Alternative titles; symbols
HGNC Approved Gene Symbol: IFT43
Cytogenetic location: 14q24.3 Genomic coordinates (GRCh38) : 14:75,985,763-76,084,073 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q24.3 | ?Cranioectodermal dysplasia 3 | 614099 | Autosomal recessive | 3 |
| ?Retinitis pigmentosa 81 | 617871 | Autosomal recessive | 3 | |
| Short-rib thoracic dysplasia 18 with polydactyly | 617866 | Autosomal recessive | 3 |
IFT43 is a subunit of intraflagellar transport complex A (IFTA). IFTA is involved in retrograde ciliary transport along axonemal microtubules (summary by Arts et al., 2011).
Arts et al. (2011) reported that alternative splicing of human IFT43 produces 2 major protein isoforms. The 2 isoforms contain 213 and 208 amino acids and differ only in a central region.
By RT-PCR of ocular tissues in a 2-month-old mouse, Biswas et al. (2017) observed high expression of IFT43 in the retina and minimal expression in the retinal pigment epithelium. Immunohistochemical analysis of IFT43 in mouse and human retinal tissue showed that IFT43 is localized predominantly to the photoreceptor outer segment region, with no significant expression in other layers of the retina.
Arts et al. (2011) reported that the IFT43 gene contains 10 exons.
Gross (2011) mapped the IFT43 gene to chromosome 14q24.3 based on an alignment of the IFT43 sequence (GenBank BC010436) with the genomic sequence (GRCh37).
Cranioectodermal Dysplasia 3
In a brother and sister from a consanguineous family of Moroccan descent with cranioectodermal dysplasia mapping to chromosome 14 (CED3; 614099), Arts et al. (2011) analyzed 2 candidate genes and identified homozygosity for a missense mutation in the translation initiation codon of the IFT43 gene (M1V; 614068.0001). Analysis of fibroblasts from 1 of the sibs and from a previously studied patient (Gilissen et al., 2010) with CED2 (613610) and mutations in WDR35 (613602) showed similar ciliary defects, with accumulation of IFTB-complex proteins in the distal part of the ciliary axoneme and in the ciliary tip, whereas in the cilia of control fibroblasts, those proteins were less abundant and primarily located at the basal body and transition zone. Cilia in mutant IFT43 fibroblasts were also somewhat shorter than those of control fibroblasts, as had been previously reported (Walczak-Sztulpa et al., 2010) in patients with CED1 (218330) and mutations in IFT122 (606045). Arts et al. (2011) concluded that CED results from defects in retrograde intraflagellar transport due to disruption of the IFTA protein complex.
Short-Rib Thoracic Dysplasia 18 with Polydactyly
In 3 affected individuals from 2 unrelated families with short-rib thoracic dysplasia with polydactyly (SRTD18; 617866), Duran et al. (2017) identified homozygosity for missense mutations in the IFT143 gene, M1K (614068.0002) and W179R (614068.0003), respectively.
Retinitis Pigmentosa 81
In a large consanguineous Pakistani family with nonsyndromic early-onset retinal degeneration (RP81; 617871), Biswas et al. (2017) identified homozygosity for a missense mutation in the IFT43 gene (E34K; 614068.0004) that segregated fully with disease and was not found in controls.
In an affected brother and sister from a consanguineous family of Moroccan descent with cranioectodermal dysplasia-3 (CED3; 614099), Arts et al. (2011) identified homozygosity for a 1A-G transition at the translation initiation codon of the IFT43 gene, resulting in a met1-to-val (M1V) substitution. The unaffected first-cousin parents were heterozygous for the mutation, which was not found in 192 Dutch or 122 Moroccan control alleles. Western blot analysis revealed that the mutant IFT43 protein had a molecular mass that was approximately 3 kD lower than wildtype, consistent with translation initiation in exon 2, at the next available ATG initiation codon of the coding sequence, resulting in an N-terminal deletion of 21 amino acids in the same open reading frame. Patient fibroblasts showed accumulation of IFTB complex proteins in the distal part of the ciliary axoneme and in the ciliary tip, whereas in the cilia of control fibroblasts, those proteins were less abundant and primarily located at the basal body and transition zone; the mutant cilia were also somewhat shorter than those of controls.
In 2 sibs with short-rib thoracic dysplasia with polydactyly (SRTD18; 617866), Duran et al. (2017) identified homozygosity for a c.2T-A transversion in the IFT43 gene, resulting in a met1-to-lys (M1K) substitution. Their unaffected parents were heterozygous for the mutation, which was not found in the dbSNP, 1000 Genomes Project, or ExAC databases. One sib (R06-303A), who was born of a dizygotic twin pregnancy at 30 weeks' gestation, died on the second day of life; a second pregnancy (R06-303E) was interrupted at 18 weeks' gestation due to findings on prenatal ultrasound. Although cDNA levels were similar in mutant and control cells, analysis of amniocytes from patient R06-303A showed absence of IFT43, suggesting that the M1K mutation alters synthesis and/or stability of the protein and not gene expression. In addition, protein levels of IFT-A core member IFT144 (WDR19; 608151) were increased in mutant cells. Histologic analysis of distal femur growth plates from R06-303A showed a significantly abnormal pattern of proliferation and differentiation of chondrocytes extending from the reserve through the hypertrophic zones, including disruption of the polarity of the proliferating cells, with columns of chondrons showing more than one plane of division. The hypertrophic zones were irregular, reflecting the disrupted column formation, and there were decreased numbers of hypertrophic cells and lack of the normal progressive enlargement of hypertrophic chondrocytes. Retained rests of cartilage within the primary spongiosum suggested that there may be altered cartilage-to-bone transition at the distal end of the growth plate.
