The molecular basis of oral-facial-digital syndrome, type 1.

Oral-facial-digital syndrome type 1 (OFDI; OFD1; OMIM 311200) is a rare developmental disorder transmitted as an X-linked dominant condition with embryonic male lethality. OFD1 is characterized by malformation of the oral cavity, face, and digits. Central nervous system (CNS) abnormalities and cystic kidney disease can also be part of this condition. This disorder is due to mutations in the OFD1 gene that encodes a centrosomal protein localized at the basal bodies at the origin of primary cilia. Characterization of in vitro and in vivo models demonstrated that, similarly to what described for other ciliary proteins, Ofd1 inactivation is associated to defective sonic hedgehog (Shh) and canonical Wnt signaling pathways. Functional studies have demonstrated that OFD1 has a crucial role in the biology of primary cilia thus ascribing this pleiotropic disease to the growing number of disorders associated to dysfunction of primary cilia. OFD1 shares phenotypic similarities with this latter group of disorders, such as cystic kidneys, skeletal, and CNS abnormalities. Future studies will address whether all clinical manifestations of these diseases can be entirely explained by cilia dysfunction or may also be due to direct roles of the proteins involved.