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

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De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects.
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2020-07-31 , DOI: 10.1016/j.ajhg.2020.06.016
Andreea Manole ₁ , Stephanie Efthymiou ₁ , Emer O'Connor ₁ , Marisa I Mendes ₂ , Matthew Jennings ₃ , Reza Maroofian ₁ , Indran Davagnanam ₄ , Kshitij Mankad ₅ , Maria Rodriguez Lopez ₆ , Vincenzo Salpietro ₁ , Ricardo Harripaul ₇ , Lauren Badalato ₈ , Jagdeep Walia ₈ , Christopher S Francklyn ₉ , Alkyoni Athanasiou-Fragkouli ₁ , Roisin Sullivan ₁ , Sonal Desai ₁₀ , Kristin Baranano ₁₀ , Faisal Zafar ₁₁ , Nuzhat Rana ₁₁ , Muhammed Ilyas ₁₂ , Alejandro Horga ₁ , Majdi Kara ₁₃ , Francesca Mattioli ₁₄ , Alice Goldenberg ₁₅ , Helen Griffin ₃ , Amelie Piton ₁₄ , Lindsay B Henderson ₁₆ , Benyekhlef Kara ₁₇ , Ayca Dilruba Aslanger ₁₇ , Joost Raaphorst ₁₈ , Rolph Pfundt ₁₉ , Ruben Portier ₂₀ , Marwan Shinawi ₂₁ , Amelia Kirby ₂₂ , Katherine M Christensen ₂₂ , Lu Wang ₂₃ , Rasim O Rosti ₂₃ , Sohail A Paracha ₂₄ , Muhammad T Sarwar ₂₄ , Dagan Jenkins ₂₅ , ₂₆ , Jawad Ahmed ₂₄ , Federico A Santoni ₂₇ , Emmanuelle Ranza ₂₈ , Justyna Iwaszkiewicz ₂₉ , Cheryl Cytrynbaum ₃₀ , Rosanna Weksberg ₃₀ , Ingrid M Wentzensen ₁₆ , Maria J Guillen Sacoto ₁₆ , Yue Si ₁₆ , Aida Telegrafi ₁₆ , Marisa V Andrews ₂₁ , Dustin Baldridge ₂₁ , Heinz Gabriel ₃₁ , Julia Mohr ₃₁ , Barbara Oehl-Jaschkowitz ₃₂ , Sylvain Debard ₃₃ , Bruno Senger ₃₃ , Frédéric Fischer ₃₃ , Conny van Ravenwaaij ₃₄ , Annemarie J M Fock ₃₄ , Servi J C Stevens ₃₅ , Jürg Bähler ₆ , Amina Nasar ₈ , John F Mantovani ₃₆ , Adnan Manzur ₂₅ , Anna Sarkozy ₂₅ , Desirée E C Smith ₂ , Gajja S Salomons ₂ , Zubair M Ahmed ₃₇ , Shaikh Riazuddin ₃₈ , Saima Riazuddin ₃₇ , Muhammad A Usmani ₃₇ , Annette Seibt ₃₉ , Muhammad Ansar ₄₀ , Stylianos E Antonarakis ₄₁ , John B Vincent ₇ , Muhammad Ayub ₈ , Mona Grimmel ₄₂ , Anne Marie Jelsig ₄₃ , Tina Duelund Hjortshøj ₄₃ , Helena Gásdal Karstensen ₄₃ , Marybeth Hummel ₄₄ , Tobias B Haack ₄₅ , Yalda Jamshidi ₄₆ , Felix Distelmaier ₃₉ , Rita Horvath ₃ , Joseph G Gleeson ₂₃ , Hubert Becker ₃₃ , Jean-Louis Mandel ₁₄ , David A Koolen ₁₉ , Henry Houlden ₁

