A homozygous UBA5 pathogenic variant causes a fatal congenital neuropathy

MacArena Cabrera-Serrano, David Joseph Coote, DImitar Azmanov, Hayley Goullee, Erik Andersen, Catriona McLean, Mark Davis, Ryosuke Ishimura, Zornitza Stark, Jean Michel Vallat, Masaaki Komatsu, Andrew Kornberg, Monique Ryan, Nigel G. Laing, Gina Ravenscroft

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)
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Background UBA5 is the activating enzyme of UFM1 in the ufmylation post-translational modification system. Different neurological phenotypes have been associated with UBA5 pathogenic variants including epilepsy, intellectual disability, movement disorders and ataxia. Methods and results We describe a large multigenerational consanguineous family presenting with a severe congenital neuropathy causing early death in infancy. Whole exome sequencing and linkage analysis identified a novel homozygous UBA5 NM_024818.3 c.31C>T (p.Arg11Trp) mutation. Protein expression assays in mouse tissue showed similar levels of UBA5 in peripheral nerves to the central nervous system. CRISPR-Cas9 edited HEK (human embrionic kidney) cells homozygous for the UBA5 p.Arg11Trp mutation showed reduced levels of UBA5 protein compared with the wild-type. The mutant p.Arg11Trp UBA5 protein shows reduced ability to activate UFM1. Conclusion This report expands the phenotypical spectrum of UBA5 mutations to include fatal peripheral neuropathy.

Original languageEnglish
Pages (from-to)835-842
Number of pages8
JournalJournal of Medical Genetics
Issue number12
Publication statusPublished - 1 Dec 2020


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