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Original research
A homozygous UBA5 pathogenic variant causes a fatal congenital neuropathy
  1. Macarena Cabrera-Serrano1,2,3,
  2. David Joseph Coote2,
  3. Dimitar Azmanov2,4,
  4. Hayley Goullee2,
  5. Erik Andersen5,6,
  6. Catriona McLean7,
  7. Mark Davis4,
  8. Ryosuke Ishimura8,
  9. Zornitza Stark9,
  10. Jean-Michel Vallat10,
  11. Masaaki Komatsu8,
  12. Andrew Kornberg6,
  13. Monique Ryan6,
  14. Nigel G Laing2,
  15. Gina Ravenscroft2
  1. 1 Department of Neurology, Neuromuscular Unit and Instituto de Biomedicina de Sevilla/CSIC, Hospital Universitario Virgen del Rocío, Sevilla, Spain
  2. 2 Centre of Medical Research, The University of Western Australia and the Harry Perkins Institute for Medical Research, Perth, Western Australia, Australia
  3. 3 Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
  4. 4 Department of Diagnostic Genomics, PathWest, QEII Medical Centre, Perth, Western Australia, Australia
  5. 5 Pediatrics, University of Otago Wellington, Wellington, New Zealand
  6. 6 Department of Neurology and Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia
  7. 7 Anatomical Pathology, Alfred Health, Melbourne, Victoria, Australia
  8. 8 Department of Physiology, Juntendo University School of Medicine Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
  9. 9 Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Royal Children’s Hospital, Melbourne, Victoria, Australia
  10. 10 Reference center for peripheral neuropathies, University Hospital, Limoges, France
  1. Correspondence to Dr Gina Ravenscroft, Centre of Medical Research, The University of Western Australia and the Harry Perkins Institute for Medical Research, Perth, WA 6009, Australia; gina.ravenscroft{at}


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
  • UBA5
  • ufmylation
  • 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.