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

• DOI: 10.1016/j.ajhg.2020.06.016
• Publication Date: 2020-07-31T20:38:43Z
• Authors: Andreea Manole; Stephanie Efthymiou; Emer O’Connor; Marisa I. Mendes; Matthew Jennings; Reza Maroofian; Indran Davagnanam; Kshitij Mankad; Maria Rodriguez L...; Vincenzo Salpietro; Ricardo Harripaul; Lauren Badalato; Jagdeep Walia; Christopher S. Fr...; Alkyoni Athanasio...; Roisin Sullivan; Sonal Desai; Kristin Baranano; Faisal Zafar; Nuzhat Rana; Muhammed Ilyas; Alejandro Horga; Majdi Kara; Francesca Mattioli; Alice Goldenberg; Helen Griffin; Amelie Piton; Lindsay B. Henderson; Benyekhlef Kara; Ayca Dilruba Asla...; Joost Raaphorst; Rolph Pfundt; Ruben Portier; Marwan Shinawi; Amelia Kirby; Katherine M. Chri...; Lu Wang; Rasim O. Rosti; Sohail A. Paracha; Muhammad T. Sarwar; Dagan Jenkins; Jawad Ahmed; Federico A. Santoni; Emmanuelle Ranza; Justyna Iwaszkiewicz; Cheryl Cytrynbaum; Rosanna Weksberg; Ingrid M. Wentzensen; Maria J. Guillen ...; Yue Si; Aida Telegrafi; Marisa V. Andrews; Dustin Baldridge; Heinz Gabriel; Julia Mohr; Barbara Oehl-Jasc...; Sylvain Debard; Bruno Senger; Frédéric Fischer; Conny van Ravenwaaij; Annemarie J.M. Fock; Servi J.C. Stevens; Jürg Bähler; Amina Nasar; John F. Mantovani; Adnan Manzur; Anna Sarkozy; Desirée E.C. Smith; Gajja S. Salomons; Zubair M. Ahmed; Shaikh Riazuddin; Saima Riazuddin; Muhammad A. Usmani; Annette Seibt; Muhammad Ansar; Stylianos E. Anto...; John B. Vincent; Muhammad Ayub; Mona Grimmel; Anne Marie Jelsig; Tina Duelund Hjor...; Helena Gásdal Kar...; Marybeth Hummel; Tobias B. Haack; Yalda Jamshidi; Felix Distelmaier; Rita Horvath; Joseph G. Gleeson; Hubert Becker; Jean-Louis Mandel; David A. Koolen; Henry Houlden
• Keywords: EXPRESSION; Male; 0301 basic medicine; transfer-rna synthetase; Developmental delay; [SDV]Life Sciences [q-bio]; Aspartate-tRNA Ligase; TRANSFER-RNA SYNTHETASE; RNA, Transfer, Amino Acyl; Cell Line; Amino Acyl-tRNA Synthetases; 03 medical and health sciences; aminoacyl-tRNA synthetase; developmental delay; epilepsy; neurodevelopment; neuropathy; next generation sequencing; Alleles; Amino Acyl-tRNA Synthetases; Aspartate-tRNA Ligase; Cell Line; Female; Gain of Function Mutation; Genetic Predisposition to Disease; Humans; Loss of Function Mutation; Male; Neurodevelopmental Disorders; Pedigree; RNA, Transfer; RNA, Transfer, Amino Acyl; Stem Cells; 2 SIBLINGS; RNA, Transfer; Loss of Function Mutation; expression; Medicine and Health Sciences; Humans; Genetic Predisposition to Disease; Alleles; Epilepsy; Radboudumc 7: Neurodevelopmental disorders DCMN: Donders Center for Medical Neuroscience; MUTATIONS; Stem Cells; ICTS (Institute of Clinical and Translational Sciences); Neurology - Radboud University Medical Center; Radboudumc 3: Disorders of movement DCMN: Donders Center for Medical Neuroscience; Radboudumc 9: Rare cancers RIHS: Radboud Institute for Health Sciences; mutations; Pedigree; Transfer; Neurodevelopmental Disorders; Gain of Function Mutation; Aminoacyl-tRNA synthetase; RNA; Amino Acyl; Female; 2 siblings

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.