VRK1 (Y213H) homozygous mutant impairs Cajal bodies in a hereditary case of distal motor neuropathy

Ann Clin Transl Neurol. 2020 May;7(5):808-818. doi: 10.1002/acn3.51050. Epub 2020 May 4.


Background: Distal motor neuropathies with a genetic origin have a heterogeneous clinical presentation with overlapping features affecting distal nerves and including spinal muscular atrophies and amyotrophic lateral sclerosis. This indicates that their genetic background is heterogeneous.

Patient and methods: In this work, we have identified and characterized the genetic and molecular base of a patient with a distal sensorimotor neuropathy of unknown origin. For this study, we performed whole-exome sequencing, molecular modelling, cloning and expression of mutant gene, and biochemical and cell biology analysis of the mutant protein.

Results: A novel homozygous recessive mutation in the human VRK1 gene, coding for a chromatin kinase, causing a substitution (c.637T > C; p.Tyr213His) in exon 8, was detected in a patient presenting since childhood a progressive distal sensorimotor neuropathy and spinal muscular atrophy syndrome, with normal intellectual development. Molecular modelling predicted this mutant VRK1 has altered the kinase activation loop by disrupting its interaction with the C-terminal regulatory region. The p.Y213H mutant protein has a reduced kinase activity with different substrates, including histones H3 and H2AX, proteins involved in DNA damage responses, such as p53 and 53BP1, and coilin, the scaffold for Cajal bodies. The mutant VRK1(Y213H) protein is unable to rescue the formation of Cajal bodies assembled on coilin, in the absence of wild-type VRK1.

Conclusion: The VRK1(Y213H) mutant protein alters the activation loop, impairs the kinase activity of VRK1 causing a functional insufficiency that impairs the formation of Cajal bodies assembled on coilin, a protein that regulates SMN1 and Cajal body formation.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Coiled Bodies*
  • Consanguinity
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Male
  • Muscular Atrophy, Spinal / enzymology*
  • Muscular Atrophy, Spinal / genetics*
  • Protein Serine-Threonine Kinases / genetics*


  • Intracellular Signaling Peptides and Proteins
  • Protein Serine-Threonine Kinases
  • VRK1 protein, human

Grant support

This work was funded by Junta de Castilla y León‐Fondo Social Europeo grant ; Ministerio de Educación‐FPU grant FPU16/01883; Ministerio de Ciencia, Innovación y Universidades‐ grants SAF2016‐75744‐R and RED2018‐102801‐T; Agencia Estatal de Investigación grants SAF2016‐75744‐R and RED2018‐102801‐T; Consejería de Educación‐Junta de Castilla y León‐ERDF grant UIC‐258; Ministerio de Ciencia, Innovación y Universidades‐ grants RTC‐2017‐6494‐1 and RTI2018‐094434‐B‐I00; Agencia Estatal de Investigación grants RTC‐2017‐6494‐1 and RTI2018‐094434‐B‐I00; CONNECT‐JPIAMR Virtual Research Institute grant ; The Instituto de Biología Molecular y Celular del Cáncer grant ; Junta de Castilla y León‐European Regional Development Fund grant CLC–2017–01.