Alternative titles; symbols
HGNC Approved Gene Symbol: IFT122
Cytogenetic location: 3q21.3-q22.1 Genomic coordinates (GRCh38) : 3:129,440,224-129,520,507 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q21.3-q22.1 | Cranioectodermal dysplasia 1 | 218330 | Autosomal recessive | 3 |
A conserved core of 4 or more modular repeat units defines a group of functionally diverse regulatory proteins in eukaryotes known as the WD repeat family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Proteins belonging to the WD repeat family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation (summary by Claudio et al., 1999).
Gross et al. (2001) screened human HL60 leukemia and prostate and colon cancer cDNA libraries with degenerate oligonucleotide primers directed to sequences encoding the AF2 domains of class III nuclear receptors. They then used 5-prime and 3-prime RACE and screening of a testis cDNA library to clone IFT122, which they designated WDR10. They also isolated a longer variant of this cDNA, which appeared to have an additional 153-bp exon near the 5-prime end. The full-length WDR10 cDNA encodes a deduced 1,242-amino acid protein with an AF2-like domain, 7 N-terminal WD repeat units, and 2 potential nuclear localization sequences. Northern blot analysis detected a single 4-kb WDR10 transcript in most tissues tested, with predominant expression in testis and pituitary; a 3.5-kb transcript was detected in HL60 leukemia cells. Study of a WDR10-GFP fusion protein demonstrated that WDR10 is localized in the cytoplasm. In situ hybridization on reproductive tissues in the rat showed stage-specific expression of WDR10 within developing sperm and ovarian follicles.
Gross et al. (2001) determined that the IFT122 gene has at least 28 exons spanning approximately 65 kb of genomic DNA.
By FISH, Gross et al. (2001) mapped the IFT122 gene to chromosome 3q21.
Walczak-Sztulpa et al. (2010) performed morpholino knockdown of ift122 in zebrafish embryos and observed defects typical of other ciliopathy models including shortened body axis and curvature, cardiac edema, and small eyes at 80 hours postfertilization, with pronephric cysts and a distended cranium consistent with hydrocephalus and otolith defects at 5 days postfertilization. Cilia and their basal bodies were dramatically reduced in the pronephric duct of morphant embryos compared to control embryos, and primary cilia shortening was observed in the morphant zebrafish Kupffer vesicle.
Using transfected HEK293T cells, Takahara et al. (2018) demonstrated that IFT122 formed the trimeric IFT122-IFT140 (614620)-IFT144 (WDR19; 608151) core subcomplex of IFT-A via its C-terminal region containing the tetratricopeptide repeat domain. IFT122 interacted with the IFT43 (614068)-IFT121 (WDR35; 613602) dimer in the trimeric IFT43-IFT121-IFT139 peripheral subcomplex of IFT-A via its N-terminal region containing the WD40 domain. CED1 (218330)-associated missense mutations in IFT122 affected interaction of IFT122 with IFT43-IFT121 and IFT139 and thereby affected formation of the entire peripheral subcomplex of IFT-A. Human IFT122-knockout cells lacked recognizable cilia, in contrast with IFT121-knockout cells, which had only a ciliary trafficking defect. The lack of cilia in IFT122-knockout cells could be rescued by exogenous expression of wildtype IFT122 or IFT122 carrying CED1-associated mutations. However, IFT122-knockout cells expressing CED1-associated IFT122 mutations had abnormal localization of several ciliary proteins, indicating defective trafficking.
In a consanguineous Polish family with cranioectodermal dysplasia mapping to chromosome 3q21-q24 (CED1; 218330), Walczak-Sztulpa et al. (2010) sequenced 79 candidate genes and identified homozygosity for a missense mutation in the IFT122 gene (V553G; 606045.0001) that segregated with the disease. Fibroblasts from 1 of the sibs showed significantly reduced cilia frequency and length compared to controls. Analysis of IFT122 in 11 additional unrelated patients with CED revealed homozygosity and compound heterozygosity for mutations in 2 of the patients (606045.0002-606045.0004, respectively).
In a 21-week-old male fetus (II-8) with skeletal features consistent with CED1, Tsurusaki et al. (2014) identified compound heterozygosity for a 1-bp deletion (606045.0005) and a missense mutation (G546R; 606045.0006) in the IFT122 gene that segregated with disease in the family.
In a male infant who died shortly after birth with craniosynostosis, short ribs, micromelia, and postaxial polydactyly of the hands, Silveira et al. (2017) identified 3 mutations in the IFT122 gene: a missense mutation (A1062P; 606045.0007) on 1 allele, and a duplication followed by deletion (606045.0008) on the other allele that resulted in frameshift.
