title: Recessive coding and regulatory mutations in FBLIM1 underlie the pathogenesis of chronic recurrent multifocal osteomyelitis (CRMO).
abstract: 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.
authors.affiliation: Department of Pediatrics, The University of Iowa, Iowa City, IA, United States of America.|Interdisciplinary Graduate Program in Genetics, The University of Iowa, Iowa City, IA, United States of America.
authors.forename: Allison J
authors.identifier: http://orcid.org/0000-0002-6803-4456
authors.initials: AJ
authors.lastname: Cox
authors.affiliation: Department of Pediatrics, The University of Iowa, Iowa City, IA, United States of America.|Interdisciplinary Graduate Program in Genetics, The University of Iowa, Iowa City, IA, United States of America.
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Darbro
authors.affiliation: Division of Pediatric Rheumatology, Departments of Pediatrics and Medicine, University of Toronto and The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Laxer
authors.affiliation: Medical Scientist Training Program, University of Iowa, Iowa City, IA, United States of America.|Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA, United States of America.|Omics Laboratory, University of Iowa, Iowa City, IA, United States of America.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Velez
authors.affiliation: Department of Pediatrics, The University of Iowa, Iowa City, IA, United States of America.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Bing
authors.affiliation: Department of Pediatrics, The University of Iowa, Iowa City, IA, United States of America.
authors.forename: Alexis L
authors.initials: AL
authors.lastname: Finer
authors.affiliation: Interdisciplinary Graduate Program in Genetics, The University of Iowa, Iowa City, IA, United States of America.|Department of Biology, The University of Iowa, Iowa City, IA, United States of America.
authors.forename: Albert
authors.initials: A
authors.lastname: Erives
authors.affiliation: Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA, United States of America.|Omics Laboratory, University of Iowa, Iowa City, IA, United States of America.
authors.forename: Vinit B
authors.initials: VB
authors.lastname: Mahajan
authors.affiliation: Department of Pediatrics, The University of Iowa, Iowa City, IA, United States of America.|Interdisciplinary Graduate Program in Genetics, The University of Iowa, Iowa City, IA, United States of America.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Bassuk
authors.affiliation: Department of Pediatrics, The University of Iowa, Iowa City, IA, United States of America.
authors.forename: Polly J
authors.initials: PJ
authors.lastname: Ferguson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000235:genetics*; D045744:Cell Line, Tumor; D002648:Child; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics; D051379:Mice; D009154:Mutation; D010019:Osteomyelitis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D017386:Sequence Homology, Amino Acid
chemical_list: D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; C473794:FBLIM1 protein, human; D016753:Interleukin-10