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1. Biallelic Variants in MNS1 Are Associated with Laterality Defects and Respiratory Involvement

Author

Hjeij, Rim, primary, Leslie, Joseph, additional, Rizk, Hoda, additional, Dworniczak, Bernd, additional, Olbrich, Heike, additional, Raidt, Johanna, additional, Bode, Sebastian Felix Nepomuk, additional, Gardham, Alice, additional, Stals, Karen, additional, Al-Haggar, Mohammad, additional, Osman, Engy, additional, Crosby, Andrew, additional, Eldesoky, Tarek, additional, Baple, Emma, additional, and Omran, Heymut, additional

Published
2024
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2. Recessively Inherited Deficiency of Secreted WFDC2 (HE4) Causes Nasal Polyposis and Bronchiectasis

Author

Dougherty, Gerard W, primary, Ostrowski, Lawrence E, additional, Nöthe-Menchen, Tabea, additional, Raidt, Johanna, additional, Schramm, Andre, additional, Olbrich, Heike, additional, Yin, Weining, additional, Sears, Patrick R., additional, Dang, Hong, additional, Smith, Amanda J., additional, Beule, Achim G., additional, Hjeij, Rim, additional, Rutjies, Niels, additional, Haarman, Eric G, additional, Maas, Saskia M., additional, Ferkol, Thomas W., additional, Noone, Peadar G, additional, Olivier, Kenneth N., additional, Bracht, Diana C., additional, Barbry, Pascal, additional, Zaragosi, Laure-Emmanuelle, additional, Fierville, Morgane, additional, Kliesch, Sabine, additional, Wohlgemuth, Kai, additional, König, Julia, additional, George, Sebastian, additional, Loges, Niki T., additional, Ceppe, Agathe, additional, Markovetz, Matthew R, additional, Luo, Hong, additional, Guo, Ting, additional, Rizk, Hoda, additional, Eldesoky, Tarek, additional, Dahlke, Katrin, additional, Boldt, Karsten, additional, Ueffing, Marius, additional, Hill, David B., additional, Pang, Yuan-Ping, additional, Knowles, Michael R, additional, Zariwala, Maimoona A, additional, and Omran, Heymut, additional

Published
2024
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3. Use of Immunofluorescence Staining in Primary Ciliary Dyskinesia Diagnosis

Author

Kalyoncu, Mine, primary, Hjeij, Rim, additional, Yanaz, Mürüvvet, additional, Gulieva, Aynur, additional, Selçuk, Merve, additional, Karabulut, Şeyda, additional, Metin Çakar, Neval, additional, Ergenekon, Pınar, additional, Erdem Eralp, Ela, additional, Gokdemir, Yasemin, additional, Omran, Heymut, additional, and Karadağ, Bulent, additional

Published
2023
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4. CFAP45 deficiency causes situs abnormalities and asthenospermia by disrupting an axonemal adenine nucleotide homeostasis module

Author

Dougherty, Gerard W., Mizuno, Katsutoshi, Nöthe-Menchen, Tabea, Ikawa, Yayoi, Boldt, Karsten, Ta-Shma, Asaf, Aprea, Isabella, Minegishi, Katsura, Pang, Yuan-Ping, Pennekamp, Petra, Loges, Niki T., Raidt, Johanna, Hjeij, Rim, Wallmeier, Julia, Mussaffi, Huda, Perles, Zeev, Elpeleg, Orly, Rabert, Franziska, Shiratori, Hidetaka, Letteboer, Stef J., Horn, Nicola, Young, Samuel, Strünker, Timo, Stumme, Friederike, Werner, Claudius, Olbrich, Heike, Takaoka, Katsuyoshi, Ide, Takahiro, Twan, Wang Kyaw, Biebach, Luisa, Große-Onnebrink, Jörg, Klinkenbusch, Judith A., Praveen, Kavita, Bracht, Diana C., Höben, Inga M., Junger, Katrin, Gützlaff, Jana, Cindrić, Sandra, Aviram, Micha, Kaiser, Thomas, Memari, Yasin, Dzeja, Petras P., Dworniczak, Bernd, Ueffing, Marius, Roepman, Ronald, Bartscherer, Kerstin, Katsanis, Nicholas, Davis, Erica E., Amirav, Israel, Hamada, Hiroshi, and Omran, Heymut

Published
2020
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6. Pathogenic variants in CLXN encoding the Outer Dynein Arm Docking associated calcium-binding protein calaxin cause primary ciliary dyskinesia

Author

Hjeij, Rim, primary, Aprea, Isabella, additional, Poeta, Marco, additional, Nöthe-Menchen, Tabea, additional, Bracht, Diana, additional, Raidt, Johanna, additional, Honecker, Barbara I., additional, Dougherty, Gerard W., additional, Olbrich, Heike, additional, Schwartz, Oliver, additional, Keller, Ulrike, additional, Nüsse, Harald, additional, Diderich, Karin E.M., additional, Vogelberg, Christian, additional, Santamaria, Francesca, additional, and Omran, Heymut, additional

Published
2023
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7. Biallelic DAW1 variants cause a motile ciliopathy characterized by laterality defects and subtle ciliary beating abnormalities

