Exome sequencing identifies<i>DYNC2H1</i>mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement

Schmidts, Miriam; Arts, Heleen H.; Bongers, Ernie M.H.F.; Yap, Zhimin; Oud, Machteld M.; Antony, Dinu; Duijkers, Lonneke; Emes, Richard D.; Stalker, Jim; Yntema, J.L.; Plagnol, Vincent; Hoischen, Alexander; Gilissen, Christian; Forsythe, Elisabeth; Lausch, Ekkehart; Veltman, Joris A.; Roeleveld, Nel; Superti‐Furga, Andrea; Kutkowska-Kaźmierczak, Anna; Kamsteeg, Erik‐Jan; Elçioğlu, Nursel; Maarle, Merel C. van; Graul‐Neumann, Luitgard; Devriendt, Koenraad; Smithson, Sarah; Wellesley, Diana; Verbeek, Nienke E.; Hennekam, Raoul C. M.; Kayserili, Hülya; Scambler, Peter J.; Beales, Philip L.; Knoers, Nine V A M; Roepman, Ronald; Mitchison, Hannah M.

doi:10.1136/jmedgenet-2012-101284

Cited by 130 publications

(176 citation statements)

References 67 publications

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“…Length control in primary cilia has been linked to several developmental disorders, for example mutations in MKS3 (Tammachote et al, 2009) or NEK8 (Sohara et al, 2008) lead to cilium elongation and polycystic kidney disease. Severe ciliopathy phenotypes without overt morphological defects in cilia have been seen in both animal models [including deletion of IFT-B component IFT80 (Rix et al, 2011)] and patient groups [such as those with mutations in DYNC2H1 (Schmidts et al, 2013)]. …”

Section: Discussionmentioning

confidence: 99%

A role for the Golgi matrix protein giantin in ciliogenesis through control of the localization of dynein-2

Asante

MacCarthy‐Morrogh

Townley

et al. 2013

Journal of Cell Science

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SummaryThe correct formation of primary cilia is central to the development and function of nearly all cells and tissues. Cilia grow from the mother centriole by extension of a microtubule core, the axoneme, which is then surrounded with a specialized ciliary membrane that is continuous with the plasma membrane. Intraflagellar transport moves particles along the length of the axoneme to direct assembly of the cilium and is also required for proper cilia function. The microtubule motor, cytoplasmic dynein-2 mediates retrograde transport along the axoneme from the tip to the base; dynein-2 is also required for some aspects of cilia formation. In most cells, the Golgi lies adjacent to the centrioles and key components of the cilia machinery localize to this organelle. Golgi-localized proteins have also been implicated in ciliogenesis and in intraflagellar transport. Here, we show that the transmembrane Golgi matrix protein giantin (GOLGB1) is required for ciliogenesis. We show that giantin is not required for the Rab11-Rabin8-Rab8 pathway that has been implicated in the early stages of ciliary membrane formation. Instead we find that suppression of giantin results in mis-localization of WDR34, the intermediate chain of dynein-2. Highly effective depletion of giantin or WDR34 leads to an inability of cells to form primary cilia. Partial depletion of giantin or of WDR34 leads to an increase in cilia length consistent with the concept that giantin acts through dynein-2. Our data implicate giantin in ciliogenesis through control of dynein-2 localization.

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Section: Discussionmentioning

confidence: 99%

A role for the Golgi matrix protein giantin in ciliogenesis through control of the localization of dynein-2

Asante

MacCarthy‐Morrogh

Townley

et al. 2013

Journal of Cell Science

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“…The IFT complexes transport proteins that are necessary for the assembly and maintenance of cilia (Ishikawa and Marshall, 2011), and also move signals between the cilium and cell body (Eguether et al, 2014;Liem et al, 2012;Liew et al, 2014;Wang et al, 2006). Mutations in IFT motors and complex proteins cause defects in ciliary assembly and function, resulting in several human diseases, including Jeune asphyxiating thoracic dystrophy, short-rib polydactyly syndrome, Mainzer-Saldino syndrome and Ellis-van Creveld syndrome (Aldahmesh et al, 2014;Beales et al, 2007;Caparrós-Martín et al, 2015;Dagoneau et al, 2009;Davis et al, 2011;Halbritter et al, 2013;Huber et al, 2013;McInerney-Leo et al, 2013;Merrill et al, 2009;Perrault et al, 2012Perrault et al, , 2015Schmidts et al, 2013Schmidts et al, , 2015.…”

Section: Introductionmentioning

confidence: 99%

Together, the IFT81 and IFT74 N-termini form the main module for intraflagellar transport of tubulin

Kubo

Brown

Bellvé

et al. 2016

Journal of Cell Science

102

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The assembly and maintenance of most cilia and flagella rely on intraflagellar transport (IFT). Recent in vitro studies have suggested that, together, the calponin-homology domain within the IFT81 N-terminus and the highly basic N-terminus of IFT74 form a module for IFT of tubulin. By using Chlamydomonas mutants for IFT81 and IFT74, we tested this hypothesis in vivo. Modification of the predicted tubulin-binding residues in IFT81 did not significantly affect basic anterograde IFT and length of steady-state flagella but slowed down flagellar regeneration, a phenotype similar to that seen in a strain that lacks the IFT74 N-terminus. In both mutants, the frequency of tubulin transport by IFT was greatly reduced. A double mutant that combined the modifications to IFT81 and IFT74 was able to form only very short flagella. These results indicate that, together, the IFT81 and IFT74 N-termini are crucial for flagellar assembly, and are likely to function as the main module for IFT of tubulin.

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“…IFT80, IFT140, tetratrikopeptit tekrar dizesi 21B (TTC21B-tetratricopeptide repeat domain 21B) ve dinein-2 ağır zincir-1 (DYNC2H1-dynein 2 heavy chain 1) gen mutasyonları Jeune sendromu ile en sık ilişkilendirilen mutasyonlardır. Bu genlerin heterojen ve büyük boyutlu olması bu hastalıkta genetik tanıyı zorlaştırmaktadır [9]. Jeune sendromlu olgularda hastalığın ağırlığı ve klinik bulguları değişiklik gösterebilmektedir, bu durum altta yatan genetik farklılıklara bağlanmaktadır [3].…”

Section: Discussionunclassified

A Rare Cause of Respiratory Failure in a Newborn: Jeune Syndrome

Çelik¹,

Akbas²,

Keceli³

et al. 2013

Tur Toraks Der

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Exome sequencing identifiesDYNC2H1mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement

Cited by 130 publications

References 67 publications

A role for the Golgi matrix protein giantin in ciliogenesis through control of the localization of dynein-2

A role for the Golgi matrix protein giantin in ciliogenesis through control of the localization of dynein-2

Together, the IFT81 and IFT74 N-termini form the main module for intraflagellar transport of tubulin

A Rare Cause of Respiratory Failure in a Newborn: Jeune Syndrome

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