Alternative titles; symbols
HGNC Approved Gene Symbol: WDR35
Cytogenetic location: 2p24.1 Genomic coordinates (GRCh38) : 2:19,910,263-19,990,105 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p24.1 | Cranioectodermal dysplasia 2 | 613610 | Autosomal recessive | 3 |
| Short-rib thoracic dysplasia 7 with or without polydactyly | 614091 | Autosomal recessive | 3 |
WDR35 is a WD40 domain-containing protein. Studies in mouse and several lower organisms have implicated WDR35 in intraflagellar transport (summary by Gilissen et al. (2010)).
By sequencing clones obtained from a size-fractionated adult brain cDNA library, Nagase et al. (2000) obtained a partial WDR35 clone, which they designated KIAA1336. RT-PCR ELISA detected highest expression in adult ovary, followed by testis, kidney, brain, and liver. Low expression was detected in fetal brain and adult heart and lung, with little to no expression in fetal liver and adult skeletal muscle, pancreas, and spleen. Moderate to high expression was detected in all adult brain regions examined.
Gilissen et al. (2010) determined that the 1,181-amino acid human WDR35 protein has 4 N-terminal WD40 motifs, a central WD40 motif, and a region of low complexity near the C terminus. They identified 3 additional WDR35 isoforms by database analysis.
By screening a rat brain/spinal cord expression cDNA library for proteins reactive against anti-shigatoxin antibody, Feng et al. (2010) cloned rat Wdr35, which they called Naofen. The deduced 1,170-amino acid protein contains 4 N-terminal WD40 domains and shares 92.7% identity with human WDR35. Quantitative RT-PCR detected Wdr35 expression in all rat tissues examined, with highest expression in testis, followed by brain, and lowest expression in spleen.
Gilissen et al. (2010) determined that the WDR35 gene contains 28 coding exons.
Hartz (2010) mapped the WDR35 gene to chromosome 2p24.1 based on an alignment of the WDR35 sequence (GenBank AB037757) with the genomic sequence (GRCh37).
Using small interfering RNA, Feng et al. (2010) showed that knockdown of Naofen in HEK293 cells reduced TNF-alpha (TNF; 191160)-induced caspase-3 (CASP3; 600636) activation and apoptosis. Overexpression of rat Naofen spontaneously induced caspase-3 activation and apoptosis and increased cell susceptibility to TNF-alpha-induced apoptosis.
By immunoblot and immunofluorescence analysis of Wdr35 -/- mouse fibroblasts, Caparros-Martin et al. (2015) observed no change in total protein levels of EVC (604831) and EVC2 (607261) in the mutant fibroblasts compared to controls; however, neither EVC or EVC2 was detected in Wdr35 -/- cilia. In response to the SMO agonist SAG, which drives SMO (SMOH; 601500) into the ciliary compartment, only Wdr35 -/- cilia remained negative for SMO immunofluorescence. The authors concluded that additional intraflagellar transport complex A (IFTA)-dependent functions requiring WDR35, but not retrograde transport, are specifically required for the correct ciliary entry of EVC, EVC2, and SMO. Levels of IFT43 (614068) appeared to depend on WDR35, since IFT43 was strongly reduced in Wdr35 -/- fibroblasts.
Cranioectodermal Dysplasia 2
By exome sequencing, Gilissen et al. (2010) identified compound heterozygous mutations in the WDR35 gene (613602.0001-613602.0004) in 2 unrelated Dutch children with cranioectodermal dysplasia (CED2; 613610). Genetic analysis of 6 additional patients with a similar disorder and in 15 patients with Jeune syndrome (208500) did not yield any further WDR35 mutations. The authors noted that studies in Drosophila and C. elegans with WDR35 orthologs showed localization to the cilium and function in intraflagellar transport. Gilissen et al. (2010) postulated that the WDR35 mutations resulted in ciliary dysfunction due to disrupted intraflagellar transport.