Author

Leslie, Joseph S., primary, Hjeij, Rim, additional, Vivante, Asaf, additional, Bearce, Elizabeth A., additional, Dyer, Laura, additional, Wang, Jiaolong, additional, Rawlins, Lettie, additional, Kennedy, Joanna, additional, Ubeyratna, Nishanka, additional, Fasham, James, additional, Irons, Zoe H., additional, Craig, Samuel B., additional, Koenig, Julia, additional, George, Sebastian, additional, Pode-Shakked, Ben, additional, Bolkier, Yoav, additional, Barel, Ortal, additional, Mane, Shrikant, additional, Frederiksen, Kathrine K., additional, Wenger, Olivia, additional, Scott, Ethan, additional, Cross, Harold E., additional, Lorentzen, Esben, additional, Norris, Dominic P., additional, Anikster, Yair, additional, Omran, Heymut, additional, Grimes, Daniel T., additional, Crosby, Andrew H., additional, and Baple, Emma L., additional

Published
2022
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11. Immunofluorescence Analysis and Diagnosis of Primary Ciliary Dyskinesia with Radial Spoke Defects

Author

Frommer, Adrien, Hjeij, Rim, Loges, Niki T., Edelbusch, Christine, Jahnke, Charlotte, Raidt, Johanna, Werner, Claudius, Wallmeier, Julia, Groe-Onnebrink, Jörg, Olbrich, Heike, Cindrić, Sandra, Jaspers, Martine, Boon, Mieke, Memari, Yasin, Durbin, Richard, Kolb-Kokocinski, Anja, Sauer, Sascha, Marthin, June K., Nielsen, Kim G., Amirav, Israel, Elias, Nael, Kerem, Eitan, Shoseyov, David, Haeffner, Karsten, and Omran, Heymut

Published
2015
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12. Biallelic DAW1variants cause a motile ciliopathy characterized by laterality defects and subtle ciliary beating abnormalities

Author

Leslie, Joseph S., Hjeij, Rim, Vivante, Asaf, Bearce, Elizabeth A., Dyer, Laura, Wang, Jiaolong, Rawlins, Lettie, Kennedy, Joanna, Ubeyratna, Nishanka, Fasham, James, Irons, Zoe H., Craig, Samuel B., Koenig, Julia, George, Sebastian, Pode-Shakked, Ben, Bolkier, Yoav, Barel, Ortal, Mane, Shrikant, Frederiksen, Kathrine K., Wenger, Olivia, Scott, Ethan, Cross, Harold E., Lorentzen, Esben, Norris, Dominic P., Anikster, Yair, Omran, Heymut, Grimes, Daniel T., Crosby, Andrew H., and Baple, Emma L.

Abstract

The clinical spectrum of motile ciliopathies includes laterality defects, hydrocephalus, and infertility as well as primary ciliary dyskinesia when impaired mucociliary clearance results in otosinopulmonary disease. Importantly, approximately 30% of patients with primary ciliary dyskinesia lack a genetic diagnosis.

Published
2022
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14. SPEF2- and HYDIN-Mutant Cilia Lack the Central Pair–associated Protein SPEF2, Aiding Primary Ciliary Dyskinesia Diagnostics

Author

Cindrić, Sandra, primary, Dougherty, Gerard W., additional, Olbrich, Heike, additional, Hjeij, Rim, additional, Loges, Niki Tomas, additional, Amirav, Israel, additional, Philipsen, Maria C., additional, Marthin, June K., additional, Nielsen, Kim G., additional, Sutharsan, Sivagurunathan, additional, Raidt, Johanna, additional, Werner, Claudius, additional, Pennekamp, Petra, additional, Dworniczak, Bernd, additional, and Omran, Heymut, additional

Published
2020
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16. CiliaCarta: An integrated and validated compendium of ciliary genes

Author

van Dam, Teunis J. P., primary, Kennedy, Julie, additional, van der Lee, Robin, additional, de Vrieze, Erik, additional, Wunderlich, Kirsten A., additional, Rix, Suzanne, additional, Dougherty, Gerard W., additional, Lambacher, Nils J., additional, Li, Chunmei, additional, Jensen, Victor L., additional, Leroux, Michel R., additional, Hjeij, Rim, additional, Horn, Nicola, additional, Texier, Yves, additional, Wissinger, Yasmin, additional, van Reeuwijk, Jeroen, additional, Wheway, Gabrielle, additional, Knapp, Barbara, additional, Scheel, Jan F., additional, Franco, Brunella, additional, Mans, Dorus A., additional, van Wijk, Erwin, additional, Képès, François, additional, Slaats, Gisela G., additional, Toedt, Grischa, additional, Kremer, Hannie, additional, Omran, Heymut, additional, Szymanska, Katarzyna, additional, Koutroumpas, Konstantinos, additional, Ueffing, Marius, additional, Nguyen, Thanh-Minh T., additional, Letteboer, Stef J. F., additional, Oud, Machteld M., additional, van Beersum, Sylvia E. C., additional, Schmidts, Miriam, additional, Beales, Philip L., additional, Lu, Qianhao, additional, Giles, Rachel H., additional, Szklarczyk, Radek, additional, Russell, Robert B., additional, Gibson, Toby J., additional, Johnson, Colin A., additional, Blacque, Oliver E., additional, Wolfrum, Uwe, additional, Boldt, Karsten, additional, Roepman, Ronald, additional, Hernandez-Hernandez, Victor, additional, and Huynen, Martijn A., additional

Published
2019
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17. Recessive DNAH9 Loss-of-Function Mutations Cause Laterality Defects and Subtle Respiratory Ciliary-Beating Defects

