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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Detalles Bibliográficos
Autores: Lazo, Pedro A., Morejón-García, Patricia
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/347985
Acceso en línea:http://hdl.handle.net/10261/347985
Access Level:acceso abierto
Palabra clave:VRK1
Distal neuropathies
SMN
SMA
ALS
Charcot-Marie-Tooth
Hereditary spastic paraplegia
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spelling VRK1 variants at the cross road of Cajal body neuropathogenic mechanisms in distal neuropathies and motor neuron diseasesLazo, Pedro A.Morejón-García, PatriciaVRK1Distal neuropathiesSMNSMAALSCharcot-Marie-ToothHereditary spastic paraplegiaDistal 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.P.A.L. was supported by grants from Agencia Estatal de Investigación (10.13039/501100011033)-Ministerio de Ciencia e Innovación-FEDER (PID2019-105610RB-I00) and Consejería de Educación-Junta de Castilla y León-Fondo Europeo de Desarrollo Regional (FEDER) (CSI264P20, CLC-2017-01). P. M.-G. was supported by Ministerio de Educación-FPU-FSE predoctoral contract (FPU16/01883).Peer reviewedElsevierAgencia Estatal de Investigación (España)Ministerio de Ciencia e Innovación (España)European CommissionJunta de Castilla y LeónMinisterio de Educación (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202420242023info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/347985reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttps://doi.org/10.1016/j.nbd.2023.106172Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3479852026-05-22T06:33:51Z
dc.title.none.fl_str_mv VRK1 variants at the cross road of Cajal body neuropathogenic mechanisms in distal neuropathies and motor neuron diseases
title VRK1 variants at the cross road of Cajal body neuropathogenic mechanisms in distal neuropathies and motor neuron diseases
spellingShingle VRK1 variants at the cross road of Cajal body neuropathogenic mechanisms in distal neuropathies and motor neuron diseases
Lazo, Pedro A.
VRK1
Distal neuropathies
SMN
SMA
ALS
Charcot-Marie-Tooth
Hereditary spastic paraplegia
title_short 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_sort VRK1 variants at the cross road of Cajal body neuropathogenic mechanisms in distal neuropathies and motor neuron diseases
dc.creator.none.fl_str_mv Lazo, Pedro A.
Morejón-García, Patricia
author Lazo, Pedro A.
author_facet Lazo, Pedro A.
Morejón-García, Patricia
author_role author
author2 Morejón-García, Patricia
author2_role author
dc.contributor.none.fl_str_mv Agencia Estatal de Investigación (España)
Ministerio de Ciencia e Innovación (España)
European Commission
Junta de Castilla y León
Ministerio de Educación (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv VRK1
Distal neuropathies
SMN
SMA
ALS
Charcot-Marie-Tooth
Hereditary spastic paraplegia
topic VRK1
Distal neuropathies
SMN
SMA
ALS
Charcot-Marie-Tooth
Hereditary spastic paraplegia
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.
publishDate 2023
dc.date.none.fl_str_mv 2023
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/347985
url http://hdl.handle.net/10261/347985
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://doi.org/10.1016/j.nbd.2023.106172
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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