Biallelic Variants in UBA5 Reveal that Disruption of the UFM1 Cascade Can Result in Early-Onset Encephalopathy

Abstract

Via whole-exome sequencing, we identified rare autosomal-recessive variants in UBA5 in five children from four unrelated families affected with a similar pattern of severe intellectual deficiency, microcephaly, movement disorders, and/or early-onset intractable epilepsy. UBA5 encodes the E1-activating enzyme of ubiquitin-fold modifier 1 (UFM1), a recently identified ubiquitin-like protein. Biochemical studies of mutant UBA5 proteins and studies in fibroblasts from affected individuals revealed that UBA5 mutations impair the process of ufmylation, resulting in an abnormal endoplasmic reticulum structure. In Caenorhabditis elegans, knockout of uba-5 and of human orthologous genes in the UFM1 cascade alter cholinergic, but not glutamatergic, neurotransmission. In addition, uba5 silencing in zebrafish decreased motility while inducing abnormal movements suggestive of seizures. These clinical, biochemical, and experimental findings support our finding of UBA5 mutations as a pathophysiological cause for early-onset encephalopathies due to abnormal protein ufmylation.

A novel approach to assess the ubiquitin‐fold modifier 1‐system in cells

“…Recently, we and Bonneau's group have independently shown that compound heterozygote for a loss‐of‐function mutation on one allele and a p.Ala371Thr mutation on the other causes severe infantile‐onset encephalopathy . We have also shown that the UBA5 A371T mutation suppresses the formation of UFMylated UFBP1 .…”

“…Heterozygotes with single loss‐of‐function allele do not show any disease symptom, implying that combination of functionally defect mutation with a loss‐of‐function is crucial for the disease onset. In addition to the p.Ala371Thr mutation, Bonneau's group identified individuals from two families with biallelic compound heterozygous variants in UBA5 , p.Met57Val, and p.Gly168Glu, and p.Val260Met and p.Asp389Tyr (Fig. A and B).…”

“…A and B). These mutations, except for UBA5 D389Y , have decreased E1‐activity (i.e., transfer activated UFM1 to the E2 enzyme UFC1 at reduced rates) . Duan and colleagues reported that a family with two siblings with compound heterozygous variants in UBA5 (p.Lys310Glu and p.Arg246X) shows a childhood‐onset neurological disease with ataxia as the primary symptom (Fig.…”

“…It has also been implicated in endoplasmic reticulum (ER) stress response and autophagy . Very recently, we and another group independently showed that UBA5 mutations cause early‐onset encephalopathies due to impaired UFM1‐activation . It was also reported that compound heterozygous variants in UBA5 in a single family cause a childhood‐onset neurological disease with ataxia .…”

Trans ‐binding of UFM1 to UBA5 stimulates UBA5 homodimerization and ATP binding

“…That, therefore, suggests that modulating the stability of the UBA5 dimer can serve as a tool to regulate the UBA5 affinity to ATP. Indeed, recently, it has been found that the UBA5 mutation V260M, which affects UFMylation, is related to early onset encephalopathy (33). That mutation is located within the UBA5 dimer interface; therefore, based on our work, it has the potential to interfere with ATP binding.…”