Recessive coding and regulatory mutations in FBLIM1 underlie the pathogenesis of chronic recurrent multifocal osteomyelitis (CRMO)

• Published in: PloS one Vol. 12; no. 3; p. e0169687
• Main Authors: Cox, Allison J., Darbro, Benjamin W., Laxer, Ronald M., Velez, Gabriel, Bing, Xinyu, Finer, Alexis L., Erives, Albert, Mahajan, Vinit B., Bassuk, Alexander G., Ferguson, Polly J.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 16.03.2017; Public Library of Science (PLoS)
• Subjects: Amino Acid Sequence; Analysis; Animal models; Animals; Arthritis; Binding sites; Biocompatibility; Biology and Life Sciences; Bone marrow; Bone remodeling; Care and treatment; Cell Adhesion Molecules - chemistry; Cell Adhesion Molecules - genetics; Cell Line, Tumor; Child; Cytoskeletal Proteins - chemistry; Cytoskeletal Proteins - genetics; Diagnosis; DNA microarrays; Female; Frameshift mutation; Gene mutation; Gene sequencing; Genes; Genes, Recessive; Genetic aspects; Genetics; Genomes; Haplotypes; Humans; Immunology; Inflammation; Inflammatory bowel disease; Inflammatory bowel diseases; Interdisciplinary aspects; Interleukin-10 - genetics; Intestine; Laboratories; Macrophages; Mice; Mutation; Osteomyelitis; Osteomyelitis - genetics; Pain; Parents; Pathogenesis; Pediatrics; Promoter Regions, Genetic; Proteins; Psoriasis; Research and Analysis Methods; Rheumatology; Sequence Homology, Amino Acid; Skin diseases; Transcription factors; Tumor necrosis factor-TNF
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0169687

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 are two syndromic forms of CRMO, Majeed syndrome and DIRA, for which the genetic cause is known. However, for the majority of cases of CRMO, the genetic basis is unknown. 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) determined that the Fblim1 ortholog is the most differentially expressed gene, downregulated over 20-fold in the cmo mouse. We sequenced FBLIM1 in 96 CRMO subjects and found a second proband with a novel frameshift mutation in exon 6 and a rare regulatory variant. In SaOS2 cells, overexpressing the regulatory mutation showed the flanking region acts as an enhancer, and the mutation ablates enhancer activity. Our data implicate FBLIM1 in the pathogenesis of sterile bone inflammation and our findings suggest CRMO is a disorder of chronic inflammation and imbalanced bone remodeling.