Author

Loges, Niki T., primary, Antony, Dinu, additional, Maver, Ales, additional, Deardorff, Matthew A., additional, Güleç, Elif Yýlmaz, additional, Gezdirici, Alper, additional, Nöthe-Menchen, Tabea, additional, Höben, Inga M., additional, Jelten, Lena, additional, Frank, Diana, additional, Werner, Claudius, additional, Tebbe, Johannes, additional, Wu, Kaman, additional, Goldmuntz, Elizabeth, additional, Čuturilo, Goran, additional, Krock, Bryan, additional, Ritter, Alyssa, additional, Hjeij, Rim, additional, Bakey, Zeineb, additional, Pennekamp, Petra, additional, Dworniczak, Bernd, additional, Brunner, Han, additional, Peterlin, Borut, additional, Tanidir, Cansaran, additional, Olbrich, Heike, additional, Omran, Heymut, additional, and Schmidts, Miriam, additional

Published
2018
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18. Homozygous loss-of-function mutations in MNS1 cause laterality defects and likely male infertility

Author

Ta-Shma, Asaf, primary, Hjeij, Rim, additional, Perles, Zeev, additional, Dougherty, Gerard W., additional, Abu Zahira, Ibrahim, additional, Letteboer, Stef J. F., additional, Antony, Dinu, additional, Darwish, Alaa, additional, Mans, Dorus A., additional, Spittler, Sabrina, additional, Edelbusch, Christine, additional, Cindrić, Sandra, additional, Nöthe-Menchen, Tabea, additional, Olbrich, Heike, additional, Stuhlmann, Friederike, additional, Aprea, Isabella, additional, Pennekamp, Petra, additional, Loges, Niki T., additional, Breuer, Oded, additional, Shaag, Avraham, additional, Rein, Azaria J. J. T., additional, Gulec, Elif Yilmaz, additional, Gezdirici, Alper, additional, Abitbul, Revital, additional, Elias, Nael, additional, Amirav, Israel, additional, Schmidts, Miriam, additional, Roepman, Ronald, additional, Elpeleg, Orly, additional, and Omran, Heymut, additional

Published
2018
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19. Mutations in C11orf70 Cause Primary Ciliary Dyskinesia with Randomization of Left/Right Body Asymmetry Due to Defects of Outer and Inner Dynein Arms

Author

Höben, Inga M., primary, Hjeij, Rim, additional, Olbrich, Heike, additional, Dougherty, Gerard W., additional, Nöthe-Menchen, Tabea, additional, Aprea, Isabella, additional, Frank, Diana, additional, Pennekamp, Petra, additional, Dworniczak, Bernd, additional, Wallmeier, Julia, additional, Raidt, Johanna, additional, Nielsen, Kim G., additional, Philipsen, Maria C., additional, Santamaria, Francesca, additional, Venditto, Laura, additional, Amirav, Israel, additional, Mussaffi, Huda, additional, Prenzel, Freerk, additional, Wu, Kaman, additional, Bakey, Zeineb, additional, Schmidts, Miriam, additional, Loges, Niki T., additional, and Omran, Heymut, additional

Published
2018
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20. Mutations in C11ORF70 cause primary ciliary dyskinesia with randomization of left/right body asymmetry due to outer and inner dynein arm defects

Author

Höben, Inga M., primary, Hjeij, Rim, additional, Olbrich, Heike, additional, Dougherty, Gerard W., additional, Menchen, Tabea, additional, Aprea, Isabella, additional, Frank, Diana, additional, Pennekamp, Petra, additional, Dworniczak, Bernd, additional, Wallmeier, Julia, additional, Raidt, Johanna, additional, Nielsen, Kim Gjerum, additional, Philipsen, Maria C., additional, Santamaria, Francesca, additional, Venditto, Laura, additional, Amirav, Israel, additional, Prenzel, Freerk, additional, Wu, Kaman, additional, Schmidts, Miriam, additional, Loges, Niki T., additional, and Omran, Heymut, additional

Published
2017
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21. CiliaCarta: an integrated and validated compendium of ciliary genes

Author

van Dam, Teunis J. P., primary, Kennedy, Julie, additional, Lee, Robin van der, additional, Vrieze, Erik de, additional, Wunderlich, Kirsten A., additional, Rix, Suzanne, additional, Dougherty, Gerard W., additional, Lambacher, Nils J., additional, Li, Chunmei, additional, Jensen, Victor L., additional, Leroux, Michel R., additional, Hjeij, Rim, additional, Horn, Nicola, additional, Texier, Yves, additional, Wissinger, Yasmin, additional, van Reeuwijk, Jeroen, additional, Wheway, Gabrielle, additional, Knapp, Barbara, additional, Scheel, Jan F., additional, Franco, Brunella, additional, Mans, Dorus A., additional, van Wijk, Erwin, additional, Képès, François, additional, Slaats, Gisela G., additional, Toedt, Grischa, additional, Kremer, Hannie, additional, Omran, Heymut, additional, Szymanska, Katarzyna, additional, Koutroumpas, Konstantinos, additional, Ueffing, Marius, additional, Nguyen, Thanh-Minh T., additional, Letteboer, Stef J.F., additional, Oud, Machteld M., additional, van Beersum, Sylvia E. C., additional, Schmidts, Miriam, additional, Beales, Philip L., additional, Lu, Qianhao, additional, Giles, Rachel H., additional, Szklarczyk, Radek, additional, Russell, Robert B., additional, Gibson, Toby J., additional, Johnson, Colin A., additional, Blacque, Oliver E., additional, Wolfrum, Uwe, additional, Boldt, Karsten, additional, Roepman, Ronald, additional, Hernandez-Hernandez, Victor, additional, and Huynen, Martijn A., additional

