Journal
PLOS ONE
Volume 9, Issue 9, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0106330
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Funding
- National Institute of Dental and Craniofacial Research [F31 DE023483-01]
- National Institute of General Medical Sciences (NIGMS) Spatio Temporal Modeling Center Fellowship (STMC) [P50 GM085273]
- Wellcome Trust
- National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK050141]
- NIGMS [K12 GM088021]
- Kidney Research UK
- Kidney Research UK [RP2/2013] Funding Source: researchfish
- Worldwide Cancer Research [13-0042] Funding Source: researchfish
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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.
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