IFT140
IFT140, Intraflagellar transport 140 homolog, is a protein that in humans is encoded by the IFT140 gene. The gene product forms a core component of IFT-A complex which is indipensible for retrograde intraflagellar transport within the primary cilium.[5]
Clinical significance[edit]
Mutations in this gene have been associated to cases of skeletal ciliopathy called Mainzer Saldino Syndrome, characterised by skeletal developmental anomalies, retinal degeneration and a fibrocystic renal disease known as nephronophthisis.[6][7][8] It has also been described in patients with Jeune Syndrome[9] and isolated Lebers congenital amaurosis in the absence of other syndromic features.[10]
Model organisms[edit]
An ENU derived mouse (cauli) carrying homozygous IFT140 alleles (c.2564T>A, p. I855K) was generated at the Murdoch Children's Research Institute in Melbourne, Australia.[9] The cauli mouse presented with mid-gestational lethality, exencephaly, spina bifida, craniofacial dysmorphism, digital anomalies, cardiac anomalies and somite patterning defects.[9] Ectopic hedgehog signalling was demonstrated by wholemount in situ hybridisation in the limb buds and abnormal morphology of the primary cilium within the limb bud was demonstrated by scanning electron microscopy.[9]
A patient with Mainzer Saldino Syndrome carrying compound heterozygous variants in IFT140 had induced pluripotent stem cells reprogrammed and CRISPR gene corrected before differentiating both stem cell lines into kidney organoids for transcriptional comparison.[8] Aside from validating the club shaped morphology of the primary cilia seen in the cauli mouse limb bud within the regenerated nephron tubules of the IFT140c.634G>A/c.2176C>G organoids compared to the IFT140WT/c.2176C>G, bulk RNA sequencing comparison demonstrated significant differences in gene pathways related to apicobasal polarity, cell-cell junctions and axonemal dynein assembly.[8]
References[edit]
- ^ a b c GRCh38: Ensembl release 89: ENSG00000187535 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024169 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Stepanek, Ludek; Pigino, Gaia (2016-05-06). "Microtubule doublets are double-track railways for intraflagellar transport trains". Science. 352 (6286): 721–724. Bibcode:2016Sci...352..721S. doi:10.1126/science.aaf4594. ISSN 1095-9203. PMID 27151870. S2CID 206648246.
- ^ Schmidts M, Frank V, Eisenberger T, Al Turki S, Bizet AA, Antony D, Rix S, Decker C, Bachmann N, Bald M, Vinke T, Toenshoff B, Di Donato N, Neuhann T, Hartley JL, Maher ER, Bogdanović R, Peco-Antić A, Mache C, Hurles ME, Joksić I, Guć-Šćekić M, Dobricic J, Brankovic-Magic M, Bolz HJ, Pazour GJ, Beales PL, Scambler PJ, Saunier S, Mitchison HM, Bergmann C (May 2013). "Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney Disease". Human Mutation. 34 (5): 714–24. doi:10.1002/humu.22294. PMC 4226634. PMID 23418020.
- ^ Perrault, Isabelle; Saunier, Sophie; Hanein, Sylvain; Filhol, Emilie; Bizet, Albane A.; Collins, Felicity; Salih, Mustafa A. M.; Gerber, Sylvie; Delphin, Nathalie (2012-05-04). "Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations". American Journal of Human Genetics. 90 (5): 864–870. doi:10.1016/j.ajhg.2012.03.006. ISSN 1537-6605. PMC 3376548. PMID 22503633.
- ^ a b c Forbes, Thomas A.; Howden, Sara E.; Lawlor, Kynan; Phipson, Belinda; Maksimovic, Jovana; Hale, Lorna; Wilson, Sean; Quinlan, Catherine; Ho, Gladys (2018-05-03). "Patient-iPSC-Derived Kidney Organoids Show Functional Validation of a Ciliopathic Renal Phenotype and Reveal Underlying Pathogenetic Mechanisms". American Journal of Human Genetics. 102 (5): 816–831. doi:10.1016/j.ajhg.2018.03.014. ISSN 0002-9297. PMC 5986969. PMID 29706353.
- ^ a b c d Miller, Kerry A.; Ah-Cann, Casey J.; Welfare, Megan F.; Tan, Tiong Y.; Pope, Kate; Caruana, Georgina; Freckmann, Mary-Louise; Savarirayan, Ravi; Bertram, John F. (August 2013). "Cauli: a mouse strain with an Ift140 mutation that results in a skeletal ciliopathy modelling Jeune syndrome". PLOS Genetics. 9 (8): e1003746. doi:10.1371/journal.pgen.1003746. ISSN 1553-7404. PMC 3757063. PMID 24009529.
- ^ Beals, Rodney K.; Weleber, Richard G. (2007). "Conorenal dysplasia: A syndrome of cone-shaped epiphysis, renal disease in childhood, retinitis pigmentosa and abnormality of the proximal femur". American Journal of Medical Genetics Part A. 143A (20): 2444–2447. doi:10.1002/ajmg.a.31948. ISSN 1552-4833. PMID 17853467. S2CID 32559930.
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