dc.description.abstract | 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. | spa |