In a female infant (R03-121A) with short-rib thoracic dysplasia with polydactyly (SRTD18; 617866), Duran et al. (2017) identified homozygosity for a c.535T-C transition in the IFT43 gene, resulting in a trp179-to-arg (W179R) substitution at a highly conserved residue within a highly conserved region of IFT43. Her unaffected parents were heterozygous for the mutation, which was not found in the dbSNP, 1000 Genomes Project, or ExAC databases. Although cDNA levels were similar in mutant and control cells, analysis of patient fibroblasts showed a significantly reduced amount of IFT43, suggesting that the W179R mutation alters synthesis and/or stability of the protein and not gene expression. In addition, protein levels of IFT-A core member IFT144 (WDR19; 608151) were increased in mutant cells. Induction of cilia formation revealed that cilia were absent in mutant fibroblasts compared to controls. Histologic analysis of distal femur growth plates from R03-121A showed a significantly abnormal pattern of proliferation and differentiation of chondrocytes extending from the reserve through the hypertrophic zones, including disruption of the polarity of the proliferating cells, with columns of chondrons showing more than one plane of division. The hypertrophic zones were irregular, reflecting the disrupted column formation, and there were decreased numbers of hypertrophic cells and lack of the normal progressive enlargement of hypertrophic chondrocytes. Retained rests of cartilage within the primary spongiosum suggested that there may be altered cartilage-to-bone transition at the distal end of the growth plate.
In 9 affected members of a large consanguineous Pakistani family (PKRD272) with nonsyndromic early-onset retinal degeneration (RP81; 617871), Biswas et al. (2017) identified homozygosity for a c.100G-A transition in the IFT43 gene, resulting in a glu34-to-lys (E34K) substitution at a residue within a highly conserved domain. The mutation segregated fully with disease in the family and was not found in 150 ethnicity-matched controls or in 800 other controls. Transfected mIMCD3 cells showed significantly shorter cilia lengths with the E34K mutant than with wildtype IFT43; staining for acetylated tubulin and IFT88 (600595) showed shorter to no signal for ciliary structures and colocalization of IFT88 with acetylated tubulin signals in cells transfected with mutant IFT43, whereas IFT88 localized to the basal bodies and distal tip of cilia in wildtype cells. Similar results were obtained in transfected MDCK cells. Western blot analysis of transfected cells showed an increased amount of protein in the mutant lane compared to wildtype, indicating possible formation of higher molecular weight aggregates with accumulation of mutant protein in cells expressing E34K. Biswas et al. (2017) suggested that the E34K mutation disrupts the intraflagellar transport machinery causing abnormal cilium structure and/or affects ciliogenesis.
Arts, H. H., Bongers, E. M. H. F., Mans, D. A., van Beersum, S. E. C., Oud, M. M., Bolat, E., Spruijt, L., Cornelissen, E. A. M., Schuurs-Hoeijmakers, J. H. M., de Leeuw, N., Cormier-Daire, V., Brunner, H. G., Knoers, N. V. A. M., Roepman, R. C14ORF179 encoding IFT43 is mutated in Sensenbrenner syndrome. J. Med. Genet. 48: 390-395, 2011. [PubMed: 21378380] [Full Text: https://doi.org/10.1136/jmg.2011.088864]
Biswas, P., Duncan, J. L., Ali, M., Matsui, H., Naeem, M. A., Raghavendra, P. B., Frazer, K. A., Arts, H. H., Riazuddin, S., Akram, J., Hejtmancik, J. F., Riazuddin, S. A., Ayyagari, R. A mutation in IFT43 causes non-syndromic recessive retinal degeneration. Hum. Molec. Genet. 26: 4741-4751, 2017. [PubMed: 28973684] [Full Text: https://doi.org/10.1093/hmg/ddx356]
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]
Gilissen, C., Arts, H. H., Hoischen, A., Spruijt, L., Mans, D. A., Arts, P., van Lier, B., Steehouwer, M., van Reeuwijk, J., Kant, S. G., Roepman, R., Knoers, N. V. A. M., Veltman, J. A., Brunner, H. G. Exome sequencing identifies WDR35 variants involved in Sensenbrenner syndrome. Am. J. Hum. Genet. 87: 418-423, 2010. [PubMed: 20817137] [Full Text: https://doi.org/10.1016/j.ajhg.2010.08.004]
Gross, M. B. Personal Communication. Baltimore, Md. 6/29/2011.
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]