THUMPD1 bi-allelic variants cause loss of tRNA acetylation and a syndromic neurodevelopmental disorder.
N4-acetylcytidine
NAT10
RNA acetylation
THUMPD1
ac4C
developmental disorder
intellectual disability
tRNA biology
tRNA modifications
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
07 04 2022
07 04 2022
Historique:
received:
07
10
2021
accepted:
01
02
2022
pubmed:
24
2
2022
medline:
13
4
2022
entrez:
23
2
2022
Statut:
ppublish
Résumé
Covalent tRNA modifications play multi-faceted roles in tRNA stability, folding, and recognition, as well as the rate and fidelity of translation, and other cellular processes such as growth, development, and stress responses. Mutations in genes that are known to regulate tRNA modifications lead to a wide array of phenotypes and diseases including numerous cognitive and neurodevelopmental disorders, highlighting the critical role of tRNA modification in human disease. One such gene, THUMPD1, is involved in regulating tRNA N4-acetylcytidine modification (ac4C), and recently was proposed as a candidate gene for autosomal-recessive intellectual disability. Here, we present 13 individuals from 8 families who harbor rare loss-of-function variants in THUMPD1. Common phenotypic findings included global developmental delay, speech delay, moderate to severe intellectual deficiency, behavioral abnormalities such as angry outbursts, facial dysmorphism, and ophthalmological abnormalities. We demonstrate that the bi-allelic variants identified cause loss of function of THUMPD1 and that this defect results in a loss of ac4C modification in small RNAs, and of individually purified tRNA-Ser-CGA. We further corroborate this effect by showing a loss of tRNA acetylation in two CRISPR-Cas9-generated THUMPD1 KO cell lines. In addition, we also show the resultant amino acid substitution that occurs in a missense THUMPD1 allele identified in an individual with compound heterozygous variants results in a marked decrease in THUMPD1 stability and RNA-binding capacity. Taken together, these results suggest that the lack of tRNA acetylation due to THUMPD1 loss of function results in a syndromic form of intellectual disability associated with developmental delay, behavioral abnormalities, hearing loss, and facial dysmorphism.
Identifiants
pubmed: 35196516
pii: S0002-9297(22)00052-0
doi: 10.1016/j.ajhg.2022.02.001
pmc: PMC9069073
pii:
doi:
Substances chimiques
RNA-Binding Proteins
0
THUMPD1 protein, human
0
RNA
63231-63-0
RNA, Transfer
9014-25-9
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
587-600Subventions
Organisme : NHGRI NIH HHS
ID : UM1 HG008900
Pays : United States
Organisme : NIH HHS
ID : S10 OD025242
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG009141
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM133462
Pays : United States
Organisme : NIH HHS
ID : S10 OD021489
Pays : United States
Informations de copyright
Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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