Loss-of-function of DDR1 is responsible for a chondrodysplasia with multiple dislocations.

Autor:	Villarroel MV; Paris Cité University, Reference center for skeletal dysplasia, INSERM UMR 1163, Imagine Institute, Necker Enfants Malades Hospital (AP-HP), Paris, France., Huber C; Paris Cité University, Reference center for skeletal dysplasia, INSERM UMR 1163, Imagine Institute, Necker Enfants Malades Hospital (AP-HP), Paris, France., Baujat G; Paris Cité University, Reference center for skeletal dysplasia, INSERM UMR 1163, Imagine Institute, Necker Enfants Malades Hospital (AP-HP), Paris, France., Bonnard A; Department of Molecular Genetics, Robert Debré Hospital (AP-HP), Paris, France., Collet C; Paris Cité University, Reference center for skeletal dysplasia, INSERM UMR 1163, Imagine Institute, Necker Enfants Malades Hospital (AP-HP), Paris, France., Cormier-Daire V; Paris Cité University, Reference center for skeletal dysplasia, INSERM UMR 1163, Imagine Institute, Necker Enfants Malades Hospital (AP-HP), Paris, France.
Jazyk:	angličtina
Zdroj:	Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research [J Bone Miner Res] 2024 Dec 23. Date of Electronic Publication: 2024 Dec 23.
DOI:	10.1093/jbmr/zjae205
Abstrakt:	Chondrodysplasias with multiple dislocations are rare skeletal disorders characterized by hyperlaxity, joint dislocations, and growth retardation. Chondrodysplasias with multiple dislocations have been linked to pathogenic variants in genes encoding proteins involved in the proteoglycan biosynthesis. In this study, by exome sequencing analysis, we identified a homozygous nonsense variant (NM_001297654.2: c.1825C > T, p.Arg609*) in the discoidin domain receptor 1 (DDR1) gene in a patient presenting joint dislocations, hyperlaxity, and cerebellar hypoplasia. Functional studies revealed decreased proteoglycan production in patient fibroblasts. We further demonstrated that DDR1 inhibition impaired the Indian Hedgehog (IHH) signaling pathway in chondrocytes, decreased differentiation and mineralization in osteoblasts, and disrupted p38 MAPK signaling in both cell types. Additionally, we showed that DDR1 inhibition affected the non-canonical WNT signaling pathway in human skeletal cells and decreased proteoglycan production in chondrocytes. These findings suggest that DDR1 is a new gene involved in the group of chondrodysplasias with multiple dislocations and highlights its essential role in human skeletal and brain development. (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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