A homozygousUBA5pathogenic variant causes a fatal congenital neuropathy

Abstract

BackgroundUBA5 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 resultsWe 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.ConclusionThis report expands the phenotypical spectrum of UBA5 mutations to include fatal peripheral neuropathy.

A description of novel variants and review of phenotypic spectrum in UBA5-related early epileptic encephalopathy

“…The explanation for the apparently divergent phenotype in the family reported by Cabrera-Serrano and colleagues is not currently clear. The authors showed that, compared to wild-type, the homozygous missense variant in this family (c.31C > T, p.Arg11Trp), resulted in reduced UBA5 protein abundance and a significantly reduced ability to activate UFM1 ( P < 0.05) ( Cabrera-Serrano et al 2020 ). Unlike all but one of the other UBA5 variants described to date, this variant is intronic and unlikely to be damaging in the transcript that is most highly expressed in the brain, per GTEx ( ).…”

“…Although 17 of 19 families reported to date with biallelic UBA5 mutations have the EIEE44 phenotype, the phenotypes of the two remaining families described by Duan et al (2016) and Cabrera-Serrano et al (2020) appear to be distinct ( Supplemental Table S1 ). Other than the fact that neither of these two families carry the p.Ala371Thr variant, there is currently no identifiable genotype–phenotype correlation.…”

“…Brain and spine MRIs and EEGs, when performed, were unremarkable. Those tested were shown to have a sensory motor peripheral neuropathy ( Cabrera-Serrano et al 2020 ). Of note, none of the 24 identified EIEE44 patients are known to have had nerve conduction studies performed to assess for peripheral neuropathy.…”

“…Biallelic UBA5 mutations were first reported by Duan et al (2016) , who reported two siblings with a progressive childhood-onset cerebellar ataxia with normal intellect, listed in OMIM as spinocerebellar ataxia, autosomal recessive 24 (MIM: 617133). Most recently, Cabrera-Serrano et al (2020) described a large consanguineous family in which five affected individuals had a severe congenital neuropathy that resulted in death in early infancy due to respiratory failure.…”

Homozygous UBA5 Variant Leads to Hypomyelination with Thalamic Involvement and Axonal Neuropathy

“…3 While the UFM1 system has long been implicated in a variety of non-neurological pathological processes, 4,5 in recent years research established its involvement in neurodevelopmental disorders. [6][7][8][9][10][11][12][13][14][15] Biallelic variants in UBA5 or UFM1 have been described in cases with encephalopathy, intellectual disability, movement disorders, epilepsy, and neuropathy. Neuroimaging findings in these cases are variable and mostly consist of cerebral and cerebellar atrophy.…”