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 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.

The immunogenetics of neurological disease

“…227 Distorted patterns of gene expression are a characteristic of many neurological diseases, such as MS, Alzheimer's disease and schizophrenia, and in various cases these altered gene expressions can be correlated straightforwardly to genomic/pathogenic variations. [228][229][230] These findings support the hypothesis of a robust association between anomalous gene expression and neurological diseases, suggesting that variants in non-coding regulatory elements are outstanding candidates for some of the observed missing heritability in neurological diseases. The identification of many null or expression variants of common HLA alleles will improve our understanding of their role in immune functions.…”

Role of inflammasomes in multiple sclerosis and their potential as therapeutic targets

“…Several inflammasomes have been described to contribute to the pathology of MS, thus highlighting the overlap in function among different inflammasomes [25][26][27][28][29]. Here, we summarize the known contribution to date of the different inflammasomes to MS.…”

“…NLRP1 variants have been reported in MS pathogenesis, but the precise mechanism of action remains undefined. A recent study identified a potentially causative amino acid substitution (glycine to serine) in NLRP1 that was associated with increased IL-18 and IL-1β production in familial MS patients [27]. However, a separate study was not able to identify pathological genetic variations in the NLRP1 gene [66].…”

NLR-Dependent Regulation of Inflammation in Multiple Sclerosis

“…Several studies found an association between NLRP1 and vitiligo ( 91 ), autoimmune thyroid diseases ( 92 ), and type I diabetes ( 93 ). In a recent publication, Maver et al linked homozygous missense variant in NLRP1 gene (Gly587Ser) with familial forms of MS ( 94 ). Also, Bernales et al found several NLRP1 compound heterozygote mutations in MS patients ( 95 ).…”