Novel NR4A1 Arg293Ser Mutation in Patients With Familial Crohn's Disease

Abstract

Background/aim: The underlying etiology of Crohn's disease remains unknown. The aim of this study was to identify genomic alterations associated with the development of Crohn's disease in one Japanese family with a family history of Crohn's disease.

Materials and methods: We performed whole-exome sequence and pedigree analysis of a Japanese family in which both sisters developed Crohn's disease. Whole-exome sequencing was performed using the Ion Torrent Proton™ system. Data from the Proton runs were initially processed using the Ion Torrent platform-specific pipeline software Ion Reporter. An autosomal dominant mode of inheritance was assumed, and stringent selection criteria were applied.

Results: A substitution in the NR4A1 gene at codon 293 resulting in an amino acid change from arginine to serine was identified only in the affected sisters.

Conclusion: The impaired DNA-binding capacity of the NR4A1 protein due to an NR4A1 germline mutation may be a possible cause of Crohn's disease.

Keywords: Crohn’s disease; Nur77; exome sequence; germline mutation; steroid orphan receptor.

Figure 1. Pedigree plotting and sequencing results. A). Pedigree of the study family and the disease status of each member. Squares denote male family members, circles denote female members, shaded symbols denote affected members, and slashes denote deceased members. We performed whole-exome sequencing using DNA from peripheral blood samples from the following four family members: II-1, II-3, III-1, and III-2. B). Sequence chromatogram and direct sequence chart of the mutant genome. The NR4A1 germline mutation c.877C>T, a missense substitution of cysteine for arginine at position 293 (encoding p.Arg293Cys; position chr12:52449814 T/C), was detected with Ion Torrent technology.

Figure 2. Structure of mutated NR4A1. A). Crystal structure of the DNA-binding domain of the Arg293-containing protein. B). DNA-binding domain structures of human proteins and the conservation of the Cys293 position across human proteins. The cysteine at this position in the strand is responsible for binding to the promoter region of target genes.