Homozygous loss-of-function mutations in ...
Document type :
Article dans une revue scientifique: Article original
DOI :
PMID :
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Title :
Homozygous loss-of-function mutations in ccdc134 are responsible for a severe form of osteogenesis imperfecta
Author(s) :
Dubail, Johanne [Auteur]
Brunelle, Perrine [Auteur]
Baujat, Genevieve [Auteur]
Huber, Celine [Auteur]
Doyard, Mathilde [Auteur]
Michot, Caroline [Auteur]
Chavassieux, Pascale [Auteur]
Khairouni, Abdeslam [Auteur]
Topouchian, Vicken [Auteur]
Monnot, Sophie [Auteur]
Koumakis, Eugenie [Auteur]
Cormier-Daire, Valerie [Auteur]
Brunelle, Perrine [Auteur]
Baujat, Genevieve [Auteur]
Huber, Celine [Auteur]
Doyard, Mathilde [Auteur]
Michot, Caroline [Auteur]
Chavassieux, Pascale [Auteur]
Khairouni, Abdeslam [Auteur]
Topouchian, Vicken [Auteur]
Monnot, Sophie [Auteur]
Koumakis, Eugenie [Auteur]
Cormier-Daire, Valerie [Auteur]
Journal title :
Journal of bone and mineral research . the official journal of the American Society for Bone and Mineral Research
Abbreviated title :
J. Bone Miner. Res.
Volume number :
35
Pages :
1470-1480
Publication date :
2020-04-14
ISSN :
0884-0431
Keyword(s) :
OSTEOBLAST
CCDC134
MAPK PATHWAYS
OSTEOGENESIS IMPERFECTA
WHOLE-EXOME SEQUENCING
CCDC134
MAPK PATHWAYS
OSTEOGENESIS IMPERFECTA
WHOLE-EXOME SEQUENCING
HAL domain(s) :
Sciences du Vivant [q-bio]
English abstract : [en]
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 ...
Show more >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.Show less >
Show more >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.Show less >
Language :
Anglais
Audience :
Internationale
Popular science :
Non
Administrative institution(s) :
Université de Lille
Collections :
Submission date :
2021-09-02T07:02:26Z