In a 4-year-old Mexican boy with CED, Bacino et al. (2012) identified homozygosity for a missense mutation in the WDR35 gene (L520P; 613602.0008).
In an 8-month-old boy who had CED with multisutural craniosynostoses, Lin et al. (2013) identified compound heterozygosity for missense mutations in the WDR35 gene: H1031Y (613602.0009) and Y1068C (613602.0010).
In a 15-year-old Pakistani boy with relatively mild CED, Smith et al. (2016) identified homozygosity for a missense mutation in the WR35 gene (W1153C; 613602.0012). The authors noted that it was the most distal mutation yet reported.
In a 9-year-old Polish girl with Sensenbrenner syndrome, Walczak-Sztulpa et al. (2017) sequenced the candidate genes IFT122 (606145) and WDR35 and identified compound heterozygosity for mutations in the WDR35 gene: L641X (613602.0015) and D841V (613602.0016). The authors noted that this family exhibited intrafamilial variability, in that the proband's affected older sister had a more severe expression of the phenotype and had died in infancy. They suggested that the observed inter- and intrafamilial clinical variability within ciliopathies might be explained by 'mutational load,' including genetic heterogeneity, mutation type, genetic load, modifier effects, and/or oligogenic inheritance.
Short-Rib Thoracic Dysplasia 7 with or without Polydactyly
In 2 sibs with short-rib thoracic dysplasia-7 (SRTD7; 614091), Mill et al. (2011) identified a homozygous deletion mutation in the WDR35 gene (613602.0005). In an unrelated fetus with SRTD7, they identified compound heterozygous mutations in the WDR35 gene (613602.0006-613602.0007). All 3 patients exhibited polydactyly.
In 5 children from 3 unrelated families exhibiting a distinctive form of SRTD with overlapping features of both Ellis-van Creveld syndrome (see 225500) and cranioectodermal dysplasia, Caparros-Martin et al. (2015) identified biallelic mutations in the WDR35 gene (see, e.g., 613602.0011). All of the mutations were shown to affect splicing of WDR35.
In 3 sibs and an unrelated female infant with an unusual form of SRTD involving bent ribs and long bones as well as undermineralization of the skull, Duran et al. (2017) performed exome analysis and in both families identified compound heterozygosity for a missense mutation and a truncating mutation (see, e.g., 613602.0013 and 613602.0014). The sibs had polydactyly, whereas the unrelated female infant did not.
Toriyama et al. (2016) reported a male infant with SRTD and polydactyly due to apparent digenic inheritance; the infant exhibited double heterozygosity for a truncating mutation in the INTU gene (Q276X; 610621.0003) and a missense mutation in WDR35 (W311L; 613602.0013).
In a mouse mutation screen for developmental phenotypes, Mill et al. (2011) identified a mutation in the Wdr35 gene as the cause of midgestation lethality, with abnormalities characteristic of defects in the Hedgehog signaling pathway. Mill et al. (2011) showed that endogenous WDR35 localizes to cilia and centrosomes throughout the developing embryo and that human and mouse fibroblasts lacking the protein fail to produce cilia. Through structural modeling, Mill et al. (2011) showed that WDR35 has strong homology to the COPI coatamers involved in vesicular trafficking and that human SRPS mutations affect key structural elements in WDR35.
In a Dutch child with cranioectodermal dysplasia-2 (CED2; 613610), Gilissen et al. (2010) identified compound heterozygosity for 2 mutations in the WDR35 gene: an A-to-G transition in intron 2 (25-2A-G) resulting in a splice site mutation and premature termination, and a 1877A-G transition in exon 17 resulting in a glu626-to-gly (E626G; 613602.0002) substitution at a highly conserved residue. Neither mutation was found in 210 control alleles. The phenotype included short stature, dolichocephaly, craniosynostosis, narrow thorax with pectus excavatum, short limbs, and brachydactyly. Facial features included narrow palpebral fissures, telecanthus with hypertelorism, low-set simple ears, everted lower lip, and short neck. Teeth abnormalities included widely spaced, hypoplastic, and fused teeth. The boy also had joint laxity, inguinal hernia, and webbed fingers. There was no evidence of renal or hepatic disease, and he had normal intelligence.
