Vrk1 partial Knockdown in Mice Results in Reduced Brain Weight and Mild Motor Dysfunction, and Indicates Neuronal VRK1 Target Pathways

Vinograd-Byk, Hadar; Renbaum, Paul; Levy‐Lahad, Ephrat

doi:10.1038/s41598-018-29215-x

Cited by 15 publications

(14 citation statements)

References 62 publications

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“…The known functions of VRK1 in the context of cell cycle progression and proliferation 3,9,13,14,19,48 are consistent with this role 49 . In a murine VRK1 gene-trap model with a residual level of VRK1 protein 50 there is a reduction of brain mass and a motor impairment 51 , consistent with the situation in human compound heterozygous alleles.…”

Section: Discussionsupporting

confidence: 64%

VRK1 functional insufficiency due to alterations in protein stability or kinase activity of human VRK1 pathogenic variants implicated in neuromotor syndromes

Martín-Doncel

Rojas

Cantarero

et al. 2019

Sci Rep

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Very rare polymorphisms in the human VRK1 (vaccinia-related kinase 1) gene have been identified in complex neuromotor phenotypes associated to spinal muscular atrophy (SMA), pontocerebellar hypoplasia (PCH), microcephaly, amyotrophic lateral sclerosis (ALS) and distal motor neuron dysfunctions. The mechanisms by which these VRK1 variant proteins contribute to the pathogenesis of these neurological syndromes are unknown. The syndromes are manifested when both of these rare VRK1 polymorphic alleles are implicated, either in homozygosis or compound heterozygosis. In this report, to identify the common underlying pathogenic mechanism of VRK1 polymorphisms, we have studied all human VRK1 variants identified in these neurological phenotypes from a biochemical point of view by molecular modeling, protein stability and kinase activity assays. Molecular modelling predicted that VRK1 variant proteins are either unstable or have an altered kinase activity. The stability and kinase activity of VRK1 pathogenic variants detected two groups. One composed by variants with a reduced protein stability: R133C, R358X, L195V, G135R and R321C. The other group includes VRK1variants with a reduced kinase activity tested on several substrates: histones H3 and H2AX, p53, c-Jun, coilin and 53BP1, a DNA repair protein. VRK1 variants with reduced kinase activity are H119R, R133C, G135R, V236M, R321C and R358X. The common underlying effect of VRK1 pathogenic variants with reduced protein stability or kinase activity is a functional insufficiency of VRK1 in patients with neuromotor developmental syndromes. The G135 variant cause a defective formation of 53BP1 foci in response to DNA damage, and loss Cajal bodies assembled on coilin.

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Section: Discussionsupporting

confidence: 64%

VRK1 functional insufficiency due to alterations in protein stability or kinase activity of human VRK1 pathogenic variants implicated in neuromotor syndromes

Martín-Doncel

Rojas

Cantarero

et al. 2019

Sci Rep

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“…As a kinase, VRK1 phosphorylates several proteins such as p53, barrier-to-autointegration factor 1 (BANF1), histone H3, and CREB, all of which are involved in cell cycle regulation (12). A recent report on partial VRK1 knockout mice clarified the associated motor phenotype and identified significant changes of expression in the gene sets that predict novel roles for VRK1, such as neurotrophin signaling, axon guidance, proteasome-related genes, and oxidative phosphorylation, all of which have been implicated in the pathogenesis of ALS (13). However, the specific pathway of VRK1 dysfunction that contributes to motor neuron degeneration remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Novel <i>VRK1</i> Mutations in a Patient with Childhood-onset Motor Neuron Disease

et al. 2019

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A 24-year-old Japanese man exhibited slowly progressive gait disturbance from childhood to young adulthood. Physical and physiological examinations showed the involvement of both upper and lower motor neurons, fulfilling the diagnostic criteria for amyotrophic lateral sclerosis (ALS). Mild cognitive impairment and subclinical sensory involvement were also observed. A genetic analysis revealed novel compound heterozygous mutations, c.767C>T (p.Thr256Ile) and c.800A>G (p.Asp267Gly), in the vaccinia-related kinase 1 gene (VRK1). This is the first report of a Japanese patient with a motor neuron disease phenotype caused by VRK1 mutations. This diagnosis should be considered in atypical cases of juvenile-onset and slowly progressive types of motor neuron disease.

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“…In a murine model, the human VRK1(R358X) mutant impairs cell cycle progression and migration of neuronal progenitors in early embryogenesis 55 . Moreover, VRK1 partial knockdown in mice causes a motor dysfunction 56 . Nuclear bodies, such as CBs, are regulated during embryogenesis, 57 and their alteration is very likely to cause neurological disorders.…”

Section: Discussionmentioning

confidence: 99%

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

Marcos¹,

Martín-Doncel

Morejón‐García

et al. 2020

Ann Clin Transl Neurol

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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.

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Vrk1 partial Knockdown in Mice Results in Reduced Brain Weight and Mild Motor Dysfunction, and Indicates Neuronal VRK1 Target Pathways

Cited by 15 publications

References 62 publications

VRK1 functional insufficiency due to alterations in protein stability or kinase activity of human VRK1 pathogenic variants implicated in neuromotor syndromes

VRK1 functional insufficiency due to alterations in protein stability or kinase activity of human VRK1 pathogenic variants implicated in neuromotor syndromes

Novel <i>VRK1</i> Mutations in a Patient with Childhood-onset Motor Neuron Disease

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

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