Affiliation

Department of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Metabolic Unit, Department of Clinical Chemistry, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam Gastroenterology and Metabolism, Amsterdam, 1081 the Netherlands.
Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0QQ UK.
Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Department of Neuroradiology, Great Ormond Street Hospital for Children, London, WC1N 3JH, UK.
Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London (UCL), London, WC1E 6BT, UK.
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.
Department of Pediatrics, Queen's University, Kingston, ON, K7L 2V7, Canada.
Department of Biochemistry, University of Vermont College of Medicine, Burlington, VT 05405, USA.
Department of Neurology and Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Department of Pediatrics, Multan Hospital, Multan, 60000, Pakistan.
University of Islamabad, Islamabad, 45320, Pakistan.
Department of Pediatrics, Tripoli Children's Hospital, Tripoli, Libya.
Institute for Genetics and Molecular and Cellular Biology (IGBMC), University of Strasbourg, CNRS UMR7104, INSERM U1258, Illkirch, 67404, France.
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.
GeneDx, 207 Perry Parkway Gaithersburg, MD 20877, USA.
Bezmiâlem Vakıf Üniversitesi, Istanbul, 34093, Turkey.
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.
Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500HB Nijmegen, the Netherlands.
Department of Neurology, Medisch Spectrum Twente, 7512KZ Enschede, the Netherlands.
Department of Pediatrics, Divisions of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Division of Medical Genetics, SSM Health Cardinal Glennon Children's Hospital, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
Howard Hughes Medical Institute, University of California San Diego and Rady Children's Hospital, La Jolla, CA 92130, USA.
Institute of Basic Medical Sciences, Khyber Medical University, 25100 Peshawar, Pakistan.
Institute of Child Health, Guilford Street and Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children, London, WC1N 3JH, 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, 1206 Geneva, Switzerland; Department of Endocrinology, Diabetes, and Metabolism, University Hospital of Lausanne, 1011 Lausanne, Switzerland.
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.
Swiss Institute of Bioinformatics, Molecular Modeling Group, Batiment Genopode, Unil Sorge, Lausanne, CH-1015, Switzerland.
Hospital for Sick Children, Division of Clinical and Metabolic Genetics, 555 University Ave., Toronto, M5G 1X8, Canada.
CeGaT GmbH and Praxis für Humangenetik Tuebingen, Tuebingen, 72076, Germany.
Biomedical Centre Cardinal-Wendel-Straße 14, 66424 Hamburg, Germany.
University of Strasbourg, CNRS, GMGM UMR 7156, Strasbourg, 67083, France.
University of Groningen, University Medical Center Groningen, Department of Neurology, Groningen, 9713, the Netherlands.
Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, 6211, the Netherlands.
Division of Child Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Department of Biochemistry and Molecular Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Jinnah Burn and Reconstructive Surgery Center, Allama Iqbal Medical College, University of Health Sciences, Lahore 54550, Pakistan.
Department of General Pediatrics, Heinrich-Heine-University, Moorenstr. 5, 40225 Düsseldorf, Germany.
Department of Genetic Medicine and Development, University of Geneva, 1206 Geneva, Switzerland; Institute of Molecular and Clinical Ophthalmology Basel, Basel Switzerland.
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.
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany.
Department of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, 2100, Denmark.
Department of Pediatrics, Section of Medical Genetics, West Virginia University, Morgantown, WV 26506-9600, USA.
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany; Centre for Rare Diseases, University of Tuebingen, 72076 Tübingen, Germany.
Genetics Centre, Molecular and Clinical Sciences Institute, St George's University of London, London, SW17 0RE, UK.

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.

中文翻译：

NARS1 的从头变异和双等位基因致病变异会因毒性功能获得和部分功能丧失效应而导致神经发育迟缓。

氨酰基-tRNA 合成酶 (ARS) 是一种普遍存在的古老酶，可为同源 tRNA 分子提供氨基酸，这是蛋白质翻译必不可少的第一步。在这里，我们描述了来自 21 个家庭的 32 名个体，这些个体表现为小头畸形、神经发育迟缓、癫痫、周围神经病变和共济失调，并伴有天冬酰胺酰-tRNA 合成酶 ( NARS1 ) 的从头杂合和双等位基因突变。我们证明了单个成纤维细胞和诱导神经祖细胞 (iNPC) 中NARS1 mRNA 表达以及 NARS1 酶水平和活性的降低。隐性 c.1633C>T (p.Arg545Cys) 变体的分子模型显示较弱的空间定位和 tRNA 选择性。我们得出的结论是， NARS1的从头突变和双等位基因突变是神经发育疾病的一个重要原因，其中从头突变的机制可能是毒性功能获得，而隐性突变的机制可能是部分功能丧失。

更新日期：2020-08-06

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