Abstract Details

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

Topic Child Neurology and Developmental Neurology

Presentation(s) Child Neurology and Developmental Neurology Posters (7:00 AM-5:00 PM)

Poster/Presentation
Number 032

Objective We aimed to provide genetic proof for mutations in asparaginyl-tRNA synthetase (NARS1) and analyze their impact through the use of individual cell lines, neural progenitor cells, and molecular modelling.

Background Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation.

Design/Methods Individuals were recruited via an international collaborative network of research and diagnostic sequencing laboratories. Exome sequencing was carried out using a number of methods in different centers.

Results 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 modelling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity.

Conclusions 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.

Authors/Disclosures
Stephanie Efthymiou (UCL Institute of Neurology) PRESENTER	Stephanie Efthymiou has nothing to disclose.
	No disclosure on file
Emer Oconnor, PhD	Emer Oconnor has nothing to disclose.
Henry Houlden	No disclosure on file

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Abstract Details