Identification of rare genetic variation of NLRP1 gene in familial multiple sclerosis

Ales Maver,Jelena Drulović,Polona Lavtar,Ivana Novaković,Anja Palandačić,Gorazd Rudolf,Keli Hočevar,Nada Starčević-Čizmarević,Sanja Stopinšek,Miljenko Kapović,Borut Peterlin,Smiljana Ristić,Gordana Zamolo,Juraj Sepčić,Tatjana Pekmezović,Saša Šega,Tina Likar,Saša Simčič,Hodžić Alenka

doi:10.1038/s41598-017-03536-9

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.

Highlights

Background populationMinor allele frequency (MAF)* 0,000% 0,000% 0.004% 0,000% 0,009% 7,500% 7,200% 7,200% 7,600% 7,500%Polyphen2 / BBPBBBPBBSIFT / TTDTTTTTT variable and included relapsing-remitting, primary progressive and benign courses
We identified a family with two sibs concurrently affected by multiple sclerosis and malignant melanoma (MSMM, Fig. 1)
Multiple sclerosis was first suspected at the age of 41, after an MRI scan was performed in diagnostic evaluation of a traumatic vertebral fracture

Summary

Introduction

Background populationMAF* 0,000% 0,000% 0.004% 0,000% 0,009% 7,500% 7,200% 7,200% 7,600% 7,500%Polyphen2 / BBPBBBPBBSIFT / TTDTTTTTT variable and included relapsing-remitting, primary progressive and benign courses. The case with the frameshift NLRP1 variant had an early reported onset of the disease with symptoms presenting at 21 years of age with the disease following a relapsing-remitting pattern. We performed a statistical test of mutational burden in NLRP1 gene, including variants with moderate or high functional impact and below 5% in ExAC project in the analysis. We could not demonstrate an overall excess of potentially altering variants in the NLRP1 gene in familial MS cases (P = 0.92) when comparing them to control subjects. There was an excess of missense variants in the sporadic MS groups in comparison to control cases (P < 0.0001), likely due to a high overall number of missense variants belonging to the H3 haplotype

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