Destabilization of the IFT-B Cilia Core Complex Due to Mutations in IFT81 Causes a Spectrum of Short-Rib Polydactyly Syndrome

Overview

Journal Sci Rep

Specialty Science

Date 2016 Sep 27

PMID 27666822

Citations 27

Authors

Ivan Duran

S Paige Taylor

Wenjuan Zhang

Jorge Martin

Kimberly N Forlenza

Rhonda P Spiro

Deborah A Nickerson

Michael Bamshad

Daniel H Cohn

Deborah Krakow

Affiliations

Soon will be listed here.

Abstract

Short-rib polydactyly syndromes (SRPS) and Asphyxiating thoracic dystrophy (ATD) or Jeune Syndrome are recessively inherited skeletal ciliopathies characterized by profound skeletal abnormalities and are frequently associated with polydactyly and multiorgan system involvement. SRPS are produced by mutations in genes that participate in the formation and function of primary cilia and usually result from disruption of retrograde intraflagellar (IFT) transport of the cilium. Herein we describe a new spectrum of SRPS caused by mutations in the gene IFT81, a key component of the IFT-B complex essential for anterograde transport. In mutant chondrocytes, the mutations led to low levels of IFT81 and mutant cells produced elongated cilia, had altered hedgehog signaling, had increased post-translation modification of tubulin, and showed evidence of destabilization of additional anterograde transport complex components. These findings demonstrate the importance of IFT81 in the skeleton, its role in the anterograde transport complex, and expand the number of loci associated with SRPS.

Citing Articles

Alteration of primary cilia and intraflagellar transport 20 (IFT20) expression in oral squamous cell carcinoma (OSCC) cell lines.

Sakinah-Syed G, Liew J, Abdul Majid N, Inche Zainal Abidin S PeerJ. 2025; 13:e18931.

PMID: 40017656 PMC: 11867036. DOI: 10.7717/peerj.18931.

Defective airway intraflagellar transport underlies a combined motile and primary ciliopathy syndrome caused by IFT74 mutations.

Fassad M, Rumman N, Junger K, Patel M, Thompson J, Goggin P Hum Mol Genet. 2023; 32(21):3090-3104.

PMID: 37555648 PMC: 10586200. DOI: 10.1093/hmg/ddad132.

IFT74 variants cause skeletal ciliopathy and motile cilia defects in mice and humans.

Bakey Z, Cabrera O, Hoefele J, Antony D, Wu K, Stuck M PLoS Genet. 2023; 19(6):e1010796.

PMID: 37315079 PMC: 10298753. DOI: 10.1371/journal.pgen.1010796.

Skeletal ciliopathy: pathogenesis and related signaling pathways.

Lai B, Jiang H, Gao Y, Zhou X Mol Cell Biochem. 2023; 479(4):811-823.

PMID: 37188988 DOI: 10.1007/s11010-023-04765-5.

Polydactyly: Clinical and molecular manifestations.

Kyriazis Z, Kollia P, Grivea I, Stefanou N, Sotiriou S, Dailiana Z World J Orthop. 2023; 14(1):13-22.

PMID: 36686282 PMC: 9850794. DOI: 10.5312/wjo.v14.i1.13.

References

Schmidts M . Clinical genetics and pathobiology of ciliary chondrodysplasias. J Pediatr Genet. 2014; 3(2):46-94. PMC: 4262788. DOI: 10.3233/PGE-14089. View

Karp S, Schipani E, St-Jacques B, Hunzelman J, Kronenberg H, McMahon A . Indian hedgehog coordinates endochondral bone growth and morphogenesis via parathyroid hormone related-protein-dependent and -independent pathways. Development. 2000; 127(3):543-8. DOI: 10.1242/dev.127.3.543. View

Merrill A, Merriman B, Farrington-Rock C, Camacho N, Sebald E, Funari V . Ciliary abnormalities due to defects in the retrograde transport protein DYNC2H1 in short-rib polydactyly syndrome. Am J Hum Genet. 2009; 84(4):542-9. PMC: 2667993. DOI: 10.1016/j.ajhg.2009.03.015. View

Kozhemyakina E, Lassar A, Zelzer E . A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation. Development. 2015; 142(5):817-31. PMC: 4352987. DOI: 10.1242/dev.105536. View

Buisson J, Chenouard N, Lagache T, Blisnick T, Olivo-Marin J, Bastin P . Intraflagellar transport proteins cycle between the flagellum and its base. J Cell Sci. 2012; 126(Pt 1):327-38. DOI: 10.1242/jcs.117069. View

