%0 Journal Article
%A Cabrera-Serrano, Macarena
%A Coote, David Joseph
%A Azmanov, Dimitar
%A Goullee, Hayley
%A Andersen, Erik
%A McLean, Catriona
%A Davis, Mark
%A Ishimura, Ryosuke
%A Stark, Zornitza
%A Jean-Michel, Vallat
%A Komatsu, Masaaki
%A Kornberg, Andrew
%A Ryan, Monique
%A Laing, Nigel G
%A Ravenscroft, Gina
%T A homozygous UBA5 pathogenic variant causes a fatal congenital neuropathy.
%D 2020
%U http://hdl.handle.net/10668/15246
%X 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. 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. This report expands the phenotypical spectrum of UBA5 mutations to include fatal peripheral neuropathy.
%K UBA5
%K peripheral nerve disease
%K rare disease
%K ufmylation
%~