A homozygous pathogenic variant causes a fatal congenital neuropathy.

BACKGROUND

UBA5 is the activating enzyme of UFM1 in the ufmylation post-translational modification system. Different neurological phenotypes have been associated with 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 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.