Background/Purpose:  Chronic recurrent multifocal osteomyelitis (CRMO) is a rare, pediatric, autoinflammatory disease characterized by bone pain due to sterile osteomyelitis, and is often accompanied by psoriasis or inflammatory bowel disease. There is evidence for a genetic basis in several syndromic forms of the disease including the Deficiency of the Interleukin-1 Receptor Antagonist (DIRA; due to mutations in IL1RN), Majeed syndrome (due to mutations in LPIN2) and murine chronic multifocal osteomyelitis (due to mutations in Pstpip2). However, for the majority of cases of CRMO, the genetic basis remains unknown.

Methods:  We used whole exome and Sanger sequencing, gene expression microarray and Luciferease assays to identify additional CRMO susceptibility genes.

Results:  Via whole-exome sequencing, we detected a homozygous mutation in the filamin-binding domain of FBLIM1 in an affected child with consanguineous parents. Microarray analysis of bone marrow macrophages from the CRMO murine model (cmo mouse) determined that the Fblim1 ortholog is the most differentially expressed gene, further implicating it in disease pathogenesis. In addition, studies suggest FBLIM1/FBLP1 is an anti-inflammatory molecule regulated by STAT3, and one involved in bone remodeling via ERK1/2 phosphorylation and the subsequent regulation of RANKL activation. We sequenced FBLIM1 in 96 CRMO subjects and found a second proband with compound heterozygous mutations in FBLIM1 composed of a novel frameshift mutation in exon 6 and a rare regulatory variant. The enhancer contains binding sites for STAT3 and NR4A2. Enhancer activity of a 1-kb region around the mutation was validated by luciferase assays in fluoride-treated SaOS2 cells, as was the effect of the mutation on regulatory activity. In SaOS2 cells, overexpressing the regulatory mutation showed the flanking region acts as an enhancer, and the mutation ablates enhancer activity. 

Conclusion:  Our data implicate FBLIM1 in the pathogenesis of CRMO and autoinflammatory disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/recessive-coding-and-regulatory-mutations-in-fblim1-underlie-the-pathogenesis-of-sterile-osteomyelitis/