Journal article
Recessive coding and regulatory mutations in FBLIM1 underlie the pathogenesis of chronic recurrent multifocal osteomyelitis (CRMO)
PloS one, Vol.12(3), pp.e0169687-e0169687
2017
DOI: 10.1371/journal.pone.0169687
PMCID: PMC5354242
PMID: 28301468
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.
Details
- Title: Subtitle
- Recessive coding and regulatory mutations in FBLIM1 underlie the pathogenesis of chronic recurrent multifocal osteomyelitis (CRMO)
- Creators
- Allison J Cox - Interdisciplinary Graduate Program in Genetics, The University of Iowa, Iowa City, IA, United States of AmericaBenjamin W Darbro - Interdisciplinary Graduate Program in Genetics, The University of Iowa, Iowa City, IA, United States of AmericaRonald M Laxer - Division of Pediatric Rheumatology, Departments of Pediatrics and Medicine, University of Toronto and The Hospital for Sick Children, Toronto, ON, CanadaGabriel Velez - Omics Laboratory, University of Iowa, Iowa City, IA, United States of AmericaXinyu Bing - Department of Pediatrics, The University of Iowa, Iowa City, IA, United States of AmericaAlexis L Finer - Department of Pediatrics, The University of Iowa, Iowa City, IA, United States of AmericaAlbert Erives - Department of Biology, The University of Iowa, Iowa City, IA, United States of AmericaVinit B Mahajan - Omics Laboratory, University of Iowa, Iowa City, IA, United States of AmericaAlexander G Bassuk - Interdisciplinary Graduate Program in Genetics, The University of Iowa, Iowa City, IA, United States of AmericaPolly J Ferguson - Department of Pediatrics, The University of Iowa, Iowa City, IA, United States of America
- Resource Type
- Journal article
- Publication Details
- PloS one, Vol.12(3), pp.e0169687-e0169687
- DOI
- 10.1371/journal.pone.0169687
- PMID
- 28301468
- PMCID
- PMC5354242
- NLM abbreviation
- PLoS One
- ISSN
- 1932-6203
- eISSN
- 1932-6203
- Publisher
- United States
- Grant note
- T32 GM008629 / NIGMS NIH HHS R01 AR059703 / NIAMS NIH HHS R01 EY024665 / NEI NIH HHS T32 GM007337 / NIGMS NIH HHS
- Language
- English
- Date published
- 2017
- Academic Unit
- Neurology; Critical Care; Stead Family Department of Pediatrics; Epidemiology; Emergency Medicine; Iowa Neuroscience Institute; Medical Genetics and Genomics; Biology; Rheumatology, Allergy, and Immunology; Neurology (Pediatrics)
- Record Identifier
- 9983992062102771
Metrics
34 Record Views