By whole-exome sequencing in a Chinese male infant with CED1, Yang et al. (2021) identified compound heterozygous mutations in the IFT122 gene (606045.0009 and 606045.0010). Functional studies were not performed. The patient had macrocephaly, dysmorphic facial features, upper limb phocomelia, and postaxial polydactyly of the hands and feet.
In an affected sister and brother with cranioectodermal dysplasia (CED1; 218330), born of distantly related Polish parents, Walczak-Sztulpa et al. (2010) identified homozygosity for a T-G transversion in the IFT122 gene, resulting in a val553-to-gly (V553G) substitution at a highly conserved residue. The unaffected parents were heterozygous for the mutation, which was not found in 340 ethnically matched control chromosomes. Analysis of fibroblasts from the brother showed significantly reduced cilia frequency and length compared to 3 unrelated, healthy German controls.
In a boy with cranioectodermal dysplasia (CED1; 218330), born of fourth-cousin Norwegian parents and previously reported by Fry et al. (2009), Walczak-Sztulpa et al. (2010) identified homozygosity for a C-T transition in the IFT122 gene, resulting in a ser373-to-phe (S373F) substitution at a highly conserved residue. The unaffected parents were heterozygous for the mutation, which was not found in 340 ethnically matched control chromosomes. The patient had an unaffected sister.
In an Italian boy with cranioectodermal dysplasia (CED1; 218330), originally reported by Zaffanello et al. (2006), Walczak-Sztulpa et al. (2010) identified compound heterozygosity for a G-A transition in intron 6 (502+5G-A) of the IFT122 gene and a de novo trp7-to-cys substitution (W7C; 606045.0004) at a highly conserved residue in exon 1. The mother was a heterozygous carrier of the splice site mutation but the missense mutation was not detected in either parent; neither mutation was found in 340 ethnically matched control chromosomes.
For discussion of the trp7-to-cys (W7C) mutation in the IFT122 gene that was found in compound heterozygous state in a patient with cranioectodermal dysplasia (CED1; 218330) by Walczak-Sztulpa et al. (2010), see 606045.0003.
In a 21-week-old male fetus (II-8) with skeletal features consistent with cranioectodermal dysplasia-1 (CED1; 218330), Tsurusaki et al. (2014) identified compound heterozygosity for a 1-bp deletion (c.1108delG) in exon 11 of the IFT122 gene, causing a frameshift predicted to result in a premature termination codon (Glu370SerfsTer51), and a c.1636G-A transition in exon 14, resulting in a gly546-to-arg (G546R; 606045.0006) substitution. The same mutations were identified in the chorionic villi from another pregnancy (II-6) in the family that spontaneously aborted at 7 weeks' gestation. The unaffected mother was heterozygous for the G546R variant, and an unaffected brother was heterozygous for the 1-bp deletion; DNA was unavailable from the unaffected father, or from 3 other spontaneous abortions or 1 terminated pregnancy.
For discussion of the c.1636G-A transition in exon 14 of the IFT122 gene, resulting in a gly546-to-arg (G546R) substitution, that was found in compound heterozygosity in a 21-week-old male fetus (II-8) with skeletal features consistent with cranioectodermal dysplasia-1 (CED1; 218330) by Tsurusaki et al. (2014), see 606045.0005.
In a male infant who died shortly after birth with craniosynostosis, short ribs, micromelia, and postaxial polydactyly of the hands (CED1; 218330), who was previously studied by Cavalcanti et al. (2011), Silveira et al. (2017) identified 3 mutations in the IFT122 gene: a c.3184G-C transversion, resulting in an ala1062-to-pro (A1062P) substitution within the tetratricopeptide-like helical domain, on 1 allele; and a 1-bp duplication (c.3228dupG) followed by 3-bp deletion (c.3231_3233delCAT) on the other allele (606045.0008), predicted to result in a premature termination codon (Tyr1077ValfsTer10). The complex mutation was inherited from his unaffected mother; DNA was unavailable from the father. The A1062P variant was not found in 100 control chromosomes, but was present at low frequency (0.00002479) in the ExAC database, only in heterozygosity.
For discussion of the 1-bp duplication (c.3228dupG) and 3-bp deletion (c.3231_3233delCAT), occurring on the same allele in the IFT122 gene and causing a frameshift predicted to result in a premature termination codon (Tyr1077ValfsTer10), found in compound heterozygous state in a male infant who died shortly after birth with cranioectodermal dysplasia-1 (CED1; 218330) by Silveira et al. (2017), see 606045.0007.
In a patient with cranioectodermal dysplasia-1 (CED1; 218330), Yang et al. (2021) identified compound heterozygous mutations in the IFT122 gene: an 11-bp deletion (c.366_376delAGGCCAAGGTG, NM_052985.3) in exon 5, resulting in a frameshift and premature termination (Gly123fsTer3) in the third WD domain, and a c.3879A-G transition (606045.0010) in exon 31, resulting in a Ter1293Trpext stop-loss mutation. The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutations were not found in the dbSNP, ExAC, or gnomAD databases. Functional studies were not performed.