Published
2017
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22. TTC25 Deficiency Results in Defects of the Outer Dynein Arm Docking Machinery and Primary Ciliary Dyskinesia with Left-Right Body Asymmetry Randomization

Author

Wallmeier, Julia, primary, Shiratori, Hidetaka, additional, Dougherty, Gerard W., additional, Edelbusch, Christine, additional, Hjeij, Rim, additional, Loges, Niki T., additional, Menchen, Tabea, additional, Olbrich, Heike, additional, Pennekamp, Petra, additional, Raidt, Johanna, additional, Werner, Claudius, additional, Minegishi, Katsura, additional, Shinohara, Kyosuke, additional, Asai, Yasuko, additional, Takaoka, Katsuyoshi, additional, Lee, Chanjae, additional, Griese, Matthias, additional, Memari, Yasin, additional, Durbin, Richard, additional, Kolb-Kokocinski, Anja, additional, Sauer, Sascha, additional, Wallingford, John B., additional, Hamada, Hiroshi, additional, and Omran, Heymut, additional

Published
2016
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23. DNAH11 Localization in the Proximal Region of Respiratory Cilia Defines Distinct Outer Dynein Arm Complexes

Author

Dougherty, Gerard W., primary, Loges, Niki T., additional, Klinkenbusch, Judith A., additional, Olbrich, Heike, additional, Pennekamp, Petra, additional, Menchen, Tabea, additional, Raidt, Johanna, additional, Wallmeier, Julia, additional, Werner, Claudius, additional, Westermann, Cordula, additional, Ruckert, Christian, additional, Mirra, Virginia, additional, Hjeij, Rim, additional, Memari, Yasin, additional, Durbin, Richard, additional, Kolb-Kokocinski, Anja, additional, Praveen, Kavita, additional, Kashef, Mohammad A., additional, Kashef, Sara, additional, Eghtedari, Fardin, additional, Häffner, Karsten, additional, Valmari, Pekka, additional, Baktai, György, additional, Aviram, Micha, additional, Bentur, Lea, additional, Amirav, Israel, additional, Davis, Erica E., additional, Katsanis, Nicholas, additional, Brueckner, Martina, additional, Shaposhnykov, Artem, additional, Pigino, Gaia, additional, Dworniczak, Bernd, additional, and Omran, Heymut, additional

Published
2016
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24. Identification of distinct ciliary beat pattern abnormalities by high-speed video microscopy in primary ciliary dyskinesia

Author

Raidt, Johanna, primary, Wallmeier, Julia, additional, Hjeij, Rim, additional, Große Onnebrink, Jörg, additional, Olbrich, Heike, additional, Loges, Niki T., additional, Pennekamp, Petra, additional, Dougherty, Gerard, additional, Häffner, Karsten, additional, Omran, Heymut, additional, and Werner, Claudius, additional

Published
2015
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25. Immunofluorescence analysis and diagnosis of primary ciliary dyskinesia with radial spoke defects

Author

Loges, Niki Tomas, primary, Frommer, Adrien, additional, Hjeij, Rim, additional, Edelbusch, Christine, additional, Jahnke, Charlotte, additional, Raidt, Johanna, additional, Werner, Claudius, additional, Wallmeier, Julia, additional, Große Onnebrink, Jörg, additional, Olbrich, Heike, additional, Cindríc, Sandra, additional, Memari, Yasin, additional, Marthin, June Kehelet, additional, Nielsen, Kim, additional, Amirav, Irael, additional, Eitan, Kerem, additional, Shoseyov, David, additional, Haeffner, Karsten, additional, Boon, Mieke, additional, Jaspers, Martine, additional, and Omran, Heymut, additional

Published
2015
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26. Mutations in SPAG1 Cause Primary Ciliary Dyskinesia Associated with Defective Outer and Inner Dynein Arms

Author

Chaki, Moumita, Raidt, Johanna, Jahnke, Charlotte, Dougherty, Gerard W., Hjeij, Rim, Werner, Claudius, Carson, Johnny L., Schueler, Markus, Gee, Heon Yung, Porath, Jonathan D., Wolf, Whitney E., Loges, Niki T., Wallmeier, Julia, Sagel, Scott D., Ostrowski, Lawrence E., Huang, Lu, Baktai, György, Braun, Daniela A., Olivier, Kenneth N., Hazucha, Milan J., Diaz, Katrina A., Knowles, Michael R., Dell, Sharon D., Otto, Edgar A., Hurd, Toby, Halbritter, Jan, Pennekamp, Petra, Olbrich, Heike, Davis, Stephanie D., Ferkol, Thomas W., Leigh, Margaret W., and Yin, Weining

