Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by myelin loss and neuronal dysfunction. Although the majority of patients do not present familial aggregation, Mendelian forms have been described. We performed whole-exome sequencing analysis in 132 pati...

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Autores: Vilariño-Güell, Carles, Zimprich, Alexander, Martinelli-Boneschi, Filippo, Herculano, Bruno, Wang, Zhe, Matesanz, Fuencisla, Urcelay, Elena, Vandenbroeck, Koen, Leyva, Laura, Gris, Denis, Massaad, Charbel, Quandt, Jacqueline A, Traboulsee, Anthony L, Encarnacion, Mary, Bernales, Cecily Q, Follett, Jordan, Yee, Irene M, Criscuoli, Maria G, Deutschländer, Angela, Reinthaler, Eva M, Zrzavy, Tobias, Mascia, Elisabetta, Zauli, Andrea, Esposito, Federica, Alcina, Antonio, Izquierdo, Guillermo, Espino-Paisán, Laura, Mena, Jorge, Antigüedad, Alfredo, Urbaneja-Romero, Patricia, Ortega-Pinazo, Jesús, Song, Weihong, Sadovnick, A Dessa
Tipo de recurso: artículo
Fecha de publicación:2019
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/17874
Acceso en línea:http://hdl.handle.net/20.500.12105/17874
Access Level:acceso abierto
Palabra clave:Adult
Codon, Nonsense
Demyelinating Diseases
Exome
Female
Genetic Predisposition to Disease
Humans
Inflammation
Male
Middle Aged
Multiple Sclerosis
Myelin Sheath
Nerve Degeneration
Neurons
Pedigree
Transcriptome
Exome Sequencing
Young Adult
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oai_identifier_str oai:repisalud.isciii.es:20.500.12105/17874
network_acronym_str ES
network_name_str España
repository_id_str
spelling Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease.Vilariño-Güell, CarlesZimprich, AlexanderMartinelli-Boneschi, FilippoHerculano, BrunoWang, ZheMatesanz, FuencislaUrcelay, ElenaVandenbroeck, KoenLeyva, LauraGris, DenisMassaad, CharbelQuandt, Jacqueline ATraboulsee, Anthony LEncarnacion, MaryBernales, Cecily QFollett, JordanYee, Irene MCriscuoli, Maria GDeutschländer, AngelaReinthaler, Eva MZrzavy, TobiasMascia, ElisabettaZauli, AndreaEsposito, FedericaAlcina, AntonioIzquierdo, GuillermoEspino-Paisán, LauraMena, JorgeAntigüedad, AlfredoUrbaneja-Romero, PatriciaOrtega-Pinazo, JesúsSong, WeihongSadovnick, A DessaAdultCodon, NonsenseDemyelinating DiseasesExomeFemaleGenetic Predisposition to DiseaseHumansInflammationMaleMiddle AgedMultiple SclerosisMyelin SheathNerve DegenerationNeuronsPedigreeTranscriptomeExome SequencingYoung AdultMultiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by myelin loss and neuronal dysfunction. Although the majority of patients do not present familial aggregation, Mendelian forms have been described. We performed whole-exome sequencing analysis in 132 patients from 34 multi-incident families, which nominated likely pathogenic variants for MS in 12 genes of the innate immune system that regulate the transcription and activation of inflammatory mediators. Rare missense or nonsense variants were identified in genes of the fibrinolysis and complement pathways (PLAU, MASP1, C2), inflammasome assembly (NLRP12), Wnt signaling (UBR2, CTNNA3, NFATC2, RNF213), nuclear receptor complexes (NCOA3), and cation channels and exchangers (KCNG4, SLC24A6, SLC8B1). These genes suggest a disruption of interconnected immunological and pro-inflammatory pathways as the initial event in the pathophysiology of familial MS, and provide the molecular and biological rationale for the chronic inflammation, demyelination and neurodegeneration observed in MS patients.20242024-02-1020192019-06-0620192019-06-06research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articlehttp://hdl.handle.net/20.500.12105/17874reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/178742026-06-12T12:43:37Z
dc.title.none.fl_str_mv Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease.
title Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease.
spellingShingle Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease.
