VRK1 variants at the cross road of Cajal body neuropathogenic mechanisms in distal neuropathies and motor neuron diseases

Lazo, Pedro A.; Morejón‐García, Patricia

doi:10.1016/j.nbd.2023.106172

Cited by 8 publications

(11 citation statements)

References 175 publications

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“…We have described VRK1, as the gene responsible for dHMN in two patients from a family, with a clinical diagnosis of distal Hereditary Motor Neuropathy associated with upper MN signs (El-Bazzal et al, 2019). There are currently more than thirty mutations described in this gene (Lazo & Morejon-Garcia, 2023), but the pathomechanisms underlying the disease remain unclear. By studying cells from patient II.2 described in (El-Bazzal et al, 2019), including induced Pluripotent Stem Cell (iPSC) derived Motor Neurons (hiPSC-MNs), we have shown that the mutations identified in VRK1 lead to reduced levels of VRK1 in the nucleus.…”

Section: Discussionmentioning

confidence: 99%

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Altered NRG1/ErbB4 signaling and cholesterol metabolism dysregulation are key pathomechanisms in VRK1-related motor neuropathies and motor neuron diseases

Hamzé,

Humbert,

Rihan

et al. 2024

Preprint

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Hereditary Motor and Sensory Neuropathy (HMSN), or Charcot-Marie-Tooth disease (CMT), are the most common group of Inherited peripheral neuropathies (IPN), characterized by a strong clinical and genetic heterogeneity. Among them, distal Hereditary Motor Neuropathy (dHMN), also known as neuronopathy, is a subgroup, where only motor nerves are affected. This subgroup is also genetically heterogeneous, with 25 genes described to date, of which VRK1, that we have recently described as responsible for dHMN, associated to upper motor neuron signs. There are now more than thirty mutations in VRK1, which cause a range of neurological diseases affecting motor neurons (mainly lower, but also upper) or their axons in the peripheral nervous system, that we design as VRK1-related motor neuron diseases.In two previous studies, we have demonstrated that dHMN due to VRK1 mutations lead to reduced levels of VRK1 in the nucleus, and that this depletion alters the dynamics of coilin, a phosphorylation target of VRK1. hiPSC-derived Motor Neurons (hiPSC-MN) from these patients, display Cajal Bodies (CBs) disassembly and defects in neurite outgrowth and branching, altered Action Potential (AP) waveform and decreased Axonal Initial Segment (AIS) length.In this study, we have further studied the link between the loss of VRK1 function and the defects observed in hiPSC-MNs, by realizing bulk mRNA-Seq sequencing in this in vitro model of the disease. Our results evidenced altered NRG1/ERBB4 signaling, leading to cholesterol metabolism dysregulation and deregulation of genes encoding the glutamate receptors AMPAR and NMDAR, which role in the Axonal Initial Segment and abnormal AP initiation in hiPSC-MNs remains to be investigated.

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Section: Discussionmentioning

confidence: 99%

“…There are now more than thirty mutations in VRK1, which cause a range of neurological diseases affecting motor neurons (mainly lower, but also upper) or their axons in the peripheral nervous system (Lazo & Morejon-Garcia, 2023), that we design as VRK1-related motor neuron diseases.…”

Section: Introductionmentioning

confidence: 99%

Altered NRG1/ErbB4 signaling and cholesterol metabolism dysregulation are key pathomechanisms in VRK1-related motor neuropathies and motor neuron diseases

Hamzé,

Humbert,

Rihan

et al. 2024

Preprint

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“…VRK1 pathogenic variants are located within three clusters in the protein sequence [ 33 ]. Two clusters, I and II, are located in the kinase N-terminal domain immediately after the ATP binding site or the catalytic site respectively.…”

Section: Introductionmentioning

confidence: 99%

“…Two clusters, I and II, are located in the kinase N-terminal domain immediately after the ATP binding site or the catalytic site respectively. The third cluster (III) is located near the end of the low-complexity C-terminal regulatory region [ 33 ]. The VRK1 C-terminal region is very flexible and can have multiple alternative conformations [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

“…The VRK1 C-terminal region is very flexible and can have multiple alternative conformations [ 34 ]. This C-terminal region folds and interacts with the N-terminus, inhibiting the kinase activity, and with other proteins determining the complexes in which it participates within the nucleus [ 15 , 33 ]. Unless the patients are siblings, there is not a single case with the same combination of VRK1 variants [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

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Pathogenic effects of Leu200Pro and Arg387His VRK1 protein variants on phosphorylation targets and H4K16 acetylation in distal hereditary motor neuropathy

Campos-Díaz,

Morejón-García,

Monte-Serrano

et al. 2024

J Mol Med

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Rare recessive variants in the human VRK1 gene are associated with several motor neuron diseases (MND), such as amyotrophic lateral sclerosis, spinal muscular atrophy, or distal hereditary motor neuropathies (dHMN). A case with dHMN carrying two novel VRK1 gene variants, expressing Leu200Pro (L200P) and Arg387His (R387H) variant proteins, identified that these protein variants are functionally different. The Leu200Pro variant shares with several variants in the catalytic domain the loss of the kinase activity on different substrates, such as histones, p53, or coilin. However, the distal Arg387His variant and the distal Trp375* (W375X) chinese variant, both located at the end of the low complexity C-terminal region and proximal to the termination codon, retain their catalytic activity on some substrates, and mechanistically their functional impairment is different. The L200P variant, as well as most VRK1 pathogenic variants, impairs the phosphorylation of BAF and histone H4K16 acetylation, which are required for DNA attachment to the nuclear envelope and chromatin accessibility to DNA repair mechanisms, respectively. The R387H variant impairs phosphorylation of H2AX, an early step in different types of DNA damage responses. The functional variability of VRK1 protein variants and their different combinations are a likely contributor to the clinical phenotypic heterogeneity of motor neuron and neurological diseases associated with rare VRK1 pathogenic variants. Key messages VRK1 variants implicated in motor neuron diseases are functionally different. The L200P variant is kinase inactive, and the R387H variant is partially active. VRK1 variants alter H4K16 acetylation and loss of coilin and BAF phosphorylation. VRK1 variants alter Cajal bodies and DNA damage responses. VRK1 variant combination determines the neurological phenotype heterogeneity.

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The Current Potential Pathogenesis of Amyotrophic Lateral Sclerosis

Jiang,

2024

Mol Neurobiol

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VRK1 variants at the cross road of Cajal body neuropathogenic mechanisms in distal neuropathies and motor neuron diseases

Cited by 8 publications

References 175 publications

Altered NRG1/ErbB4 signaling and cholesterol metabolism dysregulation are key pathomechanisms in VRK1-related motor neuropathies and motor neuron diseases

Altered NRG1/ErbB4 signaling and cholesterol metabolism dysregulation are key pathomechanisms in VRK1-related motor neuropathies and motor neuron diseases

Pathogenic effects of Leu200Pro and Arg387His VRK1 protein variants on phosphorylation targets and H4K16 acetylation in distal hereditary motor neuropathy

The Current Potential Pathogenesis of Amyotrophic Lateral Sclerosis

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