Forskning
Udskriv Udskriv
Switch language
Rigshospitalet - en del af Københavns Universitetshospital
Udgivet

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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

DOI

  1. Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Recurrent, Activating Variants in the Receptor Tyrosine Kinase DDR2 Cause Warburg-Cinotti Syndrome

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  4. Estimation of Genetic Correlation via Linkage Disequilibrium Score Regression and Genomic Restricted Maximum Likelihood

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  1. Successful treatment with dupilumab of an adult with Netherton syndrome

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Revised Danish guidelines for the cancer surveillance of patients with Cowden Syndrome

    Publikation: Bidrag til tidsskriftReviewForskningpeer review

  3. Novel HARS2 missense variants identified in individuals with sensorineural hearing impairment and Perrault syndrome

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  4. Tab af X-kromosomet kan være et aldersbetinget fænomen hos kvinder

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  5. A complex phenotype in a family with a pathogenic SOX3 missense variant

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  • SYNAPS Study Group
Vis graf over relationer

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.

OriginalsprogEngelsk
TidsskriftAmerican Journal of Human Genetics
Vol/bind107
Udgave nummer2
Sider (fra-til)311-324
Antal sider14
ISSN0002-9297
DOI
StatusUdgivet - 6 aug. 2020

Bibliografisk note

Copyright © 2020. Published by Elsevier Inc.

ID: 61319109