Vilariño-Güell, Carles
Adult
Codon, Nonsense
Demyelinating Diseases
Exome
Female
Genetic Predisposition to Disease
Humans
Inflammation
Male
Middle Aged
Multiple Sclerosis
Myelin Sheath
Nerve Degeneration
Neurons
Pedigree
Transcriptome
Exome Sequencing
Young Adult
title_short Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease.
title_full Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease.
title_fullStr Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease.
title_full_unstemmed Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease.
title_sort Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease.
dc.creator.none.fl_str_mv Vilariño-Güell, Carles
Zimprich, Alexander
Martinelli-Boneschi, Filippo
Herculano, Bruno
Wang, Zhe
Matesanz, Fuencisla
Urcelay, Elena
Vandenbroeck, Koen
Leyva, Laura
Gris, Denis
Massaad, Charbel
Quandt, Jacqueline A
Traboulsee, Anthony L
Encarnacion, Mary
Bernales, Cecily Q
Follett, Jordan
Yee, Irene M
Criscuoli, Maria G
Deutschländer, Angela
Reinthaler, Eva M
Zrzavy, Tobias
Mascia, Elisabetta
Zauli, Andrea
Esposito, Federica
Alcina, Antonio
Izquierdo, Guillermo
Espino-Paisán, Laura
Mena, Jorge
Antigüedad, Alfredo
Urbaneja-Romero, Patricia
Ortega-Pinazo, Jesús
Song, Weihong
Sadovnick, A Dessa
author Vilariño-Güell, Carles
author_facet Vilariño-Güell, Carles
Zimprich, Alexander
Martinelli-Boneschi, Filippo
Herculano, Bruno
Wang, Zhe
Matesanz, Fuencisla
Urcelay, Elena
Vandenbroeck, Koen
Leyva, Laura
Gris, Denis
Massaad, Charbel
Quandt, Jacqueline A
Traboulsee, Anthony L
Encarnacion, Mary
Bernales, Cecily Q
Follett, Jordan
Yee, Irene M
Criscuoli, Maria G
Deutschländer, Angela
Reinthaler, Eva M
Zrzavy, Tobias
Mascia, Elisabetta
Zauli, Andrea
Esposito, Federica
Alcina, Antonio
Izquierdo, Guillermo
Espino-Paisán, Laura
Mena, Jorge
Antigüedad, Alfredo
Urbaneja-Romero, Patricia
Ortega-Pinazo, Jesús
Song, Weihong
Sadovnick, A Dessa
author_role author
author2 Zimprich, Alexander
Martinelli-Boneschi, Filippo
Herculano, Bruno
Wang, Zhe
Matesanz, Fuencisla
Urcelay, Elena
Vandenbroeck, Koen
Leyva, Laura
Gris, Denis
Massaad, Charbel
Quandt, Jacqueline A
Traboulsee, Anthony L
Encarnacion, Mary
Bernales, Cecily Q
Follett, Jordan
Yee, Irene M
Criscuoli, Maria G
Deutschländer, Angela
Reinthaler, Eva M
Zrzavy, Tobias
Mascia, Elisabetta
Zauli, Andrea
Esposito, Federica
Alcina, Antonio
Izquierdo, Guillermo
Espino-Paisán, Laura
Mena, Jorge
Antigüedad, Alfredo
Urbaneja-Romero, Patricia
Ortega-Pinazo, Jesús
Song, Weihong
Sadovnick, A Dessa
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv
dc.subject.none.fl_str_mv Adult
Codon, Nonsense
Demyelinating Diseases
Exome
Female
Genetic Predisposition to Disease
Humans
Inflammation
Male
Middle Aged
Multiple Sclerosis
Myelin Sheath
Nerve Degeneration
Neurons
Pedigree
Transcriptome
Exome Sequencing
Young Adult
topic Adult
Codon, Nonsense
Demyelinating Diseases
Exome
Female
Genetic Predisposition to Disease
Humans
Inflammation
Male
Middle Aged
Multiple Sclerosis
Myelin Sheath
Nerve Degeneration
Neurons
Pedigree
Transcriptome
Exome Sequencing
Young Adult
description Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by myelin loss and neuronal dysfunction. Although the majority of patients do not present familial aggregation, Mendelian forms have been described. We performed whole-exome sequencing analysis in 132 patients from 34 multi-incident families, which nominated likely pathogenic variants for MS in 12 genes of the innate immune system that regulate the transcription and activation of inflammatory mediators. Rare missense or nonsense variants were identified in genes of the fibrinolysis and complement pathways (PLAU, MASP1, C2), inflammasome assembly (NLRP12), Wnt signaling (UBR2, CTNNA3, NFATC2, RNF213), nuclear receptor complexes (NCOA3), and cation channels and exchangers (KCNG4, SLC24A6, SLC8B1). These genes suggest a disruption of interconnected immunological and pro-inflammatory pathways as the initial event in the pathophysiology of familial MS, and provide the molecular and biological rationale for the chronic inflammation, demyelination and neurodegeneration observed in MS patients.
publishDate 2019
dc.date.none.fl_str_mv 2019
2019-06-06
2019
2019-06-06
2024
2024-02-10
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/17874
url http://hdl.handle.net/20.500.12105/17874
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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