Shao Y, Wang L, Welter J, Ballock R . Primary cilia modulate Ihh signal transduction in response to hydrostatic loading of growth plate chondrocytes. Bone. 2011; 50(1):79-84. PMC: 3246537. DOI: 10.1016/j.bone.2011.08.033. View

Berbari N, Sharma N, Malarkey E, Pieczynski J, Boddu R, Gaertig J . Microtubule modifications and stability are altered by cilia perturbation and in cystic kidney disease. Cytoskeleton (Hoboken). 2012; 70(1):24-31. PMC: 3552319. DOI: 10.1002/cm.21088. View

Taschner M, Kotsis F, Braeuer P, Kuehn E, Lorentzen E . Crystal structures of IFT70/52 and IFT52/46 provide insight into intraflagellar transport B core complex assembly. J Cell Biol. 2014; 207(2):269-82. PMC: 4210449. DOI: 10.1083/jcb.201408002. View

Malicdan M, Vilboux T, Stephen J, Maglic D, Mian L, Konzman D . Mutations in human homologue of chicken talpid3 gene (KIAA0586) cause a hybrid ciliopathy with overlapping features of Jeune and Joubert syndromes. J Med Genet. 2015; 52(12):830-9. PMC: 5517294. DOI: 10.1136/jmedgenet-2015-103316. View

10.

Tavella S, Biticchi R, Schito A, Minina E, Di Martino D, Pagano A . Targeted expression of SHH affects chondrocyte differentiation, growth plate organization, and Sox9 expression. J Bone Miner Res. 2004; 19(10):1678-88. DOI: 10.1359/JBMR.040706. View

11.

Huber C, Cormier-Daire V . Ciliary disorder of the skeleton. Am J Med Genet C Semin Med Genet. 2012; 160C(3):165-74. DOI: 10.1002/ajmg.c.31336. View

12.

Broekhuis J, Verhey K, Jansen G . Regulation of cilium length and intraflagellar transport by the RCK-kinases ICK and MOK in renal epithelial cells. PLoS One. 2014; 9(9):e108470. PMC: 4171540. DOI: 10.1371/journal.pone.0108470. View

13.

Robbins D, Fei D, Riobo N . The Hedgehog signal transduction network. Sci Signal. 2012; 5(246):re6. PMC: 3705708. DOI: 10.1126/scisignal.2002906. View

14.

Bhogaraju S, cajanek L, Fort C, Blisnick T, Weber K, Taschner M . Molecular basis of tubulin transport within the cilium by IFT74 and IFT81. Science. 2013; 341(6149):1009-12. PMC: 4359902. DOI: 10.1126/science.1240985. View

15.

Vasudevan K, Jiang Y, Lechtreck K, Kushida Y, Alford L, Sale W . Kinesin-13 regulates the quantity and quality of tubulin inside cilia. Mol Biol Cell. 2014; 26(3):478-94. PMC: 4310739. DOI: 10.1091/mbc.E14-09-1354. View

16.

Brown J, Cochran D, Craige B, Kubo T, Witman G . Assembly of IFT trains at the ciliary base depends on IFT74. Curr Biol. 2015; 25(12):1583-93. PMC: 4482480. DOI: 10.1016/j.cub.2015.04.060. View

17.

Taschner M, Bhogaraju S, Vetter M, Morawetz M, Lorentzen E . Biochemical mapping of interactions within the intraflagellar transport (IFT) B core complex: IFT52 binds directly to four other IFT-B subunits. J Biol Chem. 2011; 286(30):26344-52. PMC: 3143597. DOI: 10.1074/jbc.M111.254920. View

18.

Casteels I, Demandt E, Legius E . Visual loss as the presenting sign of Jeune syndrome. Eur J Paediatr Neurol. 2000; 4(5):243-7. DOI: 10.1053/ejpn.2000.0313. View

19.

Baraitser M, Burn J, Fixsen J . A female infant with features of Mohr and Majewski syndromes: variable expression, a genetic compound, or a distinct entity?. J Med Genet. 1983; 20(1):65-7. PMC: 1048990. DOI: 10.1136/jmg.20.1.65. View

20.

Besschetnova T, Kolpakova-Hart E, Guan Y, Zhou J, Olsen B, Shah J . Identification of signaling pathways regulating primary cilium length and flow-mediated adaptation. Curr Biol. 2010; 20(2):182-7. PMC: 2990526. DOI: 10.1016/j.cub.2009.11.072. View