For discussion of the glu626-to-gly (E626G) mutation in the WDR35 gene that was found in compound heterozygous state in a patient with cranioectodermal dysplasia-2 (CED2; 613610) by Gilissen et al. (2010), see 613602.0001.
In a Dutch child with cranioectodermal dysplasia-2 (CED2; 613610), Gilissen et al. (2010) identified compound heterozygosity for 2 mutations in the WDR35 gene: a 1-bp deletion (2891delC) in exon 25 resulting in a frameshift and premature termination, and a 2623G-A transition in exon 23 resulting in an ala875-to-thr (A875T; 613602.0004) substitution at a highly conserved region. Neither mutation was found in 210 control alleles. The phenotype included short stature, dolichocephaly, craniosynostosis, narrow thorax with pectus excavatum, short limbs, and brachydactyly. Facial features included narrow palpebral fissures, telecanthus with hypertelorism, low-set simple ears, everted lower lip, and short neck. Teeth abnormalities included widely spaced, hypoplastic, and fused teeth. The boy also had joint laxity, inguinal hernia, and webbed fingers. There was no evidence of renal or hepatic disease, and he had normal intelligence.
For discussion of the ala875-to-thr (A875T) mutation in the WDR35 gene that was found in compound heterozygous state in a patient with cranioectodermal dysplasia-2 (CED2; 613610) by Gilissen et al. (2010), see 613602.0003.
In 2 sibs with short-rib thoracic dysplasia-7 with polydactyly (SRTD7; 614091), who were originally reported by Kannu et al. (2007), Mill et al. (2011) identified an in-frame homozygous 2,847-bp deletion spanning exon 5 of the WDR35 gene. Both parents and an unaffected sib were heterozygous for the deletion.
In a fetus with short-rib thoracic dysplasia-7 with polydactyly (SRTD7; 614091), Mill et al. (2011) identified compound heterozygosity for 2 mutations in the WDR35 gene: a 1633C-T transition resulting in an arg545-to-ter (R545X) substitution, and a 781T-C transition resulting in a trp261-to-arg (W261R) substitution (613602.0007). The nonsense mutation was inherited from the mother and the missense mutation from the father.
For discussion of the trp261-to-arg (W261R) mutation that was found in compound heterozygous state in a fetus with short-rib thoracic dysplasia-7 (SRTD7; 614091) by Mill et al. (2011), see 613602.0006.
In a 4-year-old Mexican boy with cranioectodermal dysplasia-2 (CED2; 613610), Bacino et al. (2012) identified homozygosity for an A-to-G transition (chr2.20,146,297A-G, GRCh37) in exon 16 of the WDR35 gene, resulting in a leu520-to-pro (L520P) substitution at a highly conserved residue. The unaffected parents and 2 unaffected sibs were heterozygous for the mutation, which was not found in the 1000 Genomes Project, NHLBI Exome Sequencing Project, or NIEHS EGP databases. DNA was unavailable from 3 more affected sibs in the family, including 2 who died at 9 months and 13 months of age, and an affected fetus terminated at 21 weeks' gestation.
In an 8-month-old boy with cranioectodermal dysplasia-2 (CED2; 613610), who had a 'cloverleaf' skull due to multiple suture synostoses, Lin et al. (2013) identified compound heterozygosity for a c.3091C-T transition (c.3091C-T, NM_001006657) in exon 26 of the WDR35 gene, resulting in a his1031-to-tyr (H1031Y) substitution, and a c.3203A-G transition in exon 27, resulting in a tyr1068-to-cys (Y1068C; 613602.0010) substitution. His unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in public variant databases.
