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.
- peripheral nerve disease
- rare disease
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Contributors MC-S, GR, NGL: Study design and concept. MR, AK, EA, CM: acquisition of clinical information. MC-S, DJC, GR, MK, HG, RI, ZS: acquisition of data, analysis and interpretation. MD, J-MV, MR, NGL: revision of the manuscript for important intellectual content. GR: study supervision. MC-S and GR: draft of the manuscript.
Funding MC-S was supported by ISCIII (JR15/00042) and Junta de Andalucia-Consejeria de Salud (B-0005-2017). This work was supported by the NHMRC, grants to NGL and GR (APP1002147, APP1035955, APP1080587). MK is supported by a Grant-in-Aid for Scientific Research on Innovative Areas (19H0506), a Grant-in-Aid for Scientific Research (B) (18H02611), the Japan Society for the Promotion of Science (an A3 foresight program) and the Takeda Science Foundation (to MK). RI is supported by a Grant-in-Aid for Young Scientists (B) (18K15061).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval The study was approved by the Human Research Ethics Committee of the University of Western Australia. Informed consent was obtained from the patients' parents.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. Anonymised data will be shared by request from any qualified investigator.