., Cytrynbaum C; Hospital for Sick Children, Division of Clinical and Metabolic Genetics, 555 University Ave., Toronto, M5G 1X8, Canada., Weksberg R; Hospital for Sick Children, Division of Clinical and Metabolic Genetics, 555 University Ave., Toronto, M5G 1X8, Canada., Wentzensen IM; GeneDx, 207 Perry Parkway Gaithersburg, MD 20877, USA., Guillen Sacoto MJ; GeneDx, 207 Perry Parkway Gaithersburg, MD 20877, USA., Si Y; GeneDx, 207 Perry Parkway Gaithersburg, MD 20877, USA., Telegrafi A; GeneDx, 207 Perry Parkway Gaithersburg, MD 20877, USA., Andrews MV; Department of Pediatrics, Divisions of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA., Baldridge D; Department of Pediatrics, Divisions of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA., Gabriel H; CeGaT GmbH and Praxis für Humangenetik Tuebingen, Tuebingen, 72076, Germany., Mohr J; CeGaT GmbH and Praxis für Humangenetik Tuebingen, Tuebingen, 72076, Germany., Oehl-Jaschkowitz B; Biomedical Centre Cardinal-Wendel-Straße 14, 66424 Hamburg, Germany., Debard S; University of Strasbourg, CNRS, GMGM UMR 7156, Strasbourg, 67083, France., Senger B; University of Strasbourg, CNRS, GMGM UMR 7156, Strasbourg, 67083, France., Fischer F; University of Strasbourg, CNRS, GMGM UMR 7156, Strasbourg, 67083, France., van Ravenwaaij C; University of Groningen, University Medical Center Groningen, Department of Neurology, Groningen, 9713, the Netherlands., Fock AJM; University of Groningen, University Medical Center Groningen, Department of Neurology, Groningen, 9713, the Netherlands., Stevens SJC; Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, 6211, the Netherlands., Bähler J; Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London (UCL), London, WC1E 6BT, UK., Nasar A; Department of Pediatrics, Queen's University, Kingston, ON, K7L 2V7, Canada., Mantovani JF; Division of Child Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA., Manzur A; Institute of Child Health, Guilford Street and Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children, London, WC1N 3JH, UK., Sarkozy A; Institute of Child Health, Guilford Street and Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children, London, WC1N 3JH, UK., Smith DEC; Metabolic Unit, Department of Clinical Chemistry, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam Gastroenterology and Metabolism, Amsterdam, 1081 the Netherlands., Salomons GS; Metabolic Unit, Department of Clinical Chemistry, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam Gastroenterology and Metabolism, Amsterdam, 1081 the Netherlands., Ahmed ZM; Department of Biochemistry and Molecular Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Riazuddin S; Jinnah Burn and Reconstructive Surgery Center, Allama Iqbal Medical College, University of Health Sciences, Lahore 54550, Pakistan., Riazuddin S; Department of Biochemistry and Molecular Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Usmani MA; Department of Biochemistry and Molecular Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Seibt A; Department of General Pediatrics, Heinrich-Heine-University, Moorenstr. 5, 40225 Düsseldorf, Germany., Ansar M; Department of Genetic Medicine and Development, University of Geneva, 1206 Geneva, Switzerland; Institute of Molecular and Clinical Ophthalmology Basel, Basel Switzerland., Antonarakis SE; Department of Genetic Medicine and Development, University of Geneva, 1206 Geneva, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland; iGE3 Institute of Genetics and Genomics of Geneva, 1211 Geneva, Switzerland., Vincent JB; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, ON, M5T 1R8, Canada; Institute of Medical Science and Department of Psychiatry, University of Toronto, Toronto, ON, M5T 1R8, Canada., Ayub M; Department of Pediatrics, Queen's University, Kingston, ON, K7L 2V7, Canada., Grimmel M; Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany., Jelsig AM; Department of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, 2100, Denmark., Hjortshøj TD; Department of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, 2100, Denmark., Karstensen HG; Department of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, 2100, Denmark., Hummel M; Department of Pediatrics, Section of Medical Genetics, West Virginia University, Morgantown, WV 26506-9600, USA., Haack TB; Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany; Centre for Rare Diseases, University of Tuebingen, 72076 Tübingen, Germany., Jamshidi Y; Genetics Centre, Molecular and Clinical Sciences Institute, St George's University of London, London, SW17 0RE, UK., Distelmaier F; Department of General Pediatrics, Heinrich-Heine-University, Moorenstr. 5, 40225 Düsseldorf, Germany., Horvath R; Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0QQ UK., Gleeson JG; Howard Hughes Medical Institute, University of California San Diego and Rady Children's Hospital, La Jolla, CA 92130, USA., Becker H; University of Strasbourg, CNRS, GMGM UMR 7156, Strasbourg, 67083, France., Mandel JL; Institute for Genetics and Molecular and Cellular Biology (IGBMC), University of Strasbourg, CNRS UMR7104, INSERM U1258, Illkirch, 67404, France., Koolen DA; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500HB Nijmegen, the Netherlands., Houlden H; Department of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK. Electronic address: h.houlden@ucl.ac.uk.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2020 Aug 06; Vol. 107 (2), pp. 311-324. Date of Electronic Publication: 2020 Jul 31.
DOI:	10.1016/j.ajhg.2020.06.016
Abstrakt:	Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function. (Copyright © 2020. Published by Elsevier Inc.)
Databáze:	MEDLINE
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