Subjects
otorhinolaryngologic diseases
Abstract

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal-recessive disorder, characterized by oto-sino-pulmonary disease and situs abnormalities. PCD-causing mutations have been identified in 20 genes, but collectively they account for only ∼65% of all PCDs. To identify mutations in additional genes that cause PCD, we performed exome sequencing on three unrelated probands with ciliary outer and inner dynein arm (ODA+IDA) defects. Mutations in SPAG1 were identified in one family with three affected siblings. Further screening of SPAG1 in 98 unrelated affected individuals (62 with ODA+IDA defects, 35 with ODA defects, 1 without available ciliary ultrastructure) revealed biallelic loss-of-function mutations in 11 additional individuals (including one sib-pair). All 14 affected individuals with SPAG1 mutations had a characteristic PCD phenotype, including 8 with situs abnormalities. Additionally, all individuals with mutations who had defined ciliary ultrastructure had ODA+IDA defects. SPAG1 was present in human airway epithelial cell lysates but was not present in isolated axonemes, and immunofluorescence staining showed an absence of ODA and IDA proteins in cilia from an affected individual, thus indicating that SPAG1 probably plays a role in the cytoplasmic assembly and/or trafficking of the axonemal dynein arms. Zebrafish morpholino studies of spag1 produced cilia-related phenotypes previously reported for PCD-causing mutations in genes encoding cytoplasmic proteins. Together, these results demonstrate that mutations in SPAG1 cause PCD with ciliary ODA+IDA defects and that exome sequencing is useful to identify genetic causes of heterogeneous recessive disorders.

Published
2013
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27. ZMYND10 Is Mutated in Primary Ciliary Dyskinesia and Interacts with LRRC6

Author

Dell, Sharon D., Al-Mutairi, Dalal A., Hjeij, Rim, Leigh, Margaret W., Kohl, Stefan, Morgan, Lucy C., Olbrich, Heike, Porath, Jonathan D., Kurkowiak, Małgorzata, Gee, Heon Yung, Ferkol, Thomas W., Sagel, Scott D., Spear, Philip C., Dougherty, Gerard W., Hurd, Toby W., Hwang, Daw-Yang, Adan, Mohamed, Olivier, Kenneth N., Halbritter, Jan, Zariwala, Maimoona A., Wolf, Whitney E., Sheridan, Eamonn, Werner, Claudius, Batten, Trevor F.C., Chaki, Moumita, Rosenfeld, Margaret, Burns, Kimberlie A., Loges, Niki T., Esteve-Rudd, Julian, Lovric, Svjetlana, Diaz, Katrina A., and Pittman, Jessica E.

Abstract

Defects of motile cilia cause primary ciliary dyskinesia (PCD), characterized by recurrent respiratory infections and male infertility. Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families. We show that ZMYND10 and LRRC6 interact and that certain ZMYND10 and LRRC6 mutations abrogate the interaction between the LRRC6 CS domain and the ZMYND10 C-terminal domain. Additionally, ZMYND10 and LRRC6 colocalize with the centriole markers SAS6 and PCM1. Mutations in ZMYND10 result in the absence of the axonemal protein components DNAH5 and DNALI1 from respiratory cilia. Animal models support the association between ZMYND10 and human PCD, given that zmynd10 knockdown in zebrafish caused ciliary paralysis leading to cystic kidneys and otolith defects and that knockdown in Xenopus interfered with ciliogenesis. Our findings suggest that a cytoplasmic protein complex containing ZMYND10 and LRRC6 is necessary for motile ciliary function.

Published
2013
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29. CCDC151 Mutations Cause Primary Ciliary Dyskinesia by Disruption of the Outer Dynein Arm Docking Complex Formation

Author

Hjeij, Rim, primary, Onoufriadis, Alexandros, additional, Watson, Christopher M., additional, Slagle, Christopher E., additional, Klena, Nikolai T., additional, Dougherty, Gerard W., additional, Kurkowiak, Małgorzata, additional, Loges, Niki T., additional, Diggle, Christine P., additional, Morante, Nicholas F.C., additional, Gabriel, George C., additional, Lemke, Kristi L., additional, Li, You, additional, Pennekamp, Petra, additional, Menchen, Tabea, additional, Konert, Franziska, additional, Marthin, June Kehlet, additional, Mans, Dorus A., additional, Letteboer, Stef J.F., additional, Werner, Claudius, additional, Burgoyne, Thomas, additional, Westermann, Cordula, additional, Rutman, Andrew, additional, Carr, Ian M., additional, O’Callaghan, Christopher, additional, Moya, Eduardo, additional, Chung, Eddie M.K., additional, Sheridan, Eamonn, additional, Nielsen, Kim G., additional, Roepman, Ronald, additional, Bartscherer, Kerstin, additional, Burdine, Rebecca D., additional, Lo, Cecilia W., additional, Omran, Heymut, additional, and Mitchison, Hannah M., additional

Published
2014
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30. Mutations in SPAG1 Cause Primary Ciliary Dyskinesia Associated with Defective Outer and Inner Dynein Arms

Author

Knowles, Michael R., primary, Ostrowski, Lawrence E., additional, Loges, Niki T., additional, Hurd, Toby, additional, Leigh, Margaret W., additional, Huang, Lu, additional, Wolf, Whitney E., additional, Carson, Johnny L., additional, Hazucha, Milan J., additional, Yin, Weining, additional, Davis, Stephanie D., additional, Dell, Sharon D., additional, Ferkol, Thomas W., additional, Sagel, Scott D., additional, Olivier, Kenneth N., additional, Jahnke, Charlotte, additional, Olbrich, Heike, additional, Werner, Claudius, additional, Raidt, Johanna, additional, Wallmeier, Julia, additional, Pennekamp, Petra, additional, Dougherty, Gerard W., additional, Hjeij, Rim, additional, Gee, Heon Yung, additional, Otto, Edgar A., additional, Halbritter, Jan, additional, Chaki, Moumita, additional, Diaz, Katrina A., additional, Braun, Daniela A., additional, Porath, Jonathan D., additional, Schueler, Markus, additional, Baktai, György, additional, Griese, Matthias, additional, Turner, Emily H., additional, Lewis, Alexandra P., additional, Bamshad, Michael J., additional, Nickerson, Deborah A., additional, Hildebrandt, Friedhelm, additional, Shendure, Jay, additional, Omran, Heymut, additional, and Zariwala, Maimoona A., additional

