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]

IFT140
Identifiers
Aliases	IFT140, MZSDS, SRTD9, WDTC2, c305C8.4, c380F5.1, gs114, intraflagellar transport 140, RP80
External IDs	OMIM: 614620 MGI: 2146906 HomoloGene: 40979 GeneCards: IFT140
Gene location (Human) Chr. Chromosome 16 (human)[1] Band 16p13.3 Start 1,510,427 bp[1] End 1,612,072 bp[1]
Gene location (Mouse) Chr. Chromosome 17 (mouse)[2] Band 17|17 A3.3 Start 25,016,085 bp[2] End 25,099,495 bp[2]
Gene ontology Molecular function • molecular function • GO:0001948 protein binding Cellular component • cytoplasm • ciliary basal body • centrosome • cell projection • photoreceptor outer segment • intraciliary transport particle A • photoreceptor connecting cilium • microtubule organizing center • ciliary tip • GO:0035085 axoneme • cytoskeleton • cilium • non-motile cilium Biological process • renal system development • cilium morphogenesis • limb morphogenesis • intraciliary transport • skeletal system morphogenesis • photoreceptor cell outer segment organization • neural tube patterning • regulation of smoothened signaling pathway • heart development • determination of left/right symmetry • cell projection organization • retina development in camera-type eye • protein localization to cilium • regulation of cilium assembly • intraciliary retrograde transport • embryonic camera-type eye development • intraciliary transport involved in cilium assembly • embryonic digit morphogenesis • embryonic cranial skeleton morphogenesis • non-motile cilium assembly • embryonic brain development Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	9742	106633
Ensembl	ENSG00000187535	ENSMUSG00000024169
UniProt	Q96RY7	E9PY46
RefSeq (mRNA)	NM_014714	NM_134126
RefSeq (protein)	NP_055529	NP_598887
Location (UCSC)	Chr 16: 1.51 – 1.61 Mb	Chr 17: 25.02 – 25.1 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Clinical significance

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

Model organisms have been used in the study of IFT140 function. A conditional knockout mouse line called Ift140^{tm1a(KOMP)Wtsi} was generated at the Wellcome Trust Sanger Institute.[11] Male and female animals underwent a standardized phenotypic screen[12] to determine the effects of deletion.[13][14][15][16] Additional screens performed: - In-depth immunological phenotyping[17]

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 IFT140^{c.634G>A/c.2176C>G} organoids compared to the IFT140^WT/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]

Ift140 knockout mouse phenotype

Characteristic	Phenotype
All data available at.[12][17]
Peripheral blood leukocytes 6 Weeks	Normal
Haematology 6 Weeks	Normal
Insulin	Normal
Homozygous viability at P14	Abnormal
Recessive lethal study	Abnormal
Body weight	Normal
Neurological assessment	Normal
Grip strength	Normal
Dysmorphology	Normal
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Normal
Radiography	Normal
Eye morphology	Normal
Clinical chemistry	Normal
Haematology 16 Weeks	Normal
Peripheral blood leukocytes 16 Weeks	Normal
Heart weight	Normal
Salmonella infection	Normal
Cytotoxic T Cell Function	Normal
Spleen Immunophenotyping	Normal
Mesenteric Lymph Node Immunophenotyping	Normal
Bone Marrow Immunophenotyping	Normal
Epidermal Immune Composition	Normal
Influenza Challenge	Normal

References

1. GRCh38: Ensembl release 89: ENSG00000187535 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000024169 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Stepanek, Ludek; Pigino, Gaia (2016-05-06). "Microtubule doublets are double-track railways for intraflagellar transport trains". Science. 352 (6286): 721–724. doi:10.1126/science.aaf4594. ISSN 1095-9203. PMID 27151870.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
12. "International Mouse Phenotyping Consortium".
13. Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
14. Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
15. Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
16. White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, Houghton R, Estabel J, Bottomley JR, Melvin DG, Sunter D, Adams NC, Tannahill D, Logan DW, Macarthur DG, Flint J, Mahajan VB, Tsang SH, Smyth I, Watt FM, Skarnes WC, Dougan G, Adams DJ, Ramirez-Solis R, Bradley A, Steel KP (Jul 2013). "Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes". Cell. 154 (2): 452–64. doi:10.1016/j.cell.2013.06.022. PMC 3717207. PMID 23870131.
17. "Infection and Immunity Immunophenotyping (3i) Consortium".