Abstract
Mutation of the X-linked oral-facial-digital syndrome type 1 (OFD1) gene is embryonic lethal in males and results in craniofacial malformations and adult onset polycystic kidney disease in females. While the OFD1 protein localizes to centriolar satellites, centrosomes and basal bodies, its cellular function and how it relates to cystic kidney disease is largely unknown. Here, we demonstrate that OFD1 is assembled into a protein complex that is localized to the primary cilium and contains the epidermal growth factor receptor (EGFR) and domain organizing flotillin proteins. This protein complex, which has similarity to a basolateral adhesion domain formed during cell polarization, also contains the polycystin proteins that when mutant cause autosomal dominant polycystic kidney disease (ADPKD). Importantly, in human ADPKD cells where mutant polycystin-1 fails to localize to cilia, there is a concomitant loss of localization of polycystin-2, OFD1, EGFR and flotillin-1 to cilia. Together, these data suggest that polycystins are necessary for assembly of a novel flotillin-containing ciliary signaling complex and provide a molecular rationale for the common renal pathologies caused by OFD1 and PKD mutations.
Highlights
Oral-facial-digital syndrome type 1 (OFD1; OMIM #311200) is an X-linked inherited disease characterized by the malformation of the face, oral cavity, hands and feet caused by heterogeneous mutations in the OFD1 gene known as CXORF5
Systemic manifestations of OFD1 mutations include polycystic kidneys that resemble those caused by mutations in the PKD1 or PKD2 genes associated with autosomal dominant polycystic kidney disease (ADPKD) [1,2]
Of interest is the recent finding that epidermal growth factor receptor (EGFR) and downstream signaling partners are scaffolded in cholesterol-rich signaling domains by the flotillins [22]
Summary
Oral-facial-digital syndrome type 1 (OFD1; OMIM #311200) is an X-linked inherited disease characterized by the malformation of the face, oral cavity, hands and feet caused by heterogeneous mutations in the OFD1 gene known as CXORF5. Systemic manifestations of OFD1 mutations include polycystic kidneys that resemble those caused by mutations in the PKD1 or PKD2 genes associated with autosomal dominant polycystic kidney disease (ADPKD) [1,2]. Many of the proteins associated with cystic kidney disorders, including polycystin-1 (PC1) and polycystin-2 (PC2) that underlie ADPKD, localize to and function in the primary cilium [3,4,5,6,7]. Deletion of the Ofd gene (Ofd1D4-5/+-) in mice causes missing/ supernumerary teeth, enamel hypoplasia, and polycystic kidney disease analogous to human oral-facial-digital syndrome type 1 [4]. Localization of OFD1 to the primary cilium of tooth ectomesenchymal odontoblasts and renal epithelial cells is speculated to be crucial for proper cellular differentiation of both cell types [3,4]
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