Published
2013
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31. ARMC4 Mutations Cause Primary Ciliary Dyskinesia with Randomization of Left/Right Body Asymmetry

Author

Hjeij, Rim, primary, Lindstrand, Anna, additional, Francis, Richard, additional, Zariwala, Maimoona A., additional, Liu, Xiaoqin, additional, Li, You, additional, Damerla, Rama, additional, Dougherty, Gerard W., additional, Abouhamed, Marouan, additional, Olbrich, Heike, additional, Loges, Niki T., additional, Pennekamp, Petra, additional, Davis, Erica E., additional, Carvalho, Claudia M.B., additional, Pehlivan, Davut, additional, Werner, Claudius, additional, Raidt, Johanna, additional, Köhler, Gabriele, additional, Häffner, Karsten, additional, Reyes-Mugica, Miguel, additional, Lupski, James R., additional, Leigh, Margaret W., additional, Rosenfeld, Margaret, additional, Morgan, Lucy C., additional, Knowles, Michael R., additional, Lo, Cecilia W., additional, Katsanis, Nicholas, additional, and Omran, Heymut, additional

Published
2013
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32. ZMYND10 Is Mutated in Primary Ciliary Dyskinesia and Interacts with LRRC6

Author

Zariwala, Maimoona A., primary, Gee, Heon Yung, additional, Kurkowiak, Małgorzata, additional, Al-Mutairi, Dalal A., additional, Leigh, Margaret W., additional, Hurd, Toby W., additional, Hjeij, Rim, additional, Dell, Sharon D., additional, Chaki, Moumita, additional, Dougherty, Gerard W., additional, Adan, Mohamed, additional, Spear, Philip C., additional, Esteve-Rudd, Julian, additional, Loges, Niki T., additional, Rosenfeld, Margaret, additional, Diaz, Katrina A., additional, Olbrich, Heike, additional, Wolf, Whitney E., additional, Sheridan, Eamonn, additional, Batten, Trevor F.C., additional, Halbritter, Jan, additional, Porath, Jonathan D., additional, Kohl, Stefan, additional, Lovric, Svjetlana, additional, Hwang, Daw-Yang, additional, Pittman, Jessica E., additional, Burns, Kimberlie A., additional, Ferkol, Thomas W., additional, Sagel, Scott D., additional, Olivier, Kenneth N., additional, Morgan, Lucy C., additional, Werner, Claudius, additional, Raidt, Johanna, additional, Pennekamp, Petra, additional, Sun, Zhaoxia, additional, Zhou, Weibin, additional, Airik, Rannar, additional, Natarajan, Sivakumar, additional, Allen, Susan J., additional, Amirav, Israel, additional, Wieczorek, Dagmar, additional, Landwehr, Kerstin, additional, Nielsen, Kim, additional, Schwerk, Nicolaus, additional, Sertic, Jadranka, additional, Köhler, Gabriele, additional, Washburn, Joseph, additional, Levy, Shawn, additional, Fan, Shuling, additional, Koerner-Rettberg, Cordula, additional, Amselem, Serge, additional, Williams, David S., additional, Mitchell, Brian J., additional, Drummond, Iain A., additional, Otto, Edgar A., additional, Omran, Heymut, additional, Knowles, Michael R., additional, and Hildebrandt, Friedhelm, additional

Published
2013
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33. Immuno fluorescence Analysis and Diagnosis of Primary Ciliary Dyskinesia with Radial Spoke Defects.

Author

Frommer, Adrien, Hjeij, Rim, Loges, Niki T., Edelbusch, Christine, Jahnke, Charlotte, Raidt, Johanna, Werner, Claudius, Wallmeier, Julia, Große-Onnebrink, Jörg, Olbrich, Heike, ć, Sandra Cindri, Jaspers, Martine, Boon, Mieke, Memari, Yasin, Durbin, Richard, Kolb-Kokocinski, Anja, Sauer, Sascha, Marthin, June K., Nielsen, Kim G., and Amirav, Israel

Published
2015
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34. Pathogenic variants in CLXNencoding the Outer Dynein Arm Docking associated calcium-binding protein calaxin cause primary ciliary dyskinesia

Author

Hjeij, Rim, Aprea, Isabella, Poeta, Marco, Nöthe-Menchen, Tabea, Bracht, Diana, Raidt, Johanna, Honecker, Barbara I., Dougherty, Gerard W., Olbrich, Heike, Schwartz, Oliver, Keller, Ulrike, Nüsse, Harald, Diderich, Karin E.M., Vogelberg, Christian, Santamaria, Francesca, and Omran, Heymut

Abstract

Primary ciliary dyskinesia (PCD) is a heterogeneous disorder including respiratory symptoms, laterality defects and infertility caused by dysfunction of motile cilia. Most PCD-causing variants result in abnormal outer dynein arms (ODAs), which provide the generative force for respiratory ciliary beating and proper mucociliary clearance.

Published
2023
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35. DYX1C1 is required for axonemal dynein assembly and ciliary motility.

