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13. An organelle-specific protein landscape identifies novel diseases and molecular mechanisms

Author

Boldt, Karsten, van Reeuwijk, Jeroen, Dougherty, Gerard, Lamers, Ideke J C, Coene, Karlien L M, Arts, Heleen H, Betts, Matthew J, Beyer, Tina, Bolat, Emine, Gloeckner, Christian Johannes, Haidari, Khatera, Hetterschijt, Lisette, Lu, Qianhao, Iaconis, Daniela, Jenkins, Dagan, Klose, Franziska, Knapp, Barbara, Latour, Brooke, Letteboer, Stef J F, Marcelis, Carlo L, Mitic, Dragana, Morleo, Manuela, Oud, Machteld M, Koutroumpas, Konstantinos, Riemersma, Moniek, Rix, Susan, Terhal, Paulien A, Toedt, Grischa, van Dam, Teunis J P, de Vrieze, Erik, Wissinger, Yasmin, Wu, Ka Man, Apic, Gordana, Beales, Philip L, Nguyen, Thanh-Minh T, Blacque, Oliver E, Gibson, Toby J, Huynen, Martijn A, Katsanis, Nicholas, Kremer, Hannie, Omran, Heymut, van Wijk, Erwin, Wolfrum, Uwe, Kepes, François, Davis, Erica E, Texier, Yves, Franco, Brunella, Giles, Rachel H, Ueffing, Marius, Russell, Robert B, Roepman, Ronald, Group, UK10K Rare Diseases, Al-Turki, Saeed, Anderson, Carl, Antony, Dinu, Barroso, Inês, van Beersum, Sylvia E C, Bentham, Jamie, Bhattacharya, Shoumo, Carss, Keren, Chatterjee, Krishna, Cirak, Sebahattin, Cosgrove, Catherine, Danecek, Petr, Durbin, Richard, Fitzpatrick, David, Floyd, Jamie, Horn, Nicola, Reghan Foley, A., Franklin, Chris, Futema, Marta, Humphries, Steve E, Hurles, Matt, Joyce, Chris, McCarthy, Shane, Mitchison, Hannah M, Muddyman, Dawn, Muntoni, Francesco, Willer, Jason R, O'Rahilly, Stephen, Onoufriadis, Alexandros, Payne, Felicity, Plagnol, Vincent, Raymond, Lucy, Savage, David B, Scambler, Peter, Schmidts, Miriam, Schoenmakers, Nadia, Semple, Robert, Mans, Dorus A, Serra, Eva, Stalker, Jim, van Kogelenberg, Margriet, Vijayarangakannan, Parthiban, Walter, Klaudia, Whittall, Ros, Williamson, Kathy, Boldt, K, van Reeuwijk, J, Lu, Q, Koutroumpas, K, Nguyen, Tmt, Texier, Y, van Beersum, Sec, Horn, N, Willer, Jr, Mans, Da, Dougherty, G, Lamers, Ijc, Coene, Klm, Arts, Hh, Betts, Mj, Beyer, T, Bolat, E, Gloeckner, Cj, Haidari, K, Hetterschijt, L, Iaconis, D, Jenkins, D, Klose, F, Knapp, B, Latour, B, Letteboer, Sjf, Marcelis, Cl, Mitic, D, Morleo, M, Oud, Mm, Riemersma, M, Rix, S, Terhal, Pa, Toedt, G, van Dam, Tjp, de Vrieze, E, Wissinger, Y, Wu, Km, Apic, G, Beales, Pl, Blacque, Oe, Gibson, Tj, Huynen, Ma, Katsanis, N, Kremer, H, Omran, H, van Wijk, E, Wolfrum, U, Kepes, F, Davis, Ee, Franco, B, Giles, Rh, Ueffing, M, Russell, Rb, Roepman, R, Boldt, Karsten, Van Reeuwijk, Jeroen, Lu, Qianhao, Koutroumpas, Konstantino, Nguyen, Thanh Minh T., Texier, Yve, Van Beersum, Sylvia E. C., Horn, Nicola, Willer, Jason R., Mans, Dorus A., Dougherty, Gerard, Lamers, Ideke J. C., Coene, Karlien L. M., Arts, Heleen H., Betts, Matthew J., Beyer, Tina, Bolat, Emine, Gloeckner, Christian Johanne, Haidari, Khatera, Hetterschijt, Lisette, Iaconis, Daniela, Jenkins, Dagan, Klose, Franziska, Knapp, Barbara, Latour, Brooke, Letteboer, Stef J. F., Marcelis, Carlo L., Mitic, Dragana, Morleo, Manuela, Oud, Machteld M., Riemersma, Moniek, Rix, Susan, Terhal, Paulien A., Toedt, Grischa, Van Dam, Teunis J. P., De Vrieze, Erik, Wissinger, Yasmin, Wu, Ka Man, Al Turki, Saeed, Anderson, Carl, Antony, Dinu, Barroso, Inê, Bentham, Jamie, Bhattacharya, Shoumo, Carss, Keren, Chatterjee, Krishna, Cirak, Sebahattin, Cosgrove, Catherine, Danecek, Petr, Durbin, Richard, Fitzpatrick, David, Floyd, Jamie, Foley, A. Reghan, Franklin, Chri, Futema, Marta, Humphries, Steve E., Hurles, Matt, Joyce, Chri, Mccarthy, Shane, Mitchison, Hannah M., Muddyman, Dawn, Muntoni, Francesco, O'Rahilly, Stephen, Onoufriadis, Alexandro, Payne, Felicity, Plagnol, Vincent, Raymond, Lucy, Savage, David B., Scambler, Peter, Schmidts, Miriam, Schoenmakers, Nadia, Semple, Robert, Serra, Eva, Stalker, Jim, Van Kogelenberg, Margriet, Vijayarangakannan, Parthiban, Walter, Klaudia, Whittall, Ro, Williamson, Kathy, Apic, Gordana, Beales, Philip L., Blacque, Oliver E., Gibson, Toby J., Huynen, Martijn A., Katsanis, Nichola, Kremer, Hannie, Omran, Heymut, Van Wijk, Erwin, Wolfrum, Uwe, Kepes, Françoi, Davis, Erica E., Franco, Brunella, Giles, Rachel H., Ueffing, Mariu, Russell, Robert B., and Roepman, Ronald

Subjects
Proteomics, 0301 basic medicine, Systems Analysis, DNA Mutational Analysis, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], General Physics and Astronomy, Datasets as Topic, methods [Chromatography, Affinity], Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Chromatography, Affinity, Mass Spectrometry, Protein Interaction Mapping, therapy [Ciliopathies], genetics [Ciliopathies], methods [Molecular Targeted Therapy], Molecular Targeted Therapy, Protein Interaction Maps, Multidisciplinary, Cilium, Chemistry (all), abnormalities [Spine], pathology [Ciliopathies], genetics [Muscle Hypotonia], therapy [Muscle Hypotonia], Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], metabolism [Proteins], isolation & purification [Proteins], physiology [Biological Transport], 3. Good health, Cell biology, Vesicular transport protein, pathology [Dwarfism], metabolism [Cilia], Muscle Hypotonia, ddc:500, pathology [Muscle Hypotonia], pathology [Spine], genetics [Dwarfism], Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Science, Dwarfism, Exocyst, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Physics and Astronomy (all), 03 medical and health sciences, Intraflagellar transport, Ciliogenesis, Organelle, Humans, Cilia, Biochemistry, Genetics and Molecular Biology (all), Proteins, Biological Transport, General Chemistry, therapy [Dwarfism], Fibroblasts, genetics [Proteins], Ciliopathies, Spine, methods [Protein Interaction Mapping], Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], 030104 developmental biology, Proteostasis, HEK293 Cells, methods [Proteomics]
Abstract

Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub-complexes in exocyst and intraflagellar transport complexes, which we validate biochemically, and by probing structurally predicted, disruptive, genetic variants from ciliary disease patients. The landscape suggests other genetic diseases could be ciliary including 3M syndrome. We show that 3M genes are involved in ciliogenesis, and that patient fibroblasts lack cilia. Overall, this organelle-specific targeting strategy shows considerable promise for Systems Medicine., Mutations in proteins that localize to primary cilia cause devastating diseases, yet the primary cilium is a poorly understood organelle. Here the authors use interaction proteomics to identify a network of human ciliary proteins that provides new insights into several biological processes and diseases.

Published
2016
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15. TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport

Author

Schmidts, Miriam, Hou, Yuqing, Cortés, Claudio R., Mans, Dorus A., Huber, Celine, Boldt, Karsten, Patel, Mitali, van Reeuwijk, Jeroen, Plaza, Jean-Marc, van Beersum, Sylvia E. C., Yap, Zhi Min, Letteboer, Stef J. F., Taylor, S. Paige, Herridge, Warren, Johnson, Colin A., Scambler, Peter J., Ueffing, Marius, Kayserili, Hulya, Krakow, Deborah, King, Stephen M., Beales, Philip L., Al-Gazali, Lihadh, Wicking, Carol, Cormier-Daire, Valerie, Roepman, Ronald, Mitchison, Hannah M., Witman, George B., Al-Turki, Saeed, Anderson, Carl, Anney, Richard, Antony, Dinu, Asimit, Jennifer, Ayub, Mohammad, Barrett, Jeff, Barroso, Inês, Bentham, Jamie, Bhattacharya, Shoumo, Blackwood, Douglas, Bobrow, Martin, Bochukova, Elena, Bolton, Patrick, Boustred, Chris, Breen, Gerome, Brion, Marie-Jo, Brown, Andrew, 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, Day, Ian, Durbin, Richard, Edkins, Sarah, Ellis, Peter, Evans, David, Farooqi, I. Sadaf, Fatemifar, Ghazaleh, Fitzpatrick, David, Flicek, Paul, Floyd, Jamie, Foley, A. Reghan, Franklin, Chris, Futema, Marta, Gallagher, Louise, Gaunt, Tom, Geschwind, Daniel, Greenwood, Celia, Grozeva, Detelina, Guo, Xiaosen, Gurling, Hugh, Hart, Deborah, Hendricks, Audrey, Holmans, Peter, Huang, Jie, Humphries, Steve E., Hurles, Matt, Hysi, Pirro, Jackson, David, Jamshidi, Yalda, Jewell, David, Chris, Joyce, Kaye, Jane, Keane, Thomas, Kemp, John, Kennedy, Karen, Kent, Alastair, Kolb-Kokocinski, Anja, Lachance, Genevieve, 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, McKechanie, Andrew, McQuillin, Andrew, Memari, Yasin, Metrustry, Sarah, Min, Josine, Moayyeri, Alireza, Morris, James, Muddyman, Dawn, Muntoni, Francesco, Northstone, Kate, O’Donovan, Michael, 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, Pietilainen, Olli, Plagnol, Vincent, Quail, Michael A., Quaye, Lydia, Raymond, Lucy, Rehnström, Karola, Brent Richards, J., Ring, Sue, Ritchie, Graham R S, Savage, David B., Schoenmakers, Nadia, Semple, Robert K., Serra, Eva, Shihab, Hashem, Shin, So-Youn, Skuse, David, Small, Kerrin, Smee, Carol, Soler, Artigas María, Soranzo, Nicole, Southam, Lorraine, Spector, Tim, St Pourcain, Beate, St. Clair, David, Stalker, Jim, Surdulescu, Gabriela, Suvisaari, Jaana, Tachmazidou, Ioanna, Tian, Jing, Timpson, Nic, Tobin, Martin, Valdes, Ana, van Kogelenberg, Margriet, Vijayarangakannan, Parthiban, Wain, Louise, Walter, Klaudia, Wang, Jun, Ward, Kirsten, Wheeler, Ellie, Whittall, Ros, Williams, Hywel, Williamson, Kathy, Wilson, Scott G., Wong, Kim, Whyte, Tamieka, ChangJiang, Xu, Zeggini, Eleftheria, Zhang, Feng, Zheng, Hou-Feng, Schmidts, Miriam, Hou, Yuqing, Cortés, Claudio R., Mans, Dorus A., Huber, Celine, Boldt, Karsten, Patel, Mitali, van Reeuwijk, Jeroen, Plaza, Jean-Marc, van Beersum, Sylvia E. C., Yap, Zhi Min, Letteboer, Stef J. F., Taylor, S. Paige, Herridge, Warren, Johnson, Colin A., Scambler, Peter J., Ueffing, Marius, Kayserili, Hulya, Krakow, Deborah, King, Stephen M., Beales, Philip L., Al-Gazali, Lihadh, Wicking, Carol, Cormier-Daire, Valerie, Roepman, Ronald, Mitchison, Hannah M., Witman, George B., Al-Turki, Saeed, Anderson, Carl, Anney, Richard, Antony, Dinu, Asimit, Jennifer, Ayub, Mohammad, Barrett, Jeff, Barroso, Inês, Bentham, Jamie, Bhattacharya, Shoumo, Blackwood, Douglas, Bobrow, Martin, Bochukova, Elena, Bolton, Patrick, Boustred, Chris, Breen, Gerome, Brion, Marie-Jo, Brown, Andrew, 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, Day, Ian, Durbin, Richard, Edkins, Sarah, Ellis, Peter, Evans, David, Farooqi, I. Sadaf, Fatemifar, Ghazaleh, Fitzpatrick, David, Flicek, Paul, Floyd, Jamie, Foley, A. Reghan, Franklin, Chris, Futema, Marta, Gallagher, Louise, Gaunt, Tom, Geschwind, Daniel, Greenwood, Celia, Grozeva, Detelina, Guo, Xiaosen, Gurling, Hugh, Hart, Deborah, Hendricks, Audrey, Holmans, Peter, Huang, Jie, Humphries, Steve E., Hurles, Matt, Hysi, Pirro, Jackson, David, Jamshidi, Yalda, Jewell, David, Chris, Joyce, Kaye, Jane, Keane, Thomas, Kemp, John, Kennedy, Karen, Kent, Alastair, Kolb-Kokocinski, Anja, Lachance, Genevieve, 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, McKechanie, Andrew, McQuillin, Andrew, Memari, Yasin, Metrustry, Sarah, Min, Josine, Moayyeri, Alireza, Morris, James, Muddyman, Dawn, Muntoni, Francesco, Northstone, Kate, O’Donovan, Michael, 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, Pietilainen, Olli, Plagnol, Vincent, Quail, Michael A., Quaye, Lydia, Raymond, Lucy, Rehnström, Karola, Brent Richards, J., Ring, Sue, Ritchie, Graham R S, Savage, David B., Schoenmakers, Nadia, Semple, Robert K., Serra, Eva, Shihab, Hashem, Shin, So-Youn, Skuse, David, Small, Kerrin, Smee, Carol, Soler, Artigas María, Soranzo, Nicole, Southam, Lorraine, Spector, Tim, St Pourcain, Beate, St. Clair, David, Stalker, Jim, Surdulescu, Gabriela, Suvisaari, Jaana, Tachmazidou, Ioanna, Tian, Jing, Timpson, Nic, Tobin, Martin, Valdes, Ana, van Kogelenberg, Margriet, Vijayarangakannan, Parthiban, Wain, Louise, Walter, Klaudia, Wang, Jun, Ward, Kirsten, Wheeler, Ellie, Whittall, Ros, Williams, Hywel, Williamson, Kathy, Wilson, Scott G., Wong, Kim, Whyte, Tamieka, ChangJiang, Xu, Zeggini, Eleftheria, Zhang, Feng, and Zheng, Hou-Feng

Abstract

The analysis of individuals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating thoracic dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retrograde intraflagellar transport (IFT) in humans and the protist Chlamydomonas, accompanied by destabilization of the retrograde IFT dynein motor. We thus define TCTEX1D2 as an integral component of the evolutionarily conserved retrograde IFT machinery. In complex with several IFT dynein light chains, it is required for correct vertebrate skeletal formation but may be functionally redundant under certain conditions.

