AUTHORS
Andreea Manole, Stephanie Efthymiou, Emer O’Connor, Marisa I Mendes, Matthew Jennings, Reza Maroofian, Indran Davagnanam, Kshitij Mankad, Maria Rodriguez Lopez, Vincenzo Salpietro, Ricardo Harripaul, Lauren Badalato, Jagdeep Walia, Christopher S Francklyn, Alkyoni Athanasiou-Fragkouli, 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 Aslanger, Joost Raaphorst, Rolph Pfundt, Ruben Portier, Marwan Shinawi, Amelia Kirby, Katherine M Christensen, Lu Wang, Rasim O Rosti, Sohail A Paracha, Muhammad T Sarwar, Dagan Jenkins, SYNAPS Study Group, Jawad Ahmed, Federico A Santoni, Emmanuelle Ranza, Justyna Iwaszkiewicz, Cheryl Cytrynbaum, Rosanna Weksberg, Ingrid M Wentzensen, Maria J Guillen Sacoto, Yue Si, Aida Telegrafi, Marisa V Andrews, Dustin Baldridge, Heinz Gabriel, Julia Mohr, Barbara Oehl-Jaschkowitz, 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 Antonarakis, John B Vincent, Muhammad Ayub, Mona Grimmel, Anne Marie Jelsig, Tina Duelund Hjortshøj, Helena Gásdal Karstensen, Marybeth Hummel, Tobias B Haack, Yalda Jamshidi, Felix Distelmaier, Rita Horvath, Joseph G Gleeson, Hubert Becker, Jean-Louis Mandel, David A Koolen, Henry Houlden
Am J Hum Genet. 2020 Aug 6;107(2):311-324. doi: 10.1016/j.ajhg.2020.06.016. Epub 2020 Jul 31.
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.
PMID:32738225 | PMC:PMC7413890 | DOI:10.1016/j.ajhg.2020.06.016