Author

Tarkar, Aarti, Loges, Niki T, Slagle, Christopher E, Francis, Richard, Dougherty, Gerard W, Tamayo, Joel V, Shook, Brett, Cantino, Marie, Schwartz, Daniel, Jahnke, Charlotte, Olbrich, Heike, Werner, Claudius, Raidt, Johanna, Pennekamp, Petra, Abouhamed, Marouan, Hjeij, Rim, Köhler, Gabriele, Griese, Matthias, Li, You, and Lemke, Kristi

Subjects
DYNEIN genetics, CILIARY motility disorders, CELL migration, DELETION mutation, GENETIC mutation, EPITHELIAL cells
Abstract

DYX1C1 has been associated with dyslexia and neuronal migration in the developing neocortex. Unexpectedly, we found that deleting exons 2-4 of Dyx1c1 in mice caused a phenotype resembling primary ciliary dyskinesia (PCD), a disorder characterized by chronic airway disease, laterality defects and male infertility. This phenotype was confirmed independently in mice with a Dyx1c1 c.T2A start-codon mutation recovered from an N-ethyl-N-nitrosourea (ENU) mutagenesis screen. Morpholinos targeting dyx1c1 in zebrafish also caused laterality and ciliary motility defects. In humans, we identified recessive loss-of-function DYX1C1 mutations in 12 individuals with PCD. Ultrastructural and immunofluorescence analyses of DYX1C1-mutant motile cilia in mice and humans showed disruptions of outer and inner dynein arms (ODAs and IDAs, respectively). DYX1C1 localizes to the cytoplasm of respiratory epithelial cells, its interactome is enriched for molecular chaperones, and it interacts with the cytoplasmic ODA and IDA assembly factor DNAAF2 (KTU). Thus, we propose that DYX1C1 is a newly identified dynein axonemal assembly factor (DNAAF4). [ABSTRACT FROM AUTHOR]

Published
2013
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36. CCDC151 Mutations Cause Primary Ciliary Dyskinesia by Disruption of the Outer Dynein Arm Docking Complex Formation

Author

Hjeij, Rim, Onoufriadis, Alexandros, Watson, Christopher M., Slagle, Christopher E., Klena, Nikolai T., Dougherty, Gerard W., Kurkowiak, Małgorzata, Loges, Niki T., Diggle, Christine P., Morante, Nicholas F.C., Gabriel, George C., Lemke, Kristi L., Li, You, Pennekamp, Petra, Menchen, Tabea, Konert, Franziska, Marthin, June Kehlet, Mans, Dorus A., Letteboer, Stef J.F., Werner, Claudius, Burgoyne, Thomas, Westermann, Cordula, Rutman, Andrew, Carr, Ian M., O’Callaghan, Christopher, Moya, Eduardo, Chung, Eddie M.K., Sheridan, Eamonn, Nielsen, Kim G., Roepman, Ronald, Bartscherer, Kerstin, Burdine, Rebecca D., Lo, Cecilia W., Omran, Heymut, and Mitchison, Hannah M.

Subjects
Male, Axoneme, Immunoblotting, Fluorescent Antibody Technique, Article, Mice, Two-Hybrid System Techniques, Genetics, Animals, Humans, Immunoprecipitation, Genetics(clinical), Exome, Cilia, Cells, Cultured, In Situ Hybridization, Zebrafish, Mice, Knockout, Kartagener Syndrome, Axonemal Dyneins, Embryo, Mammalian, Pedigree, Phenotype, Mutation, Female, Microtubule-Associated Proteins
Abstract

A diverse family of cytoskeletal dynein motors powers various cellular transport systems, including axonemal dyneins generating the force for ciliary and flagellar beating essential to movement of extracellular fluids and of cells through fluid. Multisubunit outer dynein arm (ODA) motor complexes, produced and preassembled in the cytosol, are transported to the ciliary or flagellar compartment and anchored into the axonemal microtubular scaffold via the ODA docking complex (ODA-DC) system. In humans, defects in ODA assembly are the major cause of primary ciliary dyskinesia (PCD), an inherited disorder of ciliary and flagellar dysmotility characterized by chronic upper and lower respiratory infections and defects in laterality. Here, by combined high-throughput mapping and sequencing, we identified CCDC151 loss-of-function mutations in five affected individuals from three independent families whose cilia showed a complete loss of ODAs and severely impaired ciliary beating. Consistent with the laterality defects observed in these individuals, we found Ccdc151 expressed in vertebrate left-right organizers. Homozygous zebrafish ccdc151(ts272a) and mouse Ccdc151(Snbl) mutants display a spectrum of situs defects associated with complex heart defects. We demonstrate that CCDC151 encodes an axonemal coiled coil protein, mutations in which abolish assembly of CCDC151 into respiratory cilia and cause a failure in axonemal assembly of the ODA component DNAH5 and the ODA-DC-associated components CCDC114 and ARMC4. CCDC151-deficient zebrafish, planaria, and mice also display ciliary dysmotility accompanied by ODA loss. Furthermore, CCDC151 coimmunoprecipitates CCDC114 and thus appears to be a highly evolutionarily conserved ODA-DC-related protein involved in mediating assembly of both ODAs and their axonemal docking machinery onto ciliary microtubules.

