Alternative titles; symbols
HGNC Approved Gene Symbol: IFT80
Cytogenetic location: 3q25.33 Genomic coordinates (GRCh38) : 3:160,256,986-160,399,225 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q25.33 | Short-rib thoracic dysplasia 2 with or without polydactyly | 611263 | Autosomal recessive | 3 |
The IFT80 gene encodes a protein with 7 WD40 domains that is a component of the intraflagellar transport (IFT) complex B (Beales et al., 2007). The IFT is essential for the development and maintenance of motile and sensory cilia.
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2000) cloned IFT80, which they designated KIAA1374. The transcript contains repetitive elements in its 3-prime UTR, and the deduced protein contains 764 amino acids. RT-PCR ELISA detected moderate expression of IFT80 in adult brain, lung, liver, kidney, testis, and ovary, in all specific adult brain regions examined, and in fetal liver and brain. Little to no expression was detected in adult heart, skeletal muscle, pancreas, and spleen.
By database analysis, followed by PCR of a human brain cDNA library, Huang et al. (2008) identified a read-through transcript that had 5-prime exons from the TRIM59 gene (616148) spliced in-frame to 3-prime exons of the downstream IFT80 gene. The deduced 1,080-amino acid chimeric protein, which Huang et al. (2008) called IFT80-long (IFT80L), has an N terminus that consists of the RING finger, B-box, and coiled-coil motifs of TRIM59, and a C terminus that consists of 7 WD40 repeats of IFT80. Quantitative real-time PCR confirmed expression of IFT80L in HEK293 cells. Huang et al. (2008) noted that orthologs of IFT80 are found in all ciliated organisms, but that IFT80L is found in vertebrates only.
By immunohistochemical analysis of mouse tibia, Wang et al. (2013) detected high Ift80 expression at the growth plate and trabecular bone. At the growth plate, Ift80 was expressed in nearly all chondrocytes. In mouse bone marrow-derived stromal cells (BMSCs), Ift80 expression peaked during chondrogenic differentiation, and was detected in mature chondrocytes. Ift80 staining overlapped that of acetylated tubulin (see 191130) at cilia.
Huang et al. (2008) found that Ift80l was expressed in neural progenitor rat PC12 cells and mouse embryonic stem cells. Ift80l expression was downregulated following NGF (162030)-induced neuronal differentiation in both cell lines.
By radiation hybrid analysis, Nagase et al. (2000) mapped the IFT80 gene to chromosome 3. The IFT80 gene resides in chromosome 3q24-q26 (Beales et al., 2007).
By genomic sequence analysis, Huang et al. (2008) mapped the IFT80 gene to chromosome 3q26.1.
Gross (2018) mapped the IFT80 gene to chromosome 3q25.33 based on an alignment of the IFT80 sequence (GenBank BC101494) with the genomic sequence (GRCh38).
Using RNA interference, Wang et al. (2013) found that knockdown of Ift80 in mouse BMSCs reduced the number of cells with cilia, impaired BMSC chondrogenic differentiation and expression of chondrocyte-specific genes, and hampered hedgehog (see 600725) signaling. Knockdown of Ift80 also induced Wnt signaling (see 164820), with induction of Wnt3a (606359) transcriptional activity, and nuclear accumulation of beta-catenin (CTNNB1; 116806). Chondrogenic deficiency in Ift80-silenced cells was rescued by overexpression of the hedgehog signaling molecule Gli2 (165230).
In members of 3 consanguineous families with a diagnosis of asphyxiating thoracic dystrophy (SRTD2; 611263), Beales et al. (2007) identified 3 different homozygous mutations in the IFT80 gene (611177.0001-611177.0003). All affected individuals had narrow chest and limb anomalies, but none had extraskeletal manifestations. Work in animal cells suggested that Ift80 is involved in ciliary functions, and Beales et al. (2007) concluded that the phenotype results from disrupted function of primary cilia.
In a patient with a clinical diagnosis of lethal short-rib polydactyly syndrome, Cavalcanti et al. (2011) identified a homozygous missense mutation in the IFT80 gene (611177.0004).
In 2 fetuses from a consanguineous Pakistani family (family 1) with SRTD, Bizaoui et al. (2019) identified homozygosity for a missense mutation in the IFT80 gene (A430T; 611177.0005) that segregated with disease and was not found in public variant databases. In 2 fetuses from an unrelated family with SRTD (family 2), Bizaoui et al. (2019) identified compound heterozygosity for 2 missense mutations in IFT80: a synonymous change (K460K; 611177.0006) that was shown to affect splicing, and a G683V substitution (611177.0007).
Beales et al. (2007) found that mouse Ift80 localized to the basal body and ciliary axoneme in a mouse chondrocyte cell line. Ift80 knockdown in zebrafish resulted in a phenotype of curled tail, large kidney cysts, and pericardial edema.
In a child with a clinical diagnosis of asphyxiating thoracic dystrophy (SRTD2; 611263), born of consanguineous Turkish parents, Beales et al. (2007) identified a C-to-G transversion in the IFT80 gene, resulting in a his105-to-gln (H105Q) substitution in a conserved residue in the second WDR56 WD40 domain of the protein. The child had narrow chest, short femora, and postaxial polydactyly.
