Identification of conserved residues essential for the ciliogenic functions of WDPCP

Here, we report a genetically engineered mouse model expressing a mutant Wdpcp gene that harbors a deletion of two codons encoding D481 and W482 that correspond to N512 and W513 in human WDPCP. Homozygous mutant mice, designated as Wdpcp-Z11, exhibited severe developmental abnormalities, including neural tube defects, craniofacial malformation, anophthalmia and polydactyly. The mutant WDPCP protein was expressed but failed to dock to the apical surface of the cell. Cilia formation and Hh signaling were severely impaired. Structure predictions located these residues at the juncture of two alpha helices in a conserved, but otherwise uncharacterized, region of WDPCP. Their absence was predicted to impair the linker and reduce conformational stability of WDPCP. Rescue experiments demonstrated that restoring both D481 and W482 are required for a phenotypic recovery. Because a variant of W513 (p.Trp513Ser) is associated with Bardet-Beidl syndrome, insight gained into the structure-function relationship may be valuable for understanding WDPCP-associated ciliopathy.