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37. Randomization of Left-Right Asymmetry and Congenital Heart Defects

Author

Nöthe-Menchen, Tabea, Wallmeier, Julia, Pennekamp, Petra, Höben, Inga M., Olbrich, Heike, Loges, Niki T., Raidt, Johanna, Dougherty, Gerard W., Hjeij, Rim, Dworniczak, Bernd, Omran, Heymut, Amirav, Israel, Biebach, Luisa, Fabricius, Dorit, Griese, Matthias, Große-Onnebrink, Jörg, Häffner, Karsten, Hector, Andreas, Jung, Andreas, Kaiser-Labusch, Petra, Kaiser, Thomas, Keßler, Christina, Kitz, Richard, Knowles, Michael R., Koerner-Rettberg, Cordula, Kristoffersson, Ulf, Leigh, Margaret W., Mertsch, Pontus, Mischo, Bernhard, Nielsen, Kim G., Poeta, Marco, Rietschel, Ernst, Roth, Samra, Santamaria, Francesca, Schmalstieg, Christian, Schmidts, Miriam, Schwarz, Carsten, Schwerk, Nicolaus, Seithe, Horst, Tebbe, Johannes, Werner, Claudius, and Zariwala, Maimoona A.

Abstract

Supplemental Digital Content is available in the text.

Published
2019
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38. CiliaCarta: An integrated and validated compendium of ciliary genes

Author

Gerard W. Dougherty, Victor L. Jensen, Jan Frederik Scheel, Katarzyna Szymanska, Uwe Wolfrum, Radek Szklarczyk, Miriam Schmidts, Julie Kennedy, Erwin van Wijk, Brunella Franco, Toby J. Gibson, Machteld M. Oud, Chunmei Li, Nils J. Lambacher, Erik de Vrieze, Grischa Toedt, Teunis J. P. van Dam, Karsten Boldt, Heymut Omran, Yves Texier, Rachel H. Giles, Ronald Roepman, Kirsten A. Wunderlich, Sylvia E. C. van Beersum, Oliver E. Blacque, Thanh-Minh T. Nguyen, Konstantinos Koutroumpas, Hannie Kremer, Nicola Horn, Martijn A. Huynen, Michel R. Leroux, Gabrielle Wheway, Rim Hjeij, Philip L. Beales, Gisela G. Slaats, Robert B. Russell, Robin van der Lee, François Képès, Yasmin Wissinger, Barbara Knapp, Dorus A. Mans, Suzanne Rix, Marius Ueffing, Colin A. Johnson, Stef J.F. Letteboer, Victor Hernandez-Hernandez, Qianhao Lu, Jeroen van Reeuwijk, Sub Bioinformatics, Theoretical Biology and Bioinformatics, MUMC+: DA KG Lab Centraal Lab (9), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, van Dam, Teunis J P, Kennedy, Julie, van der Lee, Robin, de Vrieze, Erik, Wunderlich, Kirsten A, Rix, Suzanne, Dougherty, Gerard W, Lambacher, Nils J, Li, Chunmei, Jensen, Victor L, Leroux, Michel R, Hjeij, Rim, Horn, Nicola, Texier, Yve, Wissinger, Yasmin, van Reeuwijk, Jeroen, Wheway, Gabrielle, Knapp, Barbara, Scheel, Jan F, Franco, Brunella, Mans, Dorus A, van Wijk, Erwin, Képès, Françoi, Slaats, Gisela G, Toedt, Grischa, Kremer, Hannie, Omran, Heymut, Szymanska, Katarzyna, Koutroumpas, Konstantino, Ueffing, Mariu, Nguyen, Thanh-Minh T, Letteboer, Stef J F, Oud, Machteld M, van Beersum, Sylvia E C, Schmidts, Miriam, Beales, Philip L, Lu, Qianhao, Giles, Rachel H, Szklarczyk, Radek, Russell, Robert B, Gibson, Toby J, Johnson, Colin A, Blacque, Oliver E, Wolfrum, Uwe, Boldt, Karsten, Roepman, Ronald, Hernandez-Hernandez, Victor, and Huynen, Martijn A

Subjects
Proteomics, Sensory Receptors, Nematoda, Social Sciences, Ciliopathies, Biochemistry, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Transcriptome, 0302 clinical medicine, Animal Cells, Psychology, RETINAL PHOTORECEPTOR CELLS, Exome, Neurons, 0303 health sciences, 030302 biochemistry & molecular biology, Eukaryota, Genomics, PRIMARY CILIUM, thecilium, 3. Good health, Nucleic acids, Genetic interference, Osteichthyes, Medicine, Epigenetics, Cellular Structures and Organelles, Cellular Types, proteomic databases, Sensory Receptor Cells, Science, education, Ciliary genes, LEBER CONGENITAL AMAUROSIS, 03 medical and health sciences, Genetics, Cilia, Caenorhabditis elegans, IDENTIFICATION, MUTATIONS, Embryos, cilia, Organisms, Biology and Life Sciences, Bayes Theorem, Molecular Sequence Annotation, medicine.disease, Invertebrates, Fish, ciliary proteome, Animal Studies, Caenorhabditis, Gene expression, embryos, 030217 neurology & neurosurgery, Developmental Biology, Neuroscience, Photoreceptors, Candidate gene, Embryology, Oligonucleotides, Morpholino, Database and Informatics Methods, RNA interference, Bayesian classifier, TRANSITION ZONE, Zebrafish, Antisense Oligonucleotides, Multidisciplinary, Spectrometric Identification of Proteins, Proteomic Databases, Nucleotides, Cilium, Stable Isotope Labeling by Amino Acids in Cell Culture, photoreceptors, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Animal Models, Phenotype, INTRAFLAGELLAR TRANSPORT, DIFFERENTIATION, Experimental Organism Systems, Caenorhabditis Elegans, Vertebrates, Sensory Perception, Research Article, Signal Transduction, EXