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

August 06, 2020

Andreea Manole1, Stephanie Efthymiou1, Emer O’Connor1, Marisa I Mendes2, Matthew Jennings 3, Reza Maroofian1, Indran Davagnanam4, Kshitij Mankad5, Maria Rodriguez Lopez6, Vincenzo Salpietro1, Ricardo Harripaul7, Lauren Badalato8, Jagdeep Walia8, Christopher S Francklyn9, Alkyoni Athanasiou-Fragkouli 1, Roisin Sullivan1, Sonal Desai10, Kristin Baranano10, Faisal Zafar 11, Nuzhat Rana11, Muhammed Ilyas12, Alejandro Horga1, Majdi Kara 13, Francesca Mattioli14, Alice Goldenberg15, Helen Griffin3, Amelie Piton14, Lindsay B Henderson16, Benyekhlef Kara17, Ayca Dilruba Aslanger17, Joost Raaphorst18, Rolph Pfundt19, Ruben Portier20, Marwan Shinawi 21, Amelia Kirby22, Katherine M Christensen22, Lu Wang23, Rasim O Rosti23, Sohail A Paracha24, Muhammad T Sarwar24, Dagan Jenkins25, SYNAPS Study Group; Jawad Ahmed24, Federico A Santoni26, Emmanuelle Ranza27, Justyna Iwaszkiewicz28, Cheryl Cytrynbaum29, Rosanna Weksberg29, Ingrid M Wentzensen16, Maria J Guillen Sacoto16, Yue Si16, Aida Telegrafi16, Marisa V Andrews21, Dustin Baldridge21, Heinz Gabriel30, Julia Mohr30, Barbara Oehl-Jaschkowitz31, Sylvain Debard32, Bruno Senger32, Frédéric Fischer32, Conny van Ravenwaaij 33, Annemarie J M Fock33, Servi J C Stevens34, Jürg Bähler6, Amina Nasar8, John F Mantovani35, Adnan Manzur25, Anna Sarkozy25, Desirée E C Smith2, Gajja S Salomons2,Zubair M Ahmed36, Shaikh Riazuddin37, Saima Riazuddin36,Muhammad A Usmani36, Annette Seibt38, Muhammad Ansar39, Stylianos E Antonarakis40, John B Vincent7, Muhammad Ayub8,Mona Grimmel41, Anne Marie Jelsig42,Tina Duelund Hjortshøj42, Helena Gásdal Karstensen42, Marybeth Hummel43, Tobias B Haack44, Yalda Jamshidi45, Felix Distelmaier38, Rita Horvath3, Joseph G Gleeson23, Gleeson23, Hubert Becker32, Jean-Louis Mandel 14, David A Koolen19, Henry Houlden46.

Abstract

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.