Biology:IFT140
 Generic protein structure example |
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.[1]
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.[2][3][4] It has also been described in patients with Jeune Syndrome[5] and isolated Lebers congenital amaurosis in the absence of other syndromic features.[6]
Model organisms
Model organisms have been used in the study of IFT140 function. A conditional knockout mouse line called Ift140tm1a(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute.[7] Male and female animals underwent a standardized phenotypic screen[8] to determine the effects of deletion.[9][10][11][12] Additional screens performed: - In-depth immunological phenotyping[13]
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.[5] The cauli mouse presented with mid-gestational lethality, exencephaly, spina bifida, craniofacial dysmorphism, digital anomalies, cardiac anomalies and somite patterning defects.[5] 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.[5]
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.[4] 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.[4]
| Characteristic | Phenotype |
|---|---|
| All data available at.[8][13] | |
| 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
- ↑ 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.
- ↑ "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. May 2013. doi:10.1002/humu.22294. PMID 23418020.
- ↑ Perrault, Isabelle; Saunier, Sophie; Hanein, Sylvain; Filhol, Emilie; Bizet, Albane A.; Collins, Felicity; Salih, Mustafa A. M.; Gerber, Sylvie et al. (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. PMID 22503633.
- ↑ 4.0 4.1 4.2 Forbes, Thomas A.; Howden, Sara E.; Lawlor, Kynan; Phipson, Belinda; Maksimovic, Jovana; Hale, Lorna; Wilson, Sean; Quinlan, Catherine et al. (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. PMID 29706353.
- ↑ 5.0 5.1 5.2 5.3 Miller, Kerry A.; Ah-Cann, Casey J.; Welfare, Megan F.; Tan, Tiong Y.; Pope, Kate; Caruana, Georgina; Freckmann, Mary-Louise; Savarirayan, Ravi et al. (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. 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.
- ↑ 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.
- ↑ 8.0 8.1 "International Mouse Phenotyping Consortium". http://www.mousephenotype.org/data/search?q=Ift140#fq=*:*&facet=gene.
- ↑ "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–42. Jun 2011. doi:10.1038/nature10163. PMID 21677750.
- ↑ "Mouse library set to be knockout". Nature 474 (7351): 262–3. Jun 2011. doi:10.1038/474262a. PMID 21677718.
- ↑ "A mouse for all reasons". Cell 128 (1): 9–13. Jan 2007. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
- ↑ "Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes". Cell 154 (2): 452–64. Jul 2013. doi:10.1016/j.cell.2013.06.022. PMID 23870131.
- ↑ 13.0 13.1 "Infection and Immunity Immunophenotyping (3i) Consortium". http://www.immunophenotyping.org/data/search?keys=Ift140&field_gene_construct_tid=All.
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