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

Marcos, Ana T. and Martín‐Doncel, Elena and Morejón‐García, Patricia and Marcos‐Alcalde, Iñigo and Gómez‐Puertas, Paulino and Segura‐Puimedon, María and Armengol, Lluis and Navarro‐Pando, José M. and Lazo, Pedro A. UNSPECIFIED, UNSPECIFIED, UNSPECIFIED, UNSPECIFIED, UNSPECIFIED, UNSPECIFIED, UNSPECIFIED, jose.navarro@uneatlantico.es, UNSPECIFIED (2020) VRK1 (Y213H) homozygous mutant impairs Cajal bodies in a hereditary case of distal motor neuropathy. Annals of Clinical and Translational Neurology, 7 (5). pp. 808-818. ISSN 2328-9503

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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.

Item Type:	Article
Commentary on:	Eprints 0 not found.
Subjects:	Subjects > Biomedicine
Divisions:	Europe University of Atlantic > Research > Scientific Production
SWORD Depositor:	Users 0 not found.
Depositing User:	Sr Bibliotecario
Date Deposited:	20 May 2021 11:01
Last Modified:	03 Jul 2023 11:28
URI:	http://repositorio.funiber.org/id/eprint/121

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• VRK1 (Y213H) homozygous mutant impairs Cajal bodies in a hereditary case of distal motor neuropathy. (deposited 20 May 2021 11:01) [Currently Displayed]

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• Marcos, Ana T. and Martín‐Doncel, Elena and Morejón‐García, Patricia and Marcos‐Alcalde, Iñigo and Gómez‐Puertas, Paulino and Segura‐Puimedon, María and Armengol, Lluis and Navarro‐Pando, José M. and Lazo, Pedro A. VRK1 (Y213H) homozygous mutant impairs Cajal bodies in a hereditary case of distal motor neuropathy. (deposited 20 May 2021 11:01) [Currently Displayed]

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