Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/17874
Title
Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease.
Author(s)
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
Date issued
2019-06-06
Language
Inglés
Document type
research article
Abstract
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.
MESH
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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