Biallelic variants in NSUN6 cause an autosomal recessive neurodevelopmental disorder.

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Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_D38F5D2EC77B
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Biallelic variants in NSUN6 cause an autosomal recessive neurodevelopmental disorder.
Journal
Genetics in medicine
Author(s)
Mattioli F., Worpenberg L., Li C.T., Ibrahim N., Naz S., Sharif S., Firouzabadi S.G., Vosoogh S., Saraeva-Lamri R., Raymond L., Trujillo C., Guex N., Antonarakis S.E., Ansar M., Darvish H., Liu R.J., Roignant J.Y., Reymond A.
ISSN
1530-0366 (Electronic)
ISSN-L
1098-3600
Publication state
Published
Issued date
09/2023
Peer-reviewed
Oui
Volume
25
Number
9
Pages
100900
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
5-methylcytosine RNA modifications are driven by NSUN methyltransferases. Although variants in NSUN2 and NSUN3 were associated with neurodevelopmental diseases, the physiological role of NSUN6 modifications on transfer RNAs and messenger RNAs remained elusive.
We combined exome sequencing of consanguineous families with functional characterization to identify a new neurodevelopmental disorder gene.
We identified 3 unrelated consanguineous families with deleterious homozygous variants in NSUN6. Two of these variants are predicted to be loss-of-function. One maps to the first exon and is predicted to lead to the absence of NSUN6 via nonsense-mediated decay, whereas we showed that the other maps to the last exon and encodes a protein that does not fold correctly. Likewise, we demonstrated that the missense variant identified in the third family has lost its enzymatic activity and is unable to bind the methyl donor S-adenosyl-L-methionine. The affected individuals present with developmental delay, intellectual disability, motor delay, and behavioral anomalies. Homozygous ablation of the NSUN6 ortholog in Drosophila led to locomotion and learning impairment.
Our data provide evidence that biallelic pathogenic variants in NSUN6 cause one form of autosomal recessive intellectual disability, establishing another link between RNA modification and cognition.
Keywords
Humans, Intellectual Disability/genetics, Homozygote, Neurodevelopmental Disorders/genetics, Methyltransferases/genetics, Methyltransferases/metabolism, RNA, Pedigree, tRNA Methyltransferases/genetics, tRNA Methyltransferases/metabolism, Autosomal recessive, Consanguinity, Neurodevelopmental disorder, RNA methyltransferase, m(5)C
Pubmed
Web of science
Open Access
Yes
Create date
31/05/2023 7:59
Last modification date
10/02/2024 7:28
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