The critical role of the TB5 domain of fibrillin-1 in endochondral ossification - Université Paris Cité Accéder directement au contenu
Article Dans Une Revue Human Molecular Genetics Année : 2022

The critical role of the TB5 domain of fibrillin-1 in endochondral ossification

Résumé

Abstract Mutations in the fibrillin-1 (FBN1) gene are responsible for the autosomal dominant form of geleophysic dysplasia (GD), which is characterized by short stature and extremities, thick skin and cardiovascular disease. All known FBN1 mutations in patients with GD are localized within the region encoding the transforming growth factor-β binding protein-like 5 (TB5) domain of this protein. Herein, we generated a knock-in mouse model, Fbn1Y1698C by introducing the p.Tyr1696Cys mutation from a patient with GD into the TB5 domain of murine Fbn1 to elucidate the specific role of this domain in endochondral ossification. We found that both Fbn1Y1698C/+ and Fbn1Y1698C/Y1698C mice exhibited a reduced stature reminiscent of the human GD phenotype. The Fbn1 point mutation introduced in these mice affected the growth plate formation owing to abnormal chondrocyte differentiation such that mutant chondrocytes failed to establish a dense microfibrillar network composed of FBN1. This original Fbn1 mutant mouse model offers new insight into the pathogenic events underlying GD. Our findings suggest that the etiology of GD involves the dysregulation of the extracellular matrix composed of an abnormal FBN1 microfibril network impacting the differentiation of the chondrocytes.
Fichier non déposé

Dates et versions

hal-03946887 , version 1 (19-01-2023)

Identifiants

Citer

Laure Delhon, Zakaria Mougin, Jérémie Jonquet, Angélique Bibimbou, Johanne Dubail, et al.. The critical role of the TB5 domain of fibrillin-1 in endochondral ossification. Human Molecular Genetics, 2022, 31 (22), pp.3777-3788. ⟨10.1093/hmg/ddac131⟩. ⟨hal-03946887⟩
9 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More