Published
2015

16. Refinement of Variant Selection for the LDL Cholesterol Genetic Risk Score in the Diagnosis of the Polygenic Form of Clinical Familial Hypercholesterolemia and Replication in Samples from 6 Countries

Author

Futema, Marta, primary, Shah, Sonia, primary, Cooper, Jackie A, primary, Li, KaWah, primary, Whittall, Ros A, primary, Sharifi, Mahtab, primary, Goldberg, Olivia, primary, Drogari, Euridiki, primary, Mollaki, Vasiliki, primary, Wiegman, Albert, primary, Defesche, Joep, primary, D'Agostino, Maria N, primary, D'Angelo, Antonietta, primary, Rubba, Paolo, primary, Fortunato, Giuliana, primary, Waluś-Miarka, Małgorzata, primary, Hegele, Robert A, primary, Aderayo Bamimore, Mary, primary, Durst, Ronen, primary, Leitersdorf, Eran, primary, Mulder, Monique T, primary, Roeters van Lennep, Jeanine E, primary, Sijbrands, Eric J G, primary, Whittaker, John C, primary, Talmud, Philippa J, primary, and Humphries, Steve E, primary

Published
2015
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17. The UCL low-density lipoprotein receptor gene variant database: pathogenicity update.

Author

Leigh, Sarah, Futema, Marta, Whittall, Ros, Taylor-Beadling, Alison, Williams, Maggie, den Dunnen, Johan T., and Humphries, Steve E.

Abstract

Background: Familial hypercholesterolaemia (OMIM 143890) is most frequently caused by variations in the low-density lipoprotein receptor (LDLR) gene. Predicting whether novel variants are pathogenic may not be straightforward, especially for missense and synonymous variants. In 2013, the Association of Clinical Genetic Scientists published guidelines for the classification of variants, with categories 1 and 2 representing clearly not or unlikely pathogenic, respectively, 3 representing variants of unknown significance (VUS), and 4 and 5 representing likely to be or clearly pathogenic, respectively. Here, we update the University College London (UCL) LDLR variant database according to these guidelines. Methods: PubMed searches and alerts were used to identify novel LDLR variants for inclusion in the database. Standard in silico tools were used to predict potential pathogenicity. Variants were designated as class 4/5 only when the predictions from the different programs were concordant and as class 3 when predictions were discordant. Results: The updated database (http://www.lovd.nl/LDLR) now includes 2925 curated variants, representing 1707 independent events. All 129 nonsense variants, 337 small frame-shifting and 117/118 large rearrangements were classified as 4 or 5. Of the 795 missense variants, 115 were in classes 1 and 2, 605 in class 4 and 75 in class 3. 111/181 intronic variants, 4/34 synonymous variants and 14/37 promoter variants were assigned to classes 4 or 5. Overall, 112 (7%) of reported variants were class 3. Conclusions: This study updates the LDLR variant database and identifies a number of reported VUS where additional family and in vitro studies will be required to confirm or refute their pathogenicity. [ABSTRACT FROM AUTHOR]

Published
2017
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20. Analysis of the frequency and spectrum of mutations recognised to cause familial hypercholesterolaemia in routine clinical practice in a UK specialist hospital lipid clinic

Author

Futema, Marta, primary, Whittall, Ros A., additional, Kiley, Amy, additional, Steel, Louisa K., additional, Cooper, Jackie A., additional, Badmus, Ebele, additional, Leigh, Sarah E., additional, Karpe, Fredrik, additional, Neil, H. Andrew W., additional, and Humphries, Steve E., additional

