Journal article
Gain-of-function mutations in a member of the Src family kinases cause autoinflammatory bone disease in mice and humans
Proceedings of the National Academy of Sciences - PNAS, Vol.116(24), pp.11872-11877
06/11/2019
DOI: 10.1073/pnas.1819825116
PMCID: PMC6575637
PMID: 31138708
Abstract
Autoinflammatory syndromes are characterized by dysregulation of the innate immune response with subsequent episodes of acute spontaneous inflammation. Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disorder that presents with bone pain and localized swelling.
mice, isolated from a mutagenesis screen, exhibit a spontaneous inflammatory paw phenotype that includes sterile osteomyelitis and systemic reduced bone mineral density. To elucidate the molecular basis of the disease, positional cloning of the causative gene for
was attempted. Using a candidate gene approach, a missense mutation in the C-terminal region of
, a member of Src family tyrosine kinases (SFKs), was identified. For functional confirmation, additional mutations at the N terminus of
were introduced in
mice by CRISPR/Cas9-mediated genome editing. N-terminal deleterious mutations of
abolished the inflammatory phenotype in
mice, but in-frame and missense mutations in the same region continue to exhibit the phenotype. The fact that
null mutant mice are morphologically normal suggests that the inflammation in this model depends on Fgr products. Furthermore, the levels of C-terminal negative regulatory phosphorylation of Fgr
are distinctly reduced compared with that of wild-type Fgr. In addition, whole-exome sequencing of 99 CRMO patients including 88 trios (proband and parents) identified 13 patients with heterozygous coding sequence variants in
, including two missense mutant proteins that affect kinase activity. Our results strongly indicate that gain-of-function mutations in
are involved in sterile osteomyelitis, and thus targeting SFKs using specific inhibitors may allow for efficient treatment of the disease.
Details
- Title: Subtitle
- Gain-of-function mutations in a member of the Src family kinases cause autoinflammatory bone disease in mice and humans
- Creators
- Koichiro Abe - Department of Molecular Life Science, Tokai University School of Medicine, Isehara 259-1193, Kanagawa, Japan; abeko@is.icc.u-tokai.ac.jpAllison Cox - Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa, IA 52242Nobuhiko Takamatsu - School of Science, Kitasato University, Sagamihara 252-0373, Kanagawa, JapanGabriel Velez - Medical Scientist Training Program, University of Iowa Carver College of Medicine, Iowa City, IA 52242Ronald M Laxer - Department of Pediatrics, Hospital for Sick Children, University of Toronto, ON M5G 1X8, CanadaShirley M L Tse - Department of Pediatrics, Hospital for Sick Children, University of Toronto, ON M5G 1X8, CanadaVinit B Mahajan - Omics Laboratory, Byers Eye Institute, Stanford University, Palo Alto, CA 94304Alexander G Bassuk - Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa, IA 52242Helmut Fuchs - Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, GermanyPolly J Ferguson - Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa, IA 52242Martin Hrabe de Angelis - German Center for Diabetes Research, 85764 Neuherberg, Germany
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.116(24), pp.11872-11877
- DOI
- 10.1073/pnas.1819825116
- PMID
- 31138708
- PMCID
- PMC6575637
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences; United States
- Grant note
- R01 EY025225 / NEI NIH HHS T32 GM007337 / NIGMS NIH HHS R01 EY024698 / NEI NIH HHS R01 AR059703 / NIAMS NIH HHS R01 EY026682 / NEI NIH HHS R01 EY024665 / NEI NIH HHS R21 AG050437 / NIA NIH HHS
- Language
- English
- Date published
- 06/11/2019
- Academic Unit
- Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Rheumatology, Allergy, and Immunology; Neurology (Pediatrics)
- Record Identifier
- 9984070676702771
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