VRK1 variants at the cross road of Cajal body neuropathogenic mechanisms in distal neuropathies and motor neuron diseases
Distal hereditary neuropathies and neuro motor diseases are complex neurological phenotypes associated with pathogenic variants in a large number of genes, but in some the origin is unknown. Recently, rare pathogenic variants of the human VRK1 gene have been associated with these neurological phenot...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-07-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996123001870 |
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| author | Pedro A. Lazo Patricia Morejón-García |
| author_facet | Pedro A. Lazo Patricia Morejón-García |
| author_sort | Pedro A. Lazo |
| collection | DOAJ |
| description | Distal hereditary neuropathies and neuro motor diseases are complex neurological phenotypes associated with pathogenic variants in a large number of genes, but in some the origin is unknown. Recently, rare pathogenic variants of the human VRK1 gene have been associated with these neurological phenotypes. All VRK1 pathogenic variants are recessive, and their clinical presentation occurs in either homozygous or compound heterozygous patients. The pathogenic VRK1 gene pathogenic variants are located in three clusters within the protein sequence. The main, and initial, shared clinical phenotype among VRK1 pathogenic variants is a distal progressive loss of motor and/or sensory function, which includes diseases such as spinal muscular atrophy, Charcot-Marie-Tooth, amyotrophic lateral sclerosis and hereditary spastic paraplegia. In most cases, symptoms start early in infancy, or in utero, and are slowly progressive. Additional neurological symptoms vary among non-related patients, probably because of their different VRK1 variants and their genetic background. The underlying common pathogenic mechanism, by its functional impairment, is a likely consequence of the roles that the VRK1 protein plays in the regulation on the stability and assembly of Cajal bodies, which affect RNA maturation and processing, neuronal migration of RNPs along axons, and DNA-damage responses. Alterations of these processes are associated with several neuro sensory or motor syndromes. The clinical heterogeneity of the neurological phenotypes associated with VRK1 is a likely consequence of the protein complexes in which VRK1 is integrated, which include several proteins known to be associated with Cajal bodies and DNA damage responses. Several hereditary distal neurological diseases are a consequence of pathogenic variants in genes that alter these cellular functions. We conclude that VRK1-related distal hereditary neuropathies and motor neuron diseases represent a novel subgroup of Cajal body related neurological syndromes. |
| first_indexed | 2024-03-13T04:56:53Z |
| format | Article |
| id | doaj.art-961a88f980c643f2af17040a7e67e78f |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-03-13T04:56:53Z |
| publishDate | 2023-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-961a88f980c643f2af17040a7e67e78f2023-06-18T05:01:05ZengElsevierNeurobiology of Disease1095-953X2023-07-01183106172VRK1 variants at the cross road of Cajal body neuropathogenic mechanisms in distal neuropathies and motor neuron diseasesPedro A. Lazo0Patricia Morejón-García1Molecular Mechanisms of Cancer Program, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) - Universidad de Salamanca, Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain; Corresponding author at: Molecular Mechanisms of Cancer Program, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) - Universidad de Salamanca, Salamanca, Spain.Molecular Mechanisms of Cancer Program, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) - Universidad de Salamanca, Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, SpainDistal hereditary neuropathies and neuro motor diseases are complex neurological phenotypes associated with pathogenic variants in a large number of genes, but in some the origin is unknown. Recently, rare pathogenic variants of the human VRK1 gene have been associated with these neurological phenotypes. All VRK1 pathogenic variants are recessive, and their clinical presentation occurs in either homozygous or compound heterozygous patients. The pathogenic VRK1 gene pathogenic variants are located in three clusters within the protein sequence. The main, and initial, shared clinical phenotype among VRK1 pathogenic variants is a distal progressive loss of motor and/or sensory function, which includes diseases such as spinal muscular atrophy, Charcot-Marie-Tooth, amyotrophic lateral sclerosis and hereditary spastic paraplegia. In most cases, symptoms start early in infancy, or in utero, and are slowly progressive. Additional neurological symptoms vary among non-related patients, probably because of their different VRK1 variants and their genetic background. The underlying common pathogenic mechanism, by its functional impairment, is a likely consequence of the roles that the VRK1 protein plays in the regulation on the stability and assembly of Cajal bodies, which affect RNA maturation and processing, neuronal migration of RNPs along axons, and DNA-damage responses. Alterations of these processes are associated with several neuro sensory or motor syndromes. The clinical heterogeneity of the neurological phenotypes associated with VRK1 is a likely consequence of the protein complexes in which VRK1 is integrated, which include several proteins known to be associated with Cajal bodies and DNA damage responses. Several hereditary distal neurological diseases are a consequence of pathogenic variants in genes that alter these cellular functions. We conclude that VRK1-related distal hereditary neuropathies and motor neuron diseases represent a novel subgroup of Cajal body related neurological syndromes.http://www.sciencedirect.com/science/article/pii/S0969996123001870VRK1Distal neuropathiesSMNSMAALSCharcot-Marie-Tooth |
| spellingShingle | Pedro A. Lazo Patricia Morejón-García VRK1 variants at the cross road of Cajal body neuropathogenic mechanisms in distal neuropathies and motor neuron diseases Neurobiology of Disease VRK1 Distal neuropathies SMN SMA ALS Charcot-Marie-Tooth |
| title | VRK1 variants at the cross road of Cajal body neuropathogenic mechanisms in distal neuropathies and motor neuron diseases |
| title_full | VRK1 variants at the cross road of Cajal body neuropathogenic mechanisms in distal neuropathies and motor neuron diseases |
| title_fullStr | VRK1 variants at the cross road of Cajal body neuropathogenic mechanisms in distal neuropathies and motor neuron diseases |
| title_full_unstemmed | VRK1 variants at the cross road of Cajal body neuropathogenic mechanisms in distal neuropathies and motor neuron diseases |
| title_short | VRK1 variants at the cross road of Cajal body neuropathogenic mechanisms in distal neuropathies and motor neuron diseases |
| title_sort | vrk1 variants at the cross road of cajal body neuropathogenic mechanisms in distal neuropathies and motor neuron diseases |
| topic | VRK1 Distal neuropathies SMN SMA ALS Charcot-Marie-Tooth |
| url | http://www.sciencedirect.com/science/article/pii/S0969996123001870 |
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