Purpose: 5-methylcytosine (m5C) RNA modifications are driven by NSUN methyltransferases. While variants in NSUN2 and NSUN3 were associated with neurodevelopmental diseases (NDD), the physiological role of NSUN6 modifications on tRNAs and mRNAs remained elusive.
Methods: We combined exome sequencing of consanguineous families with functional characterization to identify a new NDD gene.
Results: We identified three 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 non-sense mediated decay, while 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.
Conclusion: 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: Autosomal recessive; Neurodevelopmental disorder; RNA methyltransferase; RNA modification; consanguinity; m(5)C.
Copyright © 2023. Published by Elsevier Inc.