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Type: Journal article
Title: A synonymous UPF3B variant causing a speech disorder implicates NMD as a regulator of neurodevelopmental disorder gene networks
Author: Domingo, D.
Nawaz, U.
Corbett, M.
Espinoza, J.L.
Tatton-Brown, K.
Coman, D.
Wilkinson, M.F.
Gecz, J.
Jolly, L.A.
Citation: Human Molecular Genetics, 2020; 29(15):2568-2578
Publisher: Oxford University Press
Issue Date: 2020
ISSN: 0964-6906
Statement of
Deepti Domingo, Urwah Nawaz, Mark Corbett, Josh L. Espinoza, Katrina Tatton-Brown, David Coman, Miles F. Wilkinson, Jozef Gecz, and Lachlan A. Jolly
Abstract: Loss-of-function mutations of the X-chromosome gene UPF3B cause male neurodevelopmental disorders (NDDs) via largely unknown mechanisms. We investigated initially by interrogating a novel synonymous UPF3B variant in a male with absent speech. In-silico and functional studies using cell lines derived from this individual show altered UPF3B RNA splicing. The resulting mRNA species encodes a frame-shifted protein with a premature termination codon (PTC) predicted to elicit degradation via nonsense mediated mRNA decay (NMD). UPF3B mRNA was reduced in the cell line, and no UPF3B protein was produced, confirming a loss-of-function allele. UPF3B is itself involved in the NMD mechanism which degrades both PTC-bearing mutant transcripts and also many physiological transcripts. RNAseq analysis showed that ~ 1.6% of mRNAs exhibited altered expression. These mRNA changes overlapped and correlated with those we identified in additional cell lines obtained from individuals harbouring other UPF3B mutations, permitting us to interrogate pathogenic mechanisms of UPF3B associated NDDs. We identified 102 genes consistently deregulated across all UPF3B mutant cell lines. Of the 51 upregulated genes, 75% contained an NMD-targeting feature thus identifying high-confidence direct NMD targets. Intriguingly, 22 of the dysregulated genes encoded known NDD genes, suggesting UPF3B-dependent NMD regulates gene networks critical for cognition and behaviour. Indeed, we show that 78.5% of all NDD genes encode a transcript predicted to be targeted by NMD. These data describe the first synonymous UPF3B mutation in a patient with prominent speech and language disabilities, and identify plausible mechanisms of pathology downstream of UPF3B mutations involving the deregulation of NDD-gene networks.
Keywords: Cell Line
Speech Disorders
RNA-Binding Proteins
RNA, Messenger
Codon, Nonsense
RNA Splicing
Child, Preschool
Gene Regulatory Networks
Nonsense Mediated mRNA Decay
Neurodevelopmental Disorders
Silent Mutation
Loss of Function Mutation
Rights: © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email:
DOI: 10.1093/hmg/ddaa151
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