WARS1 and SARS1: Two tRNA synthetases implicated in autosomal recessive microcephaly.
ARS
CRISPR/Cas9
SARS1
WARS1
aminoacyl-tRNA synthetase
aminoacylation
intellectual disability
microcephaly
tRNA
zebrafish
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
revised:
10
06
2022
received:
03
06
2021
accepted:
01
07
2022
pubmed:
6
7
2022
medline:
9
9
2022
entrez:
5
7
2022
Statut:
ppublish
Résumé
Aminoacylation of transfer RNA (tRNA) is a key step in protein biosynthesis, carried out by highly specific aminoacyl-tRNA synthetases (ARSs). ARSs have been implicated in autosomal dominant and autosomal recessive human disorders. Autosomal dominant variants in tryptophanyl-tRNA synthetase 1 (WARS1) are known to cause distal hereditary motor neuropathy and Charcot-Marie-Tooth disease, but a recessively inherited phenotype is yet to be clearly defined. Seryl-tRNA synthetase 1 (SARS1) has rarely been implicated in an autosomal recessive developmental disorder. Here, we report five individuals with biallelic missense variants in WARS1 or SARS1, who presented with an overlapping phenotype of microcephaly, developmental delay, intellectual disability, and brain anomalies. Structural mapping showed that the SARS1 variant is located directly within the enzyme's active site, most likely diminishing activity, while the WARS1 variant is located in the N-terminal domain. We further characterize the identified WARS1 variant by showing that it negatively impacts protein abundance and is unable to rescue the phenotype of a CRISPR/Cas9 wars1 knockout zebrafish model. In summary, we describe two overlapping autosomal recessive syndromes caused by variants in WARS1 and SARS1, present functional insights into the pathogenesis of the WARS1-related syndrome and define an emerging disease spectrum: ARS-related developmental disorders with or without microcephaly.
Substances chimiques
Amino Acyl-tRNA Synthetases
EC 6.1.1.-
Ligases
EC 6.-
RNA, Transfer
9014-25-9
Tryptophan-tRNA Ligase
EC 6.1.1.2
WARS1 protein, human
EC 6.1.1.2
SARS1 protein, human
EC 6.1.1.11
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1454-1471Informations de copyright
© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.
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