Homozygous Loss-of-Function Mutations in CCDC134 Are Responsible for a Severe Form of Osteogenesis Imperfecta.
Johanne DubailPerrine BrunelleGeneviève BaujatCéline HuberMathilde DoyardCaroline MichotPascale ChavassieuxAbdeslam KhairouniVicken TopouchianSophie MonnotEugénie KoumakisValerie Cormier-DairePublished in: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (2020)
Osteogenesis imperfecta (OI) is a primary bone fragility disorder with an estimated prevalence of 1 in 15,000 births. The majority of OI cases are inherited in an autosomal-dominant manner, while 5% to 10% have recessive or X-linked inheritance. Up to now, approximately 5% of OI cases remain without mutation demonstrated, supporting the involvement of other genes in the disease spectrum. By whole-exome sequencing, we identified a homozygous variant (c.2T>C) in CCDC134 gene in three patients from two unrelated families with severe bone fragility that did not respond to bisphosphonate treatment, short stature, and gracile long bones with pseudarthroses but no dentinogenesis imperfecta. CCDC134 encodes a secreted protein widely expressed and implicated in the regulation of some mitogen-activated protein kinases (MAPK) signaling pathway. Western blot and immunofluorescence analyses confirmed the absence of CCDC134 protein in patient cells compared with controls. Furthermore, we demonstrated that CCDC134 mutations are associated with increased Erk1/2 phosphorylation, decreased OPN mRNA and COL1A1 expression and reduced mineralization in patient osteoblasts compared with controls. These data support that CCDC134 is a new gene involved in severe progressive deforming recessive osteogenesis imperfecta (type III). © 2020 American Society for Bone and Mineral Research.
Keyphrases
- signaling pathway
- bone regeneration
- induced apoptosis
- pi k akt
- bone mineral density
- end stage renal disease
- type iii
- genome wide
- binding protein
- genome wide identification
- early onset
- case report
- soft tissue
- copy number
- ejection fraction
- chronic kidney disease
- poor prognosis
- cell cycle arrest
- bone loss
- peritoneal dialysis
- intellectual disability
- newly diagnosed
- multiple sclerosis
- oxidative stress
- protein protein
- prognostic factors
- electronic health record
- drug induced
- south africa
- muscular dystrophy
- epithelial mesenchymal transition
- gene expression
- patient reported outcomes
- machine learning
- risk factors
- small molecule
- cell death
- transcription factor
- deep learning
- big data
- cord blood