Tuysuz et al. (2009) restudied the Turkish girl reported by Beales et al. (2007) and noted that she had atlantoaxial instability and spinal cord compression, features not previously reported in asphyxiating thoracic dystrophy.
In a fetus with radiographic evidence of asphyxiating thoracic dystrophy (SRTD2; 611263), Beales et al. (2007) identified a homozygous 3-bp deletion (TTA), resulting in an in-frame deletion of residue leu549 of the IFT80 gene (L549del). The fetus was conceived of consanguineous Pakistani parents and was stillborn due to chorioamnionitis at 20 weeks' gestation. Radiographic studies showed mesomelic shortening of the lower limbs with curved femora and trident acetabular roofs, as well as short metacarpals and middle phalanges.
In 2 members of a large consanguineous Pakistani family with a clinical diagnosis of asphyxiating thoracic dystrophy (SRTD2; 611263), Beales et al. (2007) identified a homozygous G-to-C transversion in the IFT80 gene, resulting in an ala701-to-pro (A701P) substitution. Both children had narrow chests and short femora, but no neonatal respiratory problems or internal organ anomalies. One had broad hands, small feet, and brachydactyly.
In a patient with a clinical diagnosis of lethal short-rib polydactyly syndrome (SRTD2; 611263), Cavalcanti et al. (2011) identified a homozygous G-to-C transversion in exon 8 of the IFT80 gene, resulting in a gly241-to-arg (G241R) substitution. The patient had preaxial polydactyly of the feet. The mother was heterozygous for the mutation; the father was unavailable for study. The mutation was not found in 340 control chromosomes.
In 2 fetuses from a consanguineous Pakistani family (family 1) with short-rib thoracic dysplasia and polydactyly (SRTD2; 611263), Bizaoui et al. (2019) identified homozygosity for a c.1288G-A transition (c.1288G-A, NM_020800.2) in exon 12 of the IFT80 gene, resulting in an ala430-to-thr (A430T) substitution at a well-conserved amino acid. The unaffected parents were heterozygous for the mutation, which was not found in the dbSNP or ExAC databases. DNA was unavailable from a spontaneous abortion that occurred early in pregnancy in this family.
In 2 fetuses from a Caucasian family (family 2) with short-rib thoracic dysplasia and polydactyly (SRTD2; 611263), Bizaoui et al. (2019) identified compound heterozygosity for a c.1380G-A transition (c.1380G-A, NM_020800.2) in exon 13 of the IFT80 gene, resulting in a lys460-to-lys (K460K) substitution, and a c.2048G-T transversion in exon 18, resulting in a gly683-to-val (G683V; 611177.0007) substitution. The unaffected parents were each heterozygous for 1 of the mutations; DNA was unavailable from a spontaneous abortion that occurred early in pregnancy in this family. RT-PCR of fetal DNA demonstrated that the synonymous K460K substitution results in a splicing defect in exon 13.
For discussion of the c.2048G-T transversion (c.2048G-T, NM_020800.2) in exon 18 of the IFT80 gene, resulting in a gly683-to-val (G683V) substitution, that was found in compound heterozygosity in 2 fetuses from a family (family 2) with short-rib thoracic dysplasia and polydactyly (SRTD2; 611263) by Bizaoui et al. (2019), see 611177.0006.
Beales, P. L., Bland, E., Tobin, J. L., Bacchelli, C., Tuysuz, B., Hill, J., Rix, S., Pearson, C. H., Kai, M., Hartley, J., Johnson, C., Irving, M., Elcioglu, N., Winey, M., Tada, M., Scambler, P. J. IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy. Nature Genet. 39: 727-729, 2007. [PubMed: 17468754] [Full Text: https://doi.org/10.1038/ng2038]
Bizaoui, V., Huber, C., Kohaut, E., Roume, J., Bonniere, M., Attie-Bitach, T., Cormier-Daire, V. Mutations in IFT80 cause SRPS Type IV: report of two families and review. Am. J. Med. Genet. 179A: 639-644, 2019. [PubMed: 30767363] [Full Text: https://doi.org/10.1002/ajmg.a.61050]
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]
Gross, M. B. Personal Communication. Baltimore, Md. 1/17/2018.
Huang, W., Kane, J. K., Li, M. D. Identification and characterization of a long isoform of human IFT80, IFT80-L. Biochem. Biophys. Res. Commun. 373: 653-658, 2008. [PubMed: 18601909] [Full Text: https://doi.org/10.1016/j.bbrc.2008.06.085]
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]
Tuysuz, B., Baris, S., Aksoy, F., Madazli, R., Ungur, S., Sever, L. Clinical variability of asphyxiating thoracic dystrophy (Jeune) syndrome: evaluation and classification of 13 patients. Am. J. Med. Genet. 149A: 1727-1733, 2009. [PubMed: 19610081] [Full Text: https://doi.org/10.1002/ajmg.a.32962]
Wang, C., Yuan, X., Yang, S. IFT80 is essential for chondrocyte differentiation by regulating hedgehog and Wnt signaling pathways. Exp. Cell Res. 319: 623-632, 2013. [PubMed: 23333501] [Full Text: https://doi.org/10.1016/j.yexcr.2012.12.028]