# Identification of a Novel NLRP12 Frameshift Mutation (Val730Glyfs∗41) by Whole-Exome Sequencing in Patients with Crohn's Disease

## TL;DR

A new NLRP12 gene mutation linked to Crohn's disease was found using whole-exome sequencing and shown to reduce protein levels, potentially contributing to the disease.

## Contribution

A novel NLRP12 frameshift mutation (Val730Glyfs∗41) is identified as a potential contributor to Crohn's disease.

## Key findings

- The NLRP12 mutation cosegregated with Crohn's disease in a family.
- Patients with the mutation had reduced NLRP12 protein levels in blood and colon.
- NMDI14 increased NLRP12 expression in mutant cells, suggesting a therapeutic target.

## Abstract

NLRP12 encodes the nucleotide-binding leucine-rich repeat-containing receptor 12 protein and has been linked to familial cold autoinflammatory syndrome 2 (FCAS2). Previous studies have reported that NLRP12 protein can dampen inflammatory responses in DSS-induced mice colitis. To date, only four alterations in the NLRP12 gene have been associated with Crohn's disease (CD). Here, we reported a novel heterozygous NLRP12 frameshift mutation (c.2188dupG, p.Val730Glyfs∗41) identified by whole-exome sequencing in the proband with CD. The Sanger sequencing confirmed that his sister and father also carried this NLRP12 mutation, which cosegregated well with the CD phenotype. In silico analysis predicted this mutation to be disease-causing. Patients heterozygous for this mutation exhibited decreased NLRP12 protein levels in the peripheral blood and colon. Functional assays showed that mutant NLRP12 plasmid-transfected HEK293T cells exhibited significantly lower NLRP12 mRNA and protein levels than wild-type plasmid-transfected cells. The nonsense-mediated decay inhibitor NMDI14 significantly increased NLRP12 mRNA and protein levels in mutant plasmid-transfected cells. Overall, our results demonstrated that this heterozygous NLRP12 mutation (c.2188dupG) resulted in decreased NLRP12 expression, which might contribute to the mechanism underlying CD.