TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport

Schmidts, Miriam; Hou, Yuqing; Cortés, Claudio R.; Mans, Dorus A.; Huber, Céline; Boldt, Karsten; Patel, Mitali; Reeuwijk, Jeroen van; Plaza, Jean-Marc; Beersum, Sylvia E. C. van; Yap, Zhi Min; Letteboer, Stef J.F.; Taylor, S. Paige; Herridge, Warren; Johnson, Colin A.; Scambler, Peter J.; Ueffing, Marius; Kayserili, Hülya; Krakow, Deborah; King, Stephen M.; Beales, Philip L.; Al‐Gazali, Lihadh; Wicking, Carol; Cormier‐Daire, Valérie; Roepman, Ronald; Mitchison, Hannah M.; Witman, George B.; Al-Turki, Saeed; Anderson, Carl E.; Anney, Richard; Antony, Dinu; Asimit, Jennifer; Ayub, Mohammad; Barrett, J. M.; Barroso, Inês; Bentham, Jamie; Bhattacharya, Shoumo; Blackwood, Douglas; Bobrow, Martin; Bochukova, Elena G.; Bolton, Patrick B.; Boustred, Chris; Breen, Gerome; Brion, Marie-Jo; Brown, Andrew H.; Calissano, Mattia; Carss, Keren; Chatterjee, Krishna; Chen, Lu; Cirak, Sebhattin; Clapham, Peter; Clement, Gail; Coates, Guy; Collier, David; Cosgrove, Catherine; Cox, Tony; Craddock, Nick; Crooks, Lucy; Curran, Sarah; Daly, Allan; Danecek, Petr; Smith, George Davey; Day‐Williams, Aaron G.; Day, Ian N.M.; Durbin, Richard; Edkins, Sarah; Ellis, Peter; Evans, David A.; Farooqi, I. Sadaf; Fatemifar, Ghazaleh; FitzPatrick, David R.; Flicek, Paul; Floyd, Jamie; Foley, A. Reghan; Franklin, Chris; Futema, Marta; Gallagher, Louise; Gaunt, Tom R.; Geschwind, Daniel H.; Greenwood, Celia; Grozeva, Detelina; Guo, Xiaosen; Gurling, Hugh; Hart, Deborah; Hendricks, Audrey E.; Holmans, Peter; Huang, Jie; Humphries, Steve E.; Hurles, Matt; Hysi, Pirro G.; Jackson, David; Jamshidi, Yalda; Jewell, David; Chris, J. Janse; Kaye, J. F.; Keane, Thomas; Kemp, John P.; Kennedy, Karen; Kent, Alastair; Kolb-Kokocinski, Anja; Lachance, Geneviève; Langford, Cordelia; Lee, Irene; Li, Rui; Li, Yingrui; Ryan, Liu; Lönnqvist, Jouko; Lopes, Margarida; MacArthur, Daniel G.; Massimo, Mangino; Marchini, Jonathan; Maslen, John; McCarthy, Shane; McGuffin, Peter; McIntosh, Andrew M.; McKechanie, Andrew; McQuillin, Andrew; Memari, Yasin; Metrustry, Sarah; Min, Josine L.; Moayyeri, Alireza; Morris, James; Muddyman, Dawn; Muntoni, F.; Northstone, Kate; O'Donovan, Michael Conlon; O’Rahilly, Stephen; Onoufriadis, Alexandros; Oualkacha, Karim; Owen, Michael; Palotie, Aarno; Panoutsopoulou, Kalliope; Parker, Victoria; Parr, Jeremy; Paternoster, Lavinia; Paunio, Tiina; Payne, Felicity; PERRY, JOHN; Pietiläinen, Olli; Plagnol, Vincent; Quail, Michael A.; Quaye, Lydia; Raymond, Lucy; Rehnström, Karola; Richards, J. Brent; Ring, Sue; Ritchie, Graham R. S.; Savage, David B.; Schoenmakers, Nadia; Semple, Robert K.; Serra, Eva; Shihab, Hashem A.; Shin, So–Youn; Skuse, David; Small, Kerrin S.; Smee, C.; Soler, Artigas María; Soranzo, Nicole; Southam, Lorraine; Spector, Tim D.; Pourcain, Beaté St; Clair, David St; Stalker, Jim; Surdulescu, Gabriela; Suvisaari, Jaana; Tachmazidou, Ioanna; Tian, Jing; Timpson, Nic; Tobin, Martin D.; Valdes, Ana M.; Kogelenberg, Margriet van; Vijayarangakannan, Parthiban; Wain, Louise V.; Walter, K; Wang, Jun; Ward, K.; Wheeler, Ellie; Whittall, Ros; Williams, Hywel; Williamson, Kathy; Wilson, Scott G.; Wong, Kim Ping; Whyte, Tamieka; Xu, Changjiang; Zeggini, Eleftheria; Zhang, Feng; Zheng, Hou-Feng

doi:10.1038/ncomms8074

Cited by 52 publications

(48 citation statements)

References 68 publications

(125 reference statements)

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“…Immunofluorescence and cell culture analyses were performed as previously described (Schmidts et al., ). Briefly, IMCD3, hTERT‐RPE, SH‐SY5Y cells and patient as well as control fibroblasts were cultured in DMEM‐F12 medium with 5% FBS under standard conditions.…”

Section: Methodsmentioning

confidence: 99%

Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function

et al. 2018

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Next‐generation sequencing (NGS) has been instrumental in solving the genetic basis of rare inherited diseases, especially neurodevelopmental syndromes. However, functional workup is essential for precise phenotype definition and to understand the underlying disease mechanisms. Using whole exome (WES) and whole genome sequencing (WGS) in four independent families with hypotonia, neurodevelopmental delay, facial dysmorphism, loss of white matter, and thinning of the corpus callosum, we identified four previously unreported homozygous truncating PPP1R21 alleles: c.347delT p.(Ile116Lysfs*25), c.2170_2171insGGTA p.(Ile724Argfs*8), c.1607dupT p.(Leu536Phefs*7), c.2063delA p.(Lys688Serfs*26) and found that PPP1R21 was absent in fibroblasts of an affected individual, supporting the allele's loss of function effect. PPP1R21 function had not been studied except that a large scale affinity proteomics approach suggested an interaction with PIBF1 defective in Joubert syndrome. Our co‐immunoprecipitation studies did not confirm this but in contrast defined the localization of PPP1R21 to the early endosome. Consistent with the subcellular expression pattern and the clinical phenotype exhibiting features of storage diseases, we found patient fibroblasts exhibited a delay in clearance of transferrin‐488 while uptake was normal. In summary, we delineate a novel neurodevelopmental syndrome caused by biallelic PPP1R21 loss of function variants, and suggest a role of PPP1R21 within the endosomal sorting process or endosome maturation pathway.

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Section: Methodsmentioning

confidence: 99%

Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function

et al. 2018

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“…Indeed, mutations in human DYNC2LI1 cause SRPS, and fibroblasts derived from patients with missense and nonsense mutations in DYNC2LI1 confirmed that alleles of the gene cause abnormal cilia morphology [76]. Inactivation of mouse Dync2Ii1 and Dynll1 cause midgestation lethality and Hh pathway phenotypes like those seen in Dync2h1 mutants [81, 86] A role for Dynlt1 in ciliary length control has also been described in cell culture and in zebrafish [74,82]. …”

Section: Cytoplasmic Dynein-2: the Retrograde Ciliary Motormentioning

confidence: 99%

Microtubule Motors Drive Hedgehog Signaling in Primary Cilia

Agbu

Anderson

2017

Trends in Cell Biology

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The mammalian Hedgehog (Hh) signaling pathway is required for development and for maintenance of adult stem cells, and overactivation of the pathway can cause tumorigenesis. All responses to Hh family ligands in mammals require the primary cilium, an ancient microtubule-based organelle that extends from the cell surface. Genetic studies in mice and humans have defined specific functions for cilia-associated microtubule motor proteins: they act in the construction and disassembly of the primary cilium, they control cilia length and stability, and some have direct roles in mammalian Hh signal transduction. These studies highlight how integrated genetic and cell biological studies can define the molecular mechanisms that underlie cilia-associated health and disease.

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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

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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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TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport

Cited by 52 publications

References 68 publications

Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function

Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function

Microtubule Motors Drive Hedgehog Signaling in Primary Cilia

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

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