For discussion of the c.3203A-G transition (c.3203A-G, NM_001006657) in exon 27 of the WDR35 gene, resulting in a tyr1068-to-cys (Y2068C) substitution, that was found in compound heterozygous state in an 8-month-old boy with cranioectodermal dysplasia-2 (CED2; 613610) by Lin et al. (2013), see 613602.0009.
In 2 affected brothers with short-rib thoracic dysplasia and polydactyly (SRTD7; 614091), born of first-cousin parents from Reunion Island, Caparros-Martin et al. (2015) identified homozygosity for a splice site mutation (c.143-18T-A, NM_001006657.1) in intron 2 of the WDR35 gene. The brothers died of cardiorespiratory failure at ages 5 months and 13 months. Their unaffected parents were heterozygous for the mutation, which was not found in an unaffected brother or in the 1000 Genomes Project, NHLBI Exome Variant Server, or ExAC databases. RT-PCR of peripheral blood RNA from the parents revealed a small cDNA fragment that corresponded to skipping of exon 3, and analysis of transfected COS-7 cells confirmed no inclusion of exon 3 in amplified products. Experiments in transfected COS-7 cells using minigene constructs suggested that the mutation generates an intronic splicing silencer.
In a 15-year-old boy with cranioectodermal dysplasia-2 (CED2; 613610), born of fourth-cousin Pakistani parents, Smith et al. (2016) identified homozygosity for a c.3459G-T transversion (c.3459G-T, NM_0010066575.1) in exon 28 of the WDR35 gene, resulting in a trp1153-to-cys (W1153C) substitution at a highly conserved residue. The mutation was not found in the dbSNP, Exome Variant Server, or ExAC databases.
In a female infant (R10-483A) with short-rib thoracic dysplasia (SRTD7; 614091), who did not exhibit polydactyly and died at 1 week of life, Duran et al. (2017) identified compound heterozygosity for a c.932G-T transversion in the WDR35 gene, resulting in a trp311-to-leu (W311L) substitution, and a 1-bp deletion (c.1501delC; 613602.0014), predicted to result in a premature termination codon (Gly501LysfsTer10). Analysis of cultured patient chondrocytes showed decreased IFT43 (614068) levels. In addition, there was a reduction in the percentage of cilia present on patient chondrocytes compared to controls, and the mutant cilia showed reduced lengths and were abnormally shaped.
In a male infant (R04-176A) with SRTD and polydactyly, Toriyama et al. (2016) identified double heterozygosity for the W311L mutation in the WDR35 gene and a truncating mutation in the INTU gene (Q276X; 610621.0003). The patient died in the neonatal period.
For discussion of the 1-bp deletion (c.1501delC) in the WDR35 gene, resulting in a premature termination codon (Gln501LysfsTer10), that was found in compound heterozygous state in an infant with short-rib thoracic dysplasia (SRTD7; 614091) by Duran et al. (2017), see 613602.0013.
In a 9-year-old Polish girl with Sensenbrenner syndrome (CED2; 613610), Walczak-Sztulpa et al. (2017) identified compound heterozygosity for mutations in the WDR35 gene: a c.1922T-G transversion in exon 18, resulting in a leu641-to-ter (L641X) substitution, and a c.2522A-T transversion in exon 22, resulting in an asp841-to-val (D841V; 613602.0016) substitution. Her unaffected parents were each heterozygous for 1 of the mutations; DNA was unavailable from her affected older sister, who had died in infancy from respiratory, hepatic, and renal insufficiency. The authors noted that the nonsense mutation (L641X) had previously been reported in 2 patients with Sensenbrenner syndrome (Hoffer et al., 2013; Li et al., 2015) and was present in the ExAC and UCSC Genome Browser databases at an allele frequency of 0.018% and 0.15%, respectively. The missense mutation (D841V) is located at a highly conserved residue and was not found in the 1000 Genomes Project, NHLBI Exome Variant Server, or ExAC databases.
Bacino, C. A., Dhar, S. U., Brunetti-Pierri, N., Lee, B., Bonnen, P. E. WDR35 mutation in siblings with Sensenbrenner syndrome: a ciliopathy with variable phenotype. Am. J. Med. Genet. 158A: 2917-2924, 2012. [PubMed: 22987818] [Full Text: https://doi.org/10.1002/ajmg.a.35608]
Caparros-Martin, J. A., De Luca, A., Cartault, F., Aglan, M., Temtamy, S., Otaify, G. A., Mehrez, M., Valencia, M., Vazquez, L., Alessandri, J.-L., Nevado, J., Rudda-Arenas, I., Heath, K. E., Digilio, M. C., Dallapiccola, B., Goodship, J. A., Mill, P., Lapunzina, P., Ruiz-Perez, V. L. Specific variants in WDR35 cause a distinctive form of Ellis-van Creveld syndrome by disrupting the recruitment of the EvC complex and SMO into the cilium. Hum. Molec. Genet. 24: 4126-4137, 2015. [PubMed: 25908617] [Full Text: https://doi.org/10.1093/hmg/ddv152]
Duran, I., Taylor, S. P., Zhang, W., Martin, J., Qureshi, F., Jacques, S. M., Wallerstein, R., Lachman, R. S., Nickerson, D. A., Bamshad, M., Cohn, D. H., Krakow, D. Mutations in IFT-A satellite core component genes IFT43 and IFT121 produce short rib polydactyly syndrome with distinctive campomelia. Cilia 6: 7, 2017. Note: Electronic Article. [PubMed: 28400947] [Full Text: https://doi.org/10.1186/s13630-017-0051-y]
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Hartz, P. A. Personal Communication. Baltimore, Md. 10/12/2010.
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Li, Y., Garrod, A. S., Madan-Khetarpal, S., Sreedher, G., McGuire, M., Yagi, H., Klena, N. T., Gabriel, G. C., Khalifa, O., Zahid, M., Panigrahy, A., Weiner, D. J., Lo, C. W. Respiratory motile cilia dysfunction in a patient with cranioectodermal dysplasia. Am. J. Med. Genet. 167A: 2188-2196, 2015. [PubMed: 25914204] [Full Text: https://doi.org/10.1002/ajmg.a.37133]
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Mill, P., Lockhart, P. J., Fitzpatrick, E., Mountford, H. S., Hall, E. A., Reijns, M. A. M., Keighren, M., Bahlo, M., Bromhead, C. J., Budd, P., Aftimos, S., Delatycki, M. B., Savarirayan, R., Jackson, I. J., Amor, D. J. Human and mouse mutations in WDR35 cause short-rib polydactyly syndromes due to abnormal ciliogenesis. Am. J. Hum. Genet. 88: 508-515, 2011. [PubMed: 21473986] [Full Text: https://doi.org/10.1016/j.ajhg.2011.03.015]
Nagase, T., Kikuno, R., Ishikawa, K., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 65-73, 2000. [PubMed: 10718198] [Full Text: https://doi.org/10.1093/dnares/7.1.65]
Smith, C., Lamont, R. E., Wade, A., Bernier, F. P., Parboosingh, J. S., Innes, A. M. A relatively mild skeletal ciliopathy phenotype consistent with cranioectodermal dysplasia is associated with a homozygous nonsynonymous mutation in WDR35. Am. J. Med. Genet. 170A: 760-765, 2016. [PubMed: 26691894] [Full Text: https://doi.org/10.1002/ajmg.a.37514]
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]
Walczak-Sztulpa, J., Wawrocka, A., Sobierajewicz, A., Kuszel, L., Zawadzki, J., Grenda, R., Swiader-Lesniak, A., Kocyla-Karczmarewicz, B., Wnuk, A., Latos-Bielenska, A., Chrzanowska, K. H. Intrafamilial phenotypic variability in a Polish family with Sensenbrenner syndrome and biallelic WDR35 mutations. Am. J. Med. Genet. 173A: 1364-1368, 2017. [PubMed: 28332779] [Full Text: https://doi.org/10.1002/ajmg.a.38163]