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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Authors: 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
Format: Article
Publication date:2019
Country:España
Institution:Instituto de Salud Carlos III (ISCIII)
Repository:Repisalud
Language:English
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/17874
Online Access:http://hdl.handle.net/20.500.12105/17874
Access Level:Open access
Keyword: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
Summary: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.

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