Published
2013
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22. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study

Author

Talmud, Philippa J, primary, Shah, Sonia, additional, Whittall, Ros, additional, Futema, Marta, additional, Howard, Philip, additional, Cooper, Jackie A, additional, Harrison, Seamus C, additional, Li, KaWah, additional, Drenos, Fotios, additional, Karpe, Frederik, additional, Neil, H Andrew W, additional, Descamps, Olivier S, additional, Langenberg, Claudia, additional, Lench, Nicholas, additional, Kivimaki, Mika, additional, Whittaker, John, additional, Hingorani, Aroon D, additional, Kumari, Meena, additional, and Humphries, Steve E, additional

Published
2013
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30. R643G polymorphism in PECAM-1 influences transendothelial migration of monocytes and is associated with progression of CHD and CHD events

Author

Elrayess, Mohamed A., primary, Webb, Karen E., additional, Bellingan, Geoff J., additional, Whittall, Ros A., additional, Kabir, Jahangir, additional, Hawe, Emma, additional, Syvänne, Mikko, additional, Taskinen, Marja-Riitta, additional, Frick, M. Heikki, additional, Nieminen, Markku S., additional, Kesäniemi, Y. Antero, additional, Pasternack, Amos, additional, Miller, George J., additional, and Humphries, Steve E., additional

Published
2004
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31. High Throughput Modifications of Single-Strand Conformation Polymorphism Analysis.

Author

Walker, John M., Elles, Rob, Humphries, Steve E., Gudnason, Vilmundur, Whittall, Ros E., and Day, Ian N. M.

Abstract

In most patients with familial hypercholesterolemia (FH) the disorder is caused by a mutation in the gene coding for the low density lipoprotein receptor (LDL-R) (1). The variety of different defects observed in receptor function at the cellular level reflects mutations in different domains of the gene, and there is an increasing number of pointers to suggest that genetic factors influence clinical severity. The diagnosis of FH on clinical grounds is not 100% accurate, and some hypercholesterolemic individuals may not have a mutation in the LDL-R gene, whereas some individuals who would not be included in the clinical criteria do have such a mutation. The purpose of this chapter is to Illustrate the use of the single-strand conformational polymorphism (SSCP) technique for mutation screening in the LDL-R gene and to discuss several adaptations of published methods that improve throughput, and that we believe are appropriate for a disorder such as FH. In the next few years such techniques will help to tackle molecular diagnosis and family tracing in the large number of FH patients present in Europe and North America. [ABSTRACT FROM AUTHOR]

Published
2004
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33. TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport

Author

Schmidts, Miriam, Hou, Yuqing, Cortés, Claudio R., Mans, Dorus A., Huber, Celine, Boldt, Karsten, Patel, Mitali, van Reeuwijk, Jeroen, Plaza, Jean-Marc, van Beersum, Sylvia E. C., Yap, Zhi Min, Letteboer, Stef J. F., Taylor, S. Paige, Herridge, Warren, Johnson, Colin A., Scambler, Peter J., Ueffing, Marius, Kayserili, Hulya, Krakow, Deborah, King, Stephen M., Beales, Philip L., Al-Gazali, Lihadh, Wicking, Carol, Cormier-Daire, Valerie, Roepman, Ronald, Mitchison, Hannah M., Witman, George B., Al-Turki, Saeed, Anderson, Carl, Anney, Richard, Antony, Dinu, Asimit, Jennifer, Ayub, Mohammad, Barrett, Jeff, Barroso, Inês, Bentham, Jamie, Bhattacharya, Shoumo, Blackwood, Douglas, Bobrow, Martin, Bochukova, Elena, Bolton, Patrick, Boustred, Chris, Breen, Gerome, Brion, Marie-Jo, Brown, Andrew, 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, Day, Ian, Durbin, Richard, Edkins, Sarah, Ellis, Peter, Evans, David, Farooqi, I. Sadaf, Fatemifar, Ghazaleh, Fitzpatrick, David, Flicek, Paul, Floyd, Jamie, Foley, A. Reghan, Franklin, Chris, Futema, Marta, Gallagher, Louise, Gaunt, Tom, Geschwind, Daniel, Greenwood, Celia, Grozeva, Detelina, Guo, Xiaosen, Gurling, Hugh, Hart, Deborah, Hendricks, Audrey, Holmans, Peter, Huang, Jie, Humphries, Steve E., Hurles, Matt, Hysi, Pirro, Jackson, David, Jamshidi, Yalda, Jewell, David, Chris, Joyce, Kaye, Jane, Keane, Thomas, Kemp, John, Kennedy, Karen, Kent, Alastair, Kolb-Kokocinski, Anja, Lachance, Genevieve, 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, McKechanie, Andrew, McQuillin, Andrew, Memari, Yasin, Metrustry, Sarah, Min, Josine, Moayyeri, Alireza, Morris, James, Muddyman, Dawn, Muntoni, Francesco, Northstone, Kate, O’Donovan, Michael, 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, Pietilainen, Olli, Plagnol, Vincent, Quail, Michael A., Quaye, Lydia, Raymond, Lucy, Rehnström, Karola, Brent Richards, J., Ring, Sue, Ritchie, Graham R S, Savage, David B., Schoenmakers, Nadia, Semple, Robert K., Serra, Eva, Shihab, Hashem, Shin, So-Youn, Skuse, David, Small, Kerrin, Smee, Carol, Soler, Artigas María, Soranzo, Nicole, Southam, Lorraine, Spector, Tim, St Pourcain, Beate, St. Clair, David, Stalker, Jim, Surdulescu, Gabriela, Suvisaari, Jaana, Tachmazidou, Ioanna, Tian, Jing, Timpson, Nic, Tobin, Martin, Valdes, Ana, van Kogelenberg, Margriet, Vijayarangakannan, Parthiban, Wain, Louise, Walter, Klaudia, Wang, Jun, Ward, Kirsten, Wheeler, Ellie, Whittall, Ros, Williams, Hywel, Williamson, Kathy, Wilson, Scott G., Wong, Kim, Whyte, Tamieka, ChangJiang, Xu, Zeggini, Eleftheria, Zhang, Feng, Zheng, Hou-Feng, Schmidts, Miriam, Hou, Yuqing, Cortés, Claudio R., Mans, Dorus A., Huber, Celine, Boldt, Karsten, Patel, Mitali, van Reeuwijk, Jeroen, Plaza, Jean-Marc, van Beersum, Sylvia E. C., Yap, Zhi Min, Letteboer, Stef J. F., Taylor, S. Paige, Herridge, Warren, Johnson, Colin A., Scambler, Peter J., Ueffing, Marius, Kayserili, Hulya, Krakow, Deborah, King, Stephen M., Beales, Philip L., Al-Gazali, Lihadh, Wicking, Carol, Cormier-Daire, Valerie, Roepman, Ronald, Mitchison, Hannah M., Witman, George B., Al-Turki, Saeed, Anderson, Carl, Anney, Richard, Antony, Dinu, Asimit, Jennifer, Ayub, Mohammad, Barrett, Jeff, Barroso, Inês, Bentham, Jamie, Bhattacharya, Shoumo, Blackwood, Douglas, Bobrow, Martin, Bochukova, Elena, Bolton, Patrick, Boustred, Chris, Breen, Gerome, Brion, Marie-Jo, Brown, Andrew, 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, Day, Ian, Durbin, Richard, Edkins, Sarah, Ellis, Peter, Evans, David, Farooqi, I. Sadaf, Fatemifar, Ghazaleh, Fitzpatrick, David, Flicek, Paul, Floyd, Jamie, Foley, A. Reghan, Franklin, Chris, Futema, Marta, Gallagher, Louise, Gaunt, Tom, Geschwind, Daniel, Greenwood, Celia, Grozeva, Detelina, Guo, Xiaosen, Gurling, Hugh, Hart, Deborah, Hendricks, Audrey, Holmans, Peter, Huang, Jie, Humphries, Steve E., Hurles, Matt, Hysi, Pirro, Jackson, David, Jamshidi, Yalda, Jewell, David, Chris, Joyce, Kaye, Jane, Keane, Thomas, Kemp, John, Kennedy, Karen, Kent, Alastair, Kolb-Kokocinski, Anja, Lachance, Genevieve, 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, McKechanie, Andrew, McQuillin, Andrew, Memari, Yasin, Metrustry, Sarah, Min, Josine, Moayyeri, Alireza, Morris, James, Muddyman, Dawn, Muntoni, Francesco, Northstone, Kate, O’Donovan, Michael, 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, Pietilainen, Olli, Plagnol, Vincent, Quail, Michael A., Quaye, Lydia, Raymond, Lucy, Rehnström, Karola, Brent Richards, J., Ring, Sue, Ritchie, Graham R S, Savage, David B., Schoenmakers, Nadia, Semple, Robert K., Serra, Eva, Shihab, Hashem, Shin, So-Youn, Skuse, David, Small, Kerrin, Smee, Carol, Soler, Artigas María, Soranzo, Nicole, Southam, Lorraine, Spector, Tim, St Pourcain, Beate, St. Clair, David, Stalker, Jim, Surdulescu, Gabriela, Suvisaari, Jaana, Tachmazidou, Ioanna, Tian, Jing, Timpson, Nic, Tobin, Martin, Valdes, Ana, van Kogelenberg, Margriet, Vijayarangakannan, Parthiban, Wain, Louise, Walter, Klaudia, Wang, Jun, Ward, Kirsten, Wheeler, Ellie, Whittall, Ros, Williams, Hywel, Williamson, Kathy, Wilson, Scott G., Wong, Kim, Whyte, Tamieka, ChangJiang, Xu, Zeggini, Eleftheria, Zhang, Feng, and Zheng, Hou-Feng