For discussion of the c.3879A-G transition (c.3879A-G, NM_052985.2) in exon 31 of the IFT122 gene, resulting in a Ter1293Trpext stop-loss mutation, that was found in compound heterozygous state in a patient with cranioectodermal dysplasia-1 (CED1; 218330) by Yang et al. (2021), see 606045.0009.
Cavalcanti, D. P., Huber, C., Sang, K.-H. L. Q., Baujat, G., Collins, F., Delezoide, A.-L., Dagoneau, N., Le Merrer, M., Martinovic, J., Mello, M. F. S., Vekemans, M., Munnich, A., Cormier-Daire, V. Mutation in IFT80 in a fetus with the phenotype of Verma-Naumoff provides molecular evidence for Jeune-Verma-Naumoff dysplasia spectrum. J. Med. Genet. 48: 88-92, 2011. [PubMed: 19648123] [Full Text: https://doi.org/10.1136/jmg.2009.069468]
Claudio, J. O., Liew, C.-C., Ma, J., Heng, H. H. Q., Stewart, A. K., Hawley, R. G. Cloning and expression analysis of a novel WD repeat gene, WDR3, mapping to 1p12-p13. Genomics 59: 85-89, 1999. [PubMed: 10395803] [Full Text: https://doi.org/10.1006/geno.1999.5858]
Fry, A. E., Klingenberg, C., Matthes, J., Heimdal, K., Hennekam, R C. M., Pilz, D. T. Connective tissue involvement in two patients with features of cranioectodermal dysplasia. Am. J. Med. Genet. 149A: 2212-2215, 2009. [PubMed: 19760620] [Full Text: https://doi.org/10.1002/ajmg.a.33027]
Gross, C., De Baere, E., Lo, A., Chang, W., Messiaen, L. Cloning and characterization of human WDR10, a novel gene located at 3q21 encoding a WD-repeat protein that is highly expressed in pituitary and testis. DNA Cell Biol. 20: 41-52, 2001. [PubMed: 11242542] [Full Text: https://doi.org/10.1089/10445490150504684]
Silveira, K. C., Moreno, C. A., Cavalcanti, D. P. Beemer-Langer syndrome is a ciliopathy due to biallelic mutations in IFT122. Am. J. Med. Genet. 173A: 1186-1189, 2017. [PubMed: 28370949] [Full Text: https://doi.org/10.1002/ajmg.a.38157]
Takahara, M., Katoh, Y., Nakamura, K., Hirano, T., Sugawa, M., Tsurumi, Y., Nakayama, K. Ciliopathy-associated mutations of IFT122 impair ciliary protein trafficking but not ciliogenesis. Hum. Molec. Genet. 27: 516-528, 2018. [PubMed: 29220510] [Full Text: https://doi.org/10.1093/hmg/ddx421]
Tsurusaki, Y., Yonezawa, R., Furuya, M., Nishimura, G., Pooh, R. K., Nakashima, M., Saitsu, H., Miyake, N., Saito, S., Matsumoto, N. Whole exome sequencing revealed biallelic IFT122 mutations in a family with CED1 and recurrent pregnancy loss. Clin. Genet. 85: 592-594, 2014. [PubMed: 23826986] [Full Text: https://doi.org/10.1111/cge.12215]
Walczak-Sztulpa, J., Eggenschwiler, J., Osborn, D., Brown, D. A., Emma, F., Klingenberg, C., Hennekam, R. C., Torre, G., Garshasbi, M., Tzschach, A., Szczepanska, M., Krawczynski, M., Zachwieja, J., Zwolinska, D., Beales, P. L., Ropers, H.-H., Latos-Bielenska, A., Kuss, A. W. Cranioectodermal dysplasia, Sensenbrenner syndrome, is a ciliopathy caused by mutations in the IFT122 gene. Am. J. Hum. Genet. 86: 949-956, 2010. [PubMed: 20493458] [Full Text: https://doi.org/10.1016/j.ajhg.2010.04.012]
Yang, Q., Zhang, Q., Chen, F., Yi, S., Li, M., Yi, S., Xu, X., Luo, J. A novel combination of biallelic IFT122 variants associated with cranioectodermal dysplasia: a case report. Exp. Ther. Med. 21: 311, 2021. [PubMed: 33717254] [Full Text: https://doi.org/10.3892/etm.2021.9742]
Zaffanello, M., Diomedi-Camassei, F., Melzi, M. L., Torre, G., Callea, F., Emma, F. Sensenbrenner syndrome: a new member of the hepatorenal fibrocystic family. Am. J. Med. Genet. 140A: 2336-2340, 2006. [PubMed: 17022080] [Full Text: https://doi.org/10.1002/ajmg.a.31464]