De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects.
Journal: American journal of human genetics
Volume: 107
Issue: 2
Year of Publication: 2020
Affiliated Institutions: Department of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WCN BG, UK. Metabolic Unit, Department of Clinical Chemistry, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam Gastroenterology and Metabolism, Amsterdam, the Netherlands. Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB QQ UK. Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, Queen Square, London, WCN BG, UK. Department of Neuroradiology, Great Ormond Street Hospital for Children, London, WCN JH, UK. Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London (UCL), London, WCE BT, UK. Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, ON, MT R, Canada; Institute of Medical Science and Department of Psychiatry, University of Toronto, Toronto, ON, MT R, Canada. Department of Pediatrics, Queen's University, Kingston, ON, KL V, Canada. Department of Biochemistry, University of Vermont College of Medicine, Burlington, VT , USA. Department of Neurology and Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD , USA. Department of Pediatrics, Multan Hospital, Multan, , Pakistan. University of Islamabad, Islamabad, , Pakistan. Department of Pediatrics, Tripoli Children's Hospital, Tripoli, Libya. Institute for Genetics and Molecular and Cellular Biology (IGBMC), University of Strasbourg, CNRS UMR, INSERM U, Illkirch, , France. Département de Génétique, centre de référence anomalies du développement et syndromes malformatifs, CHU de Rouen, Inserm U, UNIROUEN, Normandie Université, Centre Normand de Génomique et de Médecine Personnalisée, Rouen, , France. GeneDx, Perry Parkway Gaithersburg, MD , USA. Bezmiâlem Vakıf Üniversitesi, Istanbul, , Turkey. Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, HB Nijmegen, the Netherlands; Department of Neurology, Amsterdam Neuroscience Institute, Amsterdam University Medical Center, AZ Amsterdam, the Netherlands. Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, HB Nijmegen, the Netherlands. Department of Neurology, Medisch Spectrum Twente, KZ Enschede, the Netherlands. Department of Pediatrics, Divisions of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, , USA. Division of Medical Genetics, SSM Health Cardinal Glennon Children's Hospital, Saint Louis University School of Medicine, St. Louis, MO , USA. Howard Hughes Medical Institute, University of California San Diego and Rady Children's Hospital, La Jolla, CA , USA. Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan. Institute of Child Health, Guilford Street and Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children, London, WCN JH, UK. SYNAPS Study Group, see Supplemental Information for the study group members who contributed clinical cases and data. Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland; Department of Endocrinology, Diabetes, and Metabolism, University Hospital of Lausanne, Lausanne, Switzerland. Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland; Medigenome, The Swiss Institute of Genomic Medicine, Geneva, CH-, Switzerland. Swiss Institute of Bioinformatics, Molecular Modeling Group, Batiment Genopode, Unil Sorge, Lausanne, CH-, Switzerland. Hospital for Sick Children, Division of Clinical and Metabolic Genetics, University Ave., Toronto, MG X, Canada. CeGaT GmbH and Praxis für Humangenetik Tuebingen, Tuebingen, , Germany. Biomedical Centre Cardinal-Wendel-Straße , Hamburg, Germany. University of Strasbourg, CNRS, GMGM UMR , Strasbourg, , France. University of Groningen, University Medical Center Groningen, Department of Neurology, Groningen, , the Netherlands. Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, , the Netherlands. Division of Child Neurology, Washington University School of Medicine, St. Louis, MO, , USA. Department of Biochemistry and Molecular Biology, Johns Hopkins School of Medicine, Baltimore, MD , USA. Jinnah Burn and Reconstructive Surgery Center, Allama Iqbal Medical College, University of Health Sciences, Lahore , Pakistan. Department of General Pediatrics, Heinrich-Heine-University, Moorenstr. , Düsseldorf, Germany. Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland; Institute of Molecular and Clinical Ophthalmology Basel, Basel Switzerland. Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland; iGE Institute of Genetics and Genomics of Geneva, Geneva, Switzerland. Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tübingen, Germany. Department of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, , Denmark. Department of Pediatrics, Section of Medical Genetics, West Virginia University, Morgantown, WV -, USA. Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tübingen, Germany; Centre for Rare Diseases, University of Tuebingen, Tübingen, Germany. Genetics Centre, Molecular and Clinical Sciences Institute, St George's University of London, London, SW RE, UK. Department of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WCN BG, UK. Electronic address: h.houlden@ucl.ac.uk.
Abstract summary
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.Authors & Co-authors: Manole Andreea A Efthymiou Stephanie S O'Connor Emer E Mendes Marisa I MI Jennings Matthew M Maroofian Reza R Davagnanam Indran I Mankad Kshitij K Lopez Maria Rodriguez MR Salpietro Vincenzo V Harripaul Ricardo R Badalato Lauren L Walia Jagdeep J Francklyn Christopher S CS Athanasiou-Fragkouli Alkyoni A Sullivan Roisin R Desai Sonal S Baranano Kristin K Zafar Faisal F Rana Nuzhat N Ilyas Muhammed M Horga Alejandro A Kara Majdi M Mattioli Francesca F Goldenberg Alice A Griffin Helen H Piton Amelie A Henderson Lindsay B LB Kara Benyekhlef B Aslanger Ayca Dilruba AD Raaphorst Joost J Pfundt Rolph R Portier Ruben R Shinawi Marwan M Kirby Amelia A Christensen Katherine M KM Wang Lu L Rosti Rasim O RO Paracha Sohail A SA Sarwar Muhammad T MT Jenkins Dagan D Ahmed Jawad J Santoni Federico A FA Ranza Emmanuelle E Iwaszkiewicz Justyna J Cytrynbaum Cheryl C Weksberg Rosanna R Wentzensen Ingrid M IM Guillen Sacoto Maria J MJ Si Yue Y Telegrafi Aida A Andrews Marisa V MV Baldridge Dustin D Gabriel Heinz H Mohr Julia J Oehl-Jaschkowitz Barbara B Debard Sylvain S Senger Bruno B Fischer Frédéric F van Ravenwaaij Conny C Fock Annemarie J M AJM Stevens Servi J C SJC Bähler Jürg J Nasar Amina A Mantovani John F JF Manzur Adnan A Sarkozy Anna A Smith Desirée E C DEC Salomons Gajja S GS Ahmed Zubair M ZM Riazuddin Shaikh S Riazuddin Saima S Usmani Muhammad A MA Seibt Annette A Ansar Muhammad M Antonarakis Stylianos E SE Vincent John B JB Ayub Muhammad M Grimmel Mona M Jelsig Anne Marie AM Hjortshøj Tina Duelund TD Karstensen Helena Gásdal HG Hummel Marybeth M Haack Tobias B TB Jamshidi Yalda Y Distelmaier Felix F Horvath Rita R Gleeson Joseph G JG Becker Hubert H Mandel Jean-Louis JL Koolen David A DA Houlden Henry H
Study Outcome
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Citations : Lee E.Y., Kim S., Kim M.H. Aminoacyl-tRNA synthetases, therapeutic targets for infectious diseases. Biochem. Pharmacol. 2018;154:424–434.Authors : 93
Identifiers
Doi : 10.1016/j.ajhg.2020.06.016SSN : 1537-6605