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

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-beta binding protein-like 5 (TB5) domain of this protein. Herein, we generated a knock-in mouse model, Fbn1(Y1698C) 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 Fbn1(Y1698C/+) and Fbn1(Y1698C/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.

Automated summary

Mutations in the FBN1 gene can cause short stature and other symptoms similar to GD. This study used a knock-in mouse model to investigate the role of the TB5 domain in bone development and found that FBN1 mutations affect chondrocyte differentiation and growth plate formation, leading to GD.