Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 107, Issue 2, Pages 311-324Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2020.06.016
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Funding
- National Institute of Neurological Disorders and Stroke (NINDS) [N01NS02331, HHSN271200723701C]
- Gene Expression Nervous System Atlas (GENSAT) Project,
- Medical Research Council (MRC)
- Wellcome Trust Synaptopathies Award
- MRC Centre [G0601943]
- Ataxia UK
- Rosetrees Trust
- Brain Research UK
- University College London (UCL) Official Development Assistance (ODA)
- Low and Middle Income Country (LMIC) award
- Multiple System Atrophy (MSA) Trust,
- Muscular Dystrophy (MDUK)
- Muscular Dystrophy Association (MDA)
- UCL/UCL Hospital (UCLH) National Institute for Health Research University College London Hospitals Biomedical Research Centre
- MRC [MR/N010035/1, MR/N025431/1, MR/N025431/2, G1000848] Funding Source: UKRI
- Wellcome Trust [095598/Z/11/Z] Funding Source: researchfish
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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.
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