The variant was uncovered while researchers observed a bizarre case of siblings, each with multiple sclerosis and malignant melanoma.
A rare case in which 2 siblings each developed multiple sclerosis (MS) and malignant melanoma has led researchers to a discovery that may help explain the genetic basis for some instances of MS.
Borut Peterlin, MD, PhD, and his colleagues at the Clinical Institute of Medical Genetics at Ljubljana University, Slovenia, wanted to look at the role of rare genetic variations in sporadic and familial MS. To do so, they started with a family in which 2 siblings had both developed MS and malignant melanoma.
The researchers performed genetic tests on members of the family, and then did the same examinations on members of 38 other families with multiple MS cases, and on 44 individual patients with sporadic MS.
The team identified a variant in the NLRP1 gene in the primary family, and, importantly, found similar variants in the broader group of patients. Peterlin and colleagues suggest the variant in the primary family could be the cause of concomitant MS and multiple myeloma. Furthermore, the researchers hypothesize that variants in NLRP1 might play a larger role in MS.
The finding is important because while researchers believe that both environmental and genetic factors can play a role in the development of MS, they have yet to pin down exactly how.
“Familial contribution to MS etiology is well recognized and many cases of families with apparent monogenic inheritance have been reported,” the authors wrote. “However, in contrast to several other complex neurological disorders no highly penetrant genetic variants have been described in MS yet.”
To evaluate genetic variants, the researchers performed whole exome sequencing for the primary family, as well as homozygosity mapping. The genetic analysis led researchers to a rare homozygous sequence variant in the NLRP1 gene.
“The variant encompasses a change of a highly evolutionary conserved amino acid residue of the NACHT domain, which is required for proper NLRP1 inflammasome oligomerization and assembly,” the authors wrote.
The scientists noted they also found other possibly associated variants of NLRP1 in both patients with and without a family history of MS.
One reason the team was able to link the variant to MS is that in patients with the NLRP1 variant, stimulation of peripheral blood mononuclear cells (PCBMs) results in overproduction of Interleukin 1-beta (IL-1β), a cytokine with pro-inflammatory qualities.
“The role of the IL-1β has been implicated in a variety of inflammatory and neurodegenerative processes occurring in multiple sclerosis,” the authors wrote. “There is evidence that IL-1β induces trans-endothelial migration of activated leukocytes across the blood-brain barrier of the central nervous system, exacerbates central neuroinflammation independently of the blood-brain barrier integrity, and facilitates T helper 17 cell induction.”
The researchers hypothesize that patients who are predisposed to increased stimulation of the NLRP1 pathway and then are exposed to certain as-yet-unidentified environmental factors might suffer from the depletion of the blood-brain barrier, which in turn could lead to recurrent active demyelination and neurodegeneration.
The study, “Identification of rare genetic variation of NLRP1 gene in familial multiple sclerosis,” was published online in Scientific Reports.