IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy

Beales, Philip L.; Bland, Elizabeth; Tobin, Jonathan L.; Bacchelli, Chiara; Tüysüz, Beyhan; Hill, Josephine; Rix, Suzanne; Pearson, Chad G.; Kai, Masahiro; Hartley, Jane; Johnson, Colin A.; Irving, Melita; Elçioğlu, Nursel; Winey, Mark; Tada, Masazumi; Scambler, Peter J.

doi:10.1038/ng2038

Cited by 310 publications

(276 citation statements)

References 14 publications

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“…We recently showed that mutations in a core intraflagellar transport (IFT) gene, IFT80, cause Jeune syndrome, a ciliopathy featuring skeletal dysplasia, renal cysts, polydactyly and situs inversus [6]. The zebrafish morphant showed cystic kidneys, random body situs (our unpublished data) and a down-turned body-axis; all features reminiscent of bona fide ciliary mutants.…”

Section: Resultsmentioning

confidence: 83%

Restoration of renal function in zebrafish models of ciliopathies

Tobin¹,

Beales²

2008

Pediatr Nephrol

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The ciliopathies are a class of rare human genetic disease whose aetioligies lie in defective primary cilia. Typical ciliopathies include Bardet-Biedl syndrome (BBS), nephronophthisis (NPHP), Jeune, Joubert, oro-facial-digital (OFD1) and Meckel (MKS) syndromes. All ciliopathies have the common denominator of renal disease, often including tubular cysts. In this study, we have modelled a range of ciliopathies in zebrafish and shown in all cases that knocking down these genes causes cystic lesions in the kidney. We have identified two drugs, rapamycin and roscovitine, which ameliorate the renal phenotype, both morphologically and functionally. This is the first study in which zebrafish has been used to identify potential therapeutic modalities for ciliopathic renal disease, and the results pave the way for further investigations in mammalian models.

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Section: Resultsmentioning

confidence: 83%

Restoration of renal function in zebrafish models of ciliopathies

Tobin¹,

Beales²

2008

Pediatr Nephrol

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“…IFT172 and IFT80 are both predicted to contain two N‐terminal WD40 β‐propeller domains followed by α‐solenoid structure akin to the domain architecture observed for coatomer subunits (van Dam et al , 2013). Mutations in IFT172 and IFT80 were reported to result in skeletal pattering defects (Beales et al , 2007; Halbritter et al , 2013), and the two components interact genetically (Halbritter et al , 2013) albeit not physically in sucrose gradients (Lucker et al , 2005). We observed no direct interaction between IFT172 and IFT80 in SEC (Appendix Fig S2A and B).…”

Section: Resultsmentioning

confidence: 99%

Intraflagellar transport proteins 172, 80, 57, 54, 38, and 20 form a stable tubulin‐binding IFT‐B2 complex

et al. 2016

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Intraflagellar transport (IFT) relies on the IFT complex and is required for ciliogenesis. The IFT‐B complex consists of 9–10 stably associated core subunits and six “peripheral” subunits that were shown to dissociate from the core structure at moderate salt concentration. We purified the six “peripheral” IFT‐B subunits of Chlamydomonas reinhardtii as recombinant proteins and show that they form a stable complex independently of the IFT‐B core. We suggest a nomenclature of IFT‐B1 (core) and IFT‐B2 (peripheral) for the two IFT‐B subcomplexes. We demonstrate that IFT88, together with the N‐terminal domain of IFT52, is necessary to bridge the interaction between IFT‐B1 and B2. The crystal structure of IFT52N reveals highly conserved residues critical for IFT‐B1/IFT‐B2 complex formation. Furthermore, we show that of the three IFT‐B2 subunits containing a calponin homology (CH) domain (IFT38, 54, and 57), only IFT54 binds αβ‐tubulin as a potential IFT cargo, whereas the CH domains of IFT38 and IFT57 mediate the interaction with IFT80 and IFT172, respectively. Crystal structures of IFT54 CH domains reveal that tubulin binding is mediated by basic surface‐exposed residues.

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“…115 Mutations in IFT80, another IFT complex B protein, cause the skeletal ciliopathy asphyxiating thoracic dystrophy (ATD, also known as Jeune syndrome) in humans, a condition that involves retinal degeneration. 121 Zebrafish ift80 morphants exhibit defects in photoreceptor OS formation and photoreceptor death 122 but hypomorphic Ift80 mutations in mice (human mutations associated with ATD are hypomorphic) have normal retinas at P21, although retinal degeneration may occur later.…”

Section: Intraflagellar Transport In the Photoreceptor Axoneme And Inmentioning

confidence: 99%