Alternative titles; symbols
HGNC Approved Gene Symbol: WDPCP
Cytogenetic location: 2p15 Genomic coordinates (GRCh38) : 2:63,119,559-63,840,826 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p15 | Bardet-Biedl syndrome 15 | 615992 | Autosomal recessive | 3 |
| Congenital heart defects, hamartomas of tongue, and polysyndactyly | 217085 | Autosomal recessive | 3 |
The WDPCP gene encodes an ortholog of Drosophila 'fritz,' a cytoplasmic WD40 repeat protein that controls planar cell polarity (Kim et al., 2010). WDPCP localizes to the base of cilia and the actin cytoskeleton and is required for ciliogenesis and directional cell migration (Cui et al., 2013).
In Drosophila, Collier et al. (2005) characterized 'fritz' (frtz), which encodes an evolutionarily conserved coiled-coil WD40 protein that functions cell-autonomously downstream of the core planar cell polarity (PCP) proteins (e.g., 'frizzled' 603408 and 'dishevelled' 601365) to regulate both the location and number of wing cell prehair initiation sites.
Collier et al. (2005) found that the human Fritz gene encodes a protein of 713 amino acids with a coiled-coil domain, 2 WD40 repeats, and a proline-enriched domain. The proline-rich region of Fritz is the most divergent among species. In the fly it contains 14.5% proline and was predicted to fold as a random coil. In the mammalian Fritz protein, the equivalent region is shorter and not significantly proline-rich, and is remarkably diverged between mouse and human, showing just 45% identity compared with 82% for the rest of the protein. The fly, mouse, and human Fritz proteins share a highly conserved hydrophobic 10-amino acid peptide at the extreme C terminus of the protein. The 2 WD40 repeats of mammalian Fritz fold together to form a beta-propeller structure that provides surfaces for protein-protein interaction.
Using immunohistochemical analysis, Cui et al. (2013) found that mouse Wdpcp was a ciliary protein that colocalized with Sept2 (601506) in a ring-like structure at the base of cilia in IMCD3 mouse inner medullary collecting duct cells and in transfected NIH3T3 fibroblasts. Wdpcp also colocalized with Sept2 in actin filaments in mouse embryonic fibroblasts (MEFs).
Hartz (2010) mapped the WDPCP gene to chromosome 2p15 based on an alignment of the WDPCP sequence (GenBank AF131737) with the genomic sequence (GRCh37).
Cui et al. (2013) stated that the mouse Wdpcp gene maps to chromosome 11.
Kim et al. (2010) identified control of septin (see SEPT7, 603151) localization by the PCP protein Fritz as a crucial control point for both collective cell movement and ciliogenesis in Xenopus embryos. The authors demonstrated that Fritz and septins control convergent extension and blastopore closure. Fritz morphants displayed defects in craniofacial morphogenesis and hedgehog (see 600725) signaling similar to those associated with defective ciliogenesis.
Using tandem affinity purification and mass spectrometry in mouse kidney IMCD3 cells, followed by pull-down and coimmunoprecipitation analyses, Toriyama et al. (2016) identified and characterized a regulatory module that they termed CPLANE (ciliogenesis and planar polarity effector). The core CPLANE complex consisted of Intu (610621), Fuz (610622), and Wdpcp, and these proteins also interacted strongly with Cplane1 (614571) and Rsg1 (CPLANE2; 620487). The authors noted that similar interactions had been observed in high-throughput screens of human proteins and are conserved in Drosophila. Intu, Fuz, Wdpcp, Rsg1, and Cplane1 localized around basal bodies in Xenopus multiciliated cells (MCCs). Knockdown experiments showed a complicated hierarchy of functional interactions among the proteins, with Cplane1, which was required for basal body localization of all the CPLANE proteins but Fuz, at the top of the hierarchy. The proteomic data showed that the CPLANE proteins interacted specifically with core and peripheral intraflagellar transport A (IFT-A) complex subunits, but not with IFT-B subunits. In Xenopus MCCs, Cplane1 was required for recruitment of peripheral IFT-A subunits to basal bodies for assembly onto the IFT-A core. Following knockdown of Cplane1 or Wdpcp, IFT-A core particles lacking peripheral proteins were injected into axonemes and underwent normal bidirectional trafficking, whereas IFT-B particles entered axonemes but failed to move in retrograde direction and accumulated. Toriyama et al. (2016) concluded that CPLANE proteins direct basal body recruitment of IFT machinery and are essential for ciliogenesis.
Bardet-Biedl Syndrome 15
Because of Fritz's role in convergent extension and ciliogenesis in Xenopus, Kim et al. (2010) investigated the contribution of human Fritz to the disorders Meckel-Gruber syndrome (see 249000) and Bardet-Biedl syndrome (209900). Kim et al. (2010) found significant enrichment of nonsynonymous coding changes in human Fritz (C2ORF86) in Meckel-Gruber syndrome and Bardet-Biedl syndrome (BBS15; 615992) patients compared with controls (6 alleles in 192 patients versus zero in 384 patients; p less than 0.015). In the Meckel-Gruber syndrome cohort, Kim et al. (2010) did not identify alleles sufficient to explain the phenotype, which suggested that these changes might interact in trans with the primary Meckel-Gruber syndrome loci. In the Bardet-Biedl syndrome cohort, Kim et al. (2010) found 2 heterozygous missense alleles that were absent from 384 ethnically matched controls, HapMap, and 1,000 genomes. Also, 2 of these changes mapped to the same surface-exposed face of the predicted beta-propeller structure of the Fritz protein. Notably, Kim et al. (2010) found that a homozygous Fritz mutation segregated with the disorder in a Bardet-Biedl syndrome family (613580.0001).
From a cohort of 125 families with ciliopathies, Shamseldin et al. (2020) identified a 14-year-old boy with BBS who was homozygous for a splice site mutation in the WDPCP gene (613580.0007).
From a cohort of 10 Pakistani families with BBS, Nawaz et al. (2023) identified a brother and sister who were homozygous for a nonsense mutation in the WDPCP gene (C240X; 613580.0008) that segregated fully with disease in their family.
Congenital Heart Defects, Hamartomas of the Tongue, and Polysyndactyly
Saari et al. (2015) reported a girl with congenital heart defects, hamartomas of the tongue, and polysyndactyly (CHDTHP; 217085) who was compound heterozygous for a missense (D54N; 613580.0004) and a frameshift mutation (613580.0005).
In a 5-year-old boy from Luxembourg with CHDTHP, Toriyama et al. (2016) identified compound heterozygosity for the previously reported D54N mutation and a frameshift mutation (613580.0006) in the WDPCP gene.
Using an ethylnitrosourea mutagenesis screen,Cui et al. (2013) identified mice with a mutation in Wdpcp that they called Wdpcp(cys40). The Wdpcp(cys40) mutation was a 224A-G transition that caused a splicing defect in the Wdpcp transcript and premature termination of the Wdpcp protein. No Wdpcp(cys40) protein was detected in mutant mice. Wdpcp(cys40) mice had a phenotype similar to that of Mks1 (609883) mutant mice, including anophthalmia, cysts in kidney and other organs, complex congenital heart defects, including truncus arteriosus or pulmonary atresia, and atrioventricular septal defects. Some Wdpcp(cys40) mice had duplex kidney, facial cleft and/or cleft palate, tracheoesophageal fistula, and cloacal septation defects. Wdpcp -/- mice died at birth with the same spectrum of developmental anomalies as Wdpcp(cys40) mice. No laterality defects were observed in Wdpcp -/- or Wdpcp(cys40) mice. Examination of Wdpcp(cys40) mutant embryos and MEFs revealed defective ciliogenesis in primary cilia, but not in motile cilia. Most Wdpcp(cys40) MEFs lacked primary cilia, and those rare cells that had cilia showed absence or mislocalization of Sept2, Mks1, and Nphp1 (607100) at the ciliary transition zone. Mutant embryos and cells showed disruption of Shh (600725) signaling and PCP defects, including reduced expression of noncanonical Wnt (see 606359) and upregulated canonical Wnt signaling. Wdpcp(cys40) cells in culture also showed absence of Sept2-positive stress fibers, reduced membrane ruffling, abnormally strong focal contacts, and lack of polarized movement. The function of Wdpcp did not appear to be conserved in lower vertebrates, since morpholino-mediated knockdown of wdpcp in zebrafish caused a constellation of phenotypes indicative of motile cilia defects but did not disrupt ciliogenesis.
Toriyama et al. (2016) generated Wdpcp-null mice and observed polydactyly with Y-shaped metacarpals at embryonic day 14.5. In addition, mutant palatal condensations formed more medially than in wildtype embryos and failed to extend into the mouth.
In cDNA from a patient with Bardet-Biedl syndrome-15 (BBS15; 615992), Kim et al. (2010) identified homozygosity for a G-to-T transition at the -1 position of a splice site in the WDPCP gene. Both parents and an unaffected sib were heterozygous carriers. The mutation, which occurred at a position invariant in Fritz, was not identified in 384 control chromosomes, HapMap, or 1,000 genomes.
In a patient with Bardet-Biedl syndrome-12 (BBS12; 615989), Kim et al. (2010) identified heterozygosity for a c.624G-C transversion in the WDPCP gene, resulting in a leucine-to-phenylalanine substitution at codon 208 (L208F). The patient was also compound heterozygous for mutations in the BBS12 gene (610683).
In a patient with Meckel-Gruber syndrome-6 (MKS6; 612284), Kim et al. (2010) identified heterozygosity for an arginine-to-leucine substitution at codon 55 of the WDPCP gene (R55K). The mutation arose from a c.164G-A transition. This patient was also compound heterozygous for mutations in the CC2D2A gene (612013).
Saari et al. (2015) reported a 3-year-old girl with congenital heart defects, hamartomas of the tongue, and polysyndactyly (CHDTHP; 217085) who was compound heterozygous for mutations in the WDPCP gene. One was a c.160G-A transition that resulted in an asp54-to-asn (D54N) substitution. The patient's mother was heterozygous for this mutation, and neither of the unaffected sibs carried it. The D54N substitution is highly conserved throughout evolution, through zebrafish and water flea; the variant is directly adjacent to the R55K (613580.0003) nonsynonymous coding variant reported by Kim et al. (2010) in a patient with Meckel syndrome-6 (MKS6; 612284). The D54N missense mutation was predicted to be deleterious by multiple algorithms due to the charge change, and may also disrupt a splice site. It was not found in the 1000 Genomes Project database and was found only once in the Exome Sequencing Project database, with a frequency of 1 in 11,827. The other mutation in WDPCP was a 2-bp deletion, c.552_553del, resulting in a frameshift substitution following cys185 (C185fs). This mutation was present in the patient's asymptomatic father, brother, and sister.
In a 5-year-old Luxembourger boy (case 1) with CHDTHP, Toriyama et al. (2016) identified compound heterozygosity for the D54N mutation and a 2-bp deletion (526_527delTT; 613580.0006) in the WDPCP gene. The latter mutation was predicted to cause a frameshift resulting in a premature termination codon (Leu176Ilefs*21). His unaffected parents were each heterozygous for 1 of the mutations. The D54N mutation was referred to as D54A, and the effect of the frameshift mutation given as Leu176PhefsTer23, in Figure 6 of the report.
For discussion of the c.552_553del mutation in the WDPCP gene that was found in compound heterozygous state in a patient with congenital heart defects, hamartomas of the tongue, and polysyndactyly (CHDTHP; 217085) by Saari et al. (2015), see 613580.0004.
For discussion of the c.526_527delTT mutation in the WDPCP gene that was found in compound heterozygous state in a patient with congenital heart defects, hamartomas of the tongue, and polysyndactyly (CHDTHP; 217085) by Toriyama et al. (2016), see 613580.0004.
In a 14-year-old boy (19DG2145) with Bardet-Biedl syndrome (BBS15; 615992) born of first-cousin parents,, Shamseldin et al. (2020) identified homozygosity for a splice site mutation (c.1601+1G-T, NM_001042692.3) in the WDPCP gene. He had retinitis pigmentosa, obesity, impaired cognition, poor pupillary reaction to light, and noticeably large hands and feet.
In a Pakistani brother and sister (family C) with Bardet-Biedl syndrome (BBS15; 615992), Nawaz et al. (2023) identified homozygosity for a c.720C-A transversion (c.720C-A, NM_015910.7) in the WDPCP gene, resulting in a cys240-to-ter (C240X) substitution. Their unaffected first-cousin parents were heterozygous for the mutation, which was not found in their unaffected brother. The variant was predicted to result in a truncated protein of only 239 amino acids, which would activate nonsense-mediated decay machinery causing degradation of the mutant mRNA, with no functional protein being produced.
Collier, S., Lee, H., Burgess, R., Adler, P. The WD40 repeat protein Fritz links cytoskeletal planar polarity to Frizzled subcellular localization in the Drosophila epidermis. Genetics 169: 2035-2045, 2005. [PubMed: 15654087] [Full Text: https://doi.org/10.1534/genetics.104.033381]
Cui, C., Chatterjee, B., Lozito, T. P., Zhang, Z., Francis, R. J., Yagi, H., Swanhart, L. M., Sanker, S., Francis, D., Yu, Q., San Agustin, J. T., Puligilla, C., and 10 others. Wdpcp, a PCP protein required for ciliogenesis, regulates directional cell migration and cell polarity by direct modulation of the actin cytoskeleton. PLoS Biol. 11: e1001720, 2013. Note: Electronic Article. [PubMed: 24302887] [Full Text: https://doi.org/10.1371/journal.pbio.1001720]
Hartz, P. A. Personal Communication. Baltimore, Md. 10/7/2010.
Kim, S. K., Shindo, A., Park, T. J., Oh, E. C., Ghosh, S., Gray, R. S., Lewis, R. A., Johnson, C. A., Attie-Bittach, T., Katsanis, N., Wallingford, J. B. Planar cell polarity acts through septins to control collective cell movement and ciliogenesis. Science 329: 1337-1340, 2010. [PubMed: 20671153] [Full Text: https://doi.org/10.1126/science.1191184]
Nawaz, H., Mujahid, Khan, S. A., Bibi, F., Waqas, A., Bari, A., Fardous, Khan, N., Muhammad, N., Khan, A., Paracha, S. A., Alam, Q., Kamal, M. A., Rafeeq, M. M., Muhammad, N., Haq, F. U., Khan, S., Mahmood, A., Khan, S., Umair, M. Biallelic variants in seven different genes associated with clinically suspected Bardet-Biedl syndrome. Genes 14: 1113, 2023. [PubMed: 37239474] [Full Text: https://doi.org/10.3390/genes14051113]
Saari, J., Lovell, M. A., Yu, H.-C., Bellus, G. A. Compound heterozygosity for a frame shift mutation and a likely pathogenic sequence variant in the planar cell polarity-ciliogenesis gene WDPCP in a girl with polysyndactyly, coarctation of the aorta, and tongue hamartomas. Am. J. Med. Genet. 167A: 421-427, 2015. [PubMed: 25427950] [Full Text: https://doi.org/10.1002/ajmg.a.36852]
Shamseldin, H. E., Shaheen, R., Ewida, N., Bubshait, D. K., Alkuraya, H., Almardawi, E., Howaidi, A., Sabr, Y., Abdalla, E. M., Alfaifi, A. Y., Alghamdi, J. M., Alsagheir, A., and 29 others. The morbid genome of ciliopathies: an update. Genet. Med. 22: 1051-1060, 2020. Note: Erratum: Genet. Med. 24: 966, 2022. [PubMed: 32055034] [Full Text: https://doi.org/10.1038/s41436-020-0761-1]
Toriyama, M., Lee, C., Taylor, S. P., Duran, I., Cohn, D. H., Bruel, A.-L., Tabler, J. M., Drew, K., Kelly, M. R., Kim, S., Park, T. J., Braun, D. A., and 21 others. The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery. Nature Genet. 48: 648-656, 2016. Note: Erratum: Nature Genet. 48: 970 only, 2016. [PubMed: 27158779] [Full Text: https://doi.org/10.1038/ng.3558]