Publication: De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects
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Date
2020-08-01T00:00:00Z
Authors
Authors
Manole, Andreea
Efthymiou, Stephanie
O'Connor, Emer
Mendes, Marisa
Jennings, Matthew
Maroofian, Reza
Davagnanam, Indran
Mankad, Kshitij
Lopez, Maria Rodriguez
Salpietro, Vincenzo
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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.
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Keywords
Aminoacyl-tRNA synthetase, Developmental delay, Epilepsy
Citation
Manole A., Efthymiou S., O-Connor E., Mendes M., Jennings M., Maroofian R., Davagnanam I., Mankad K., Lopez M. R. , Salpietro V., et al., -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, cilt.107, ss.311-324, 2020