Identification of rare genetic variation of NLRP1 gene in familial multiple sclerosis
Abstract The genetic etiology and the contribution of rare genetic variation in multiple sclerosis (MS) has not yet been elucidated. Although familial forms of MS have been described, no convincing rare and penetrant variants have been reported to date. We aimed to characterize the contribution of r...
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2017
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oai:doaj.org-article:e4072727c70249fda8baa63505e6bb7c2021-12-02T16:08:11ZIdentification of rare genetic variation of NLRP1 gene in familial multiple sclerosis10.1038/s41598-017-03536-92045-2322https://doaj.org/article/e4072727c70249fda8baa63505e6bb7c2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03536-9https://doaj.org/toc/2045-2322Abstract The genetic etiology and the contribution of rare genetic variation in multiple sclerosis (MS) has not yet been elucidated. Although familial forms of MS have been described, no convincing rare and penetrant variants have been reported to date. We aimed to characterize the contribution of rare genetic variation in familial and sporadic MS and have identified a family with two sibs affected by concomitant MS and malignant melanoma (MM). We performed whole exome sequencing in this primary family and 38 multiplex MS families and 44 sporadic MS cases and performed transcriptional and immunologic assessment of the identified variants. We identified a potentially causative homozygous missense variant in NLRP1 gene (Gly587Ser) in the primary family. Further possibly pathogenic NLRP1 variants were identified in the expanded cohort of patients. Stimulation of peripheral blood mononuclear cells from MS patients with putatively pathogenic NLRP1 variants showed an increase in IL-1B gene expression and active cytokine IL-1β production, as well as global activation of NLRP1-driven immunologic pathways. We report a novel familial association of MS and MM, and propose a possible underlying genetic basis in NLRP1 gene. Furthermore, we provide initial evidence of the broader implications of NLRP1-related pathway dysfunction in MS.Ales MaverPolona LavtarSmiljana RistićSanja StopinšekSaša SimčičKeli HočevarJuraj SepčićJelena DrulovićTatjana PekmezovićIvana NovakovićHodžić AlenkaGorazd RudolfSaša ŠegaNada Starčević-ČizmarevićAnja PalandačićGordana ZamoloMiljenko KapovićTina LikarBorut PeterlinNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-8 (2017) |
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Medicine R Science Q Ales Maver Polona Lavtar Smiljana Ristić Sanja Stopinšek Saša Simčič Keli Hočevar Juraj Sepčić Jelena Drulović Tatjana Pekmezović Ivana Novaković Hodžić Alenka Gorazd Rudolf Saša Šega Nada Starčević-Čizmarević Anja Palandačić Gordana Zamolo Miljenko Kapović Tina Likar Borut Peterlin Identification of rare genetic variation of NLRP1 gene in familial multiple sclerosis |
| description |
Abstract The genetic etiology and the contribution of rare genetic variation in multiple sclerosis (MS) has not yet been elucidated. Although familial forms of MS have been described, no convincing rare and penetrant variants have been reported to date. We aimed to characterize the contribution of rare genetic variation in familial and sporadic MS and have identified a family with two sibs affected by concomitant MS and malignant melanoma (MM). We performed whole exome sequencing in this primary family and 38 multiplex MS families and 44 sporadic MS cases and performed transcriptional and immunologic assessment of the identified variants. We identified a potentially causative homozygous missense variant in NLRP1 gene (Gly587Ser) in the primary family. Further possibly pathogenic NLRP1 variants were identified in the expanded cohort of patients. Stimulation of peripheral blood mononuclear cells from MS patients with putatively pathogenic NLRP1 variants showed an increase in IL-1B gene expression and active cytokine IL-1β production, as well as global activation of NLRP1-driven immunologic pathways. We report a novel familial association of MS and MM, and propose a possible underlying genetic basis in NLRP1 gene. Furthermore, we provide initial evidence of the broader implications of NLRP1-related pathway dysfunction in MS. |
| format |
article |
| author |
Ales Maver Polona Lavtar Smiljana Ristić Sanja Stopinšek Saša Simčič Keli Hočevar Juraj Sepčić Jelena Drulović Tatjana Pekmezović Ivana Novaković Hodžić Alenka Gorazd Rudolf Saša Šega Nada Starčević-Čizmarević Anja Palandačić Gordana Zamolo Miljenko Kapović Tina Likar Borut Peterlin |
| author_facet |
Ales Maver Polona Lavtar Smiljana Ristić Sanja Stopinšek Saša Simčič Keli Hočevar Juraj Sepčić Jelena Drulović Tatjana Pekmezović Ivana Novaković Hodžić Alenka Gorazd Rudolf Saša Šega Nada Starčević-Čizmarević Anja Palandačić Gordana Zamolo Miljenko Kapović Tina Likar Borut Peterlin |
| author_sort |
Ales Maver |
| title |
Identification of rare genetic variation of NLRP1 gene in familial multiple sclerosis |
| title_short |
Identification of rare genetic variation of NLRP1 gene in familial multiple sclerosis |
| title_full |
Identification of rare genetic variation of NLRP1 gene in familial multiple sclerosis |
| title_fullStr |
Identification of rare genetic variation of NLRP1 gene in familial multiple sclerosis |
| title_full_unstemmed |
Identification of rare genetic variation of NLRP1 gene in familial multiple sclerosis |
| title_sort |
identification of rare genetic variation of nlrp1 gene in familial multiple sclerosis |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/e4072727c70249fda8baa63505e6bb7c |
| work_keys_str_mv |
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1718384625656528896 |