A homozygous UBA5 pathogenic variant causes a fatal congenital neuropathy

J Med Genet. 2020 Dec;57(12):835-842. doi: 10.1136/jmedgenet-2019-106496. Epub 2020 Mar 16.


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.

Keywords: UBA5; peripheral nerve disease; rare disease; ufmylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia / genetics
  • Ataxia / pathology
  • CRISPR-Cas Systems / genetics*
  • Central Nervous System / metabolism
  • Central Nervous System / pathology
  • Consanguinity
  • Epilepsy / genetics
  • Epilepsy / pathology
  • Female
  • Gene Expression Regulation / genetics
  • Genetic Linkage
  • HEK293 Cells
  • Homozygote
  • Humans
  • Infant
  • Intellectual Disability / genetics*
  • Intellectual Disability / pathology
  • Male
  • Movement Disorders / genetics
  • Movement Disorders / pathology
  • Mutation / genetics
  • Nervous System Malformations / genetics*
  • Nervous System Malformations / pathology
  • Pedigree
  • Peripheral Nerves / metabolism
  • Peripheral Nerves / pathology
  • Proteins / genetics*
  • Ubiquitin-Activating Enzymes / genetics*


  • Proteins
  • UBA5 protein, human
  • UFM1 protein, human
  • Ubiquitin-Activating Enzymes