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 GD patients are localized within the region encoding the TB5 (TGF-β binding protein-like 5) domain of this protein. Herein, we generated a knock-in mouse model, Fbn1Y1698C by introducing the p.Tyr1696Cys mutation from a GD patient 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 fibrillin-1. 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 ECM composed by abnormal fibrillin-1 microfibril network impacting the differentiation of the chondrocytes.