Abstract

The analysis of individuals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating thoracic dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retrograde intraflagellar transport (IFT) in humans and the protist Chlamydomonas, accompanied by destabilization of the retrograde IFT dynein motor. We thus define TCTEX1D2 as an integral component of the evolutionarily conserved retrograde IFT machinery. In complex with several IFT dynein light chains, it is required for correct vertebrate skeletal formation but may be functionally redundant under certain conditions.

34. A functional mutation in the LDLR promoter (-139C>G) in a patient with familial hypercholesterolemia.

Author

Smith AJ, Ahmed F, Nair D, Whittall R, Wang D, Taylor A, Norbury G, and Humphries SE

Subjects
Adult, Base Sequence, Cell Line, Tumor, Female, HeLa Cells, Humans, Male, Middle Aged, Molecular Sequence Data, Pedigree, Protein Binding genetics, Receptors, LDL antagonists & inhibitors, Receptors, LDL biosynthesis, Repetitive Sequences, Nucleic Acid genetics, Sp1 Transcription Factor genetics, Hyperlipoproteinemia Type II genetics, Point Mutation, Promoter Regions, Genetic, Receptors, LDL genetics
Abstract

A novel sequence change in repeat 3 of the promoter of the low-density lipoprotein receptor (LDLR) gene, -139C>G, has been identified in a patient with familial hypercholesterolemia (FH). LDLR -139G has been passed to one offspring who also shows an FH phenotype. Transient transfection studies using luciferase gene reporter assays revealed a considerable reduction (74+/-1.4% SEM) in reporter gene expression from the -139G variant sequence compared to the wild-type sequence, strongly suggesting that this change is the basis for FH in these patients. Analysis using electrophoretic mobility shift assay demonstrated the loss of Sp1 binding to the variant sequence in vitro, explaining the reduction of transcription.

Published
2007
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