Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease
Fecha
2019-06-06Autor
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.
Deutschlander, Angela
Reinthaler, Eva M.
Zrzavy, Tobias
Mascia, Elisabetta
Zauli, Andrea
Esposito, Federica
Alcina, Antonio
Izquierdo, Guillermo
Espino Paisan, Laura
Mena Lucía, Jorge
Rodríguez-Antigüedad Zarranz, Alfredo
Urbaneja Romero, Patricia
Ortega Pinazo, Jesús
Song, Weihong
Sadovnick, A. Dessa
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https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1008180
Resumen
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.
Author summary Although the majority of patients diagnosed with multiple sclerosis do not have a family history of disease, 13% report having a close relative also diagnosed with multiple sclerosis. In these families, the cause of multiple sclerosis can be largely attributed to a single genetic variant that is transmitted through generations. In this study we analyzed DNA from 132 patients from 34 families, resulting in the identification of 12 rare genetic variants that are largely responsible for the onset of multiple sclerosis in these families. These variants are located in genes implicated in specific immunological pathways, and suggest the biological mechanisms that trigger the onset of multiple sclerosis. These genes and variants provide the means for the generation of cellular and animal models of human disease, and highlight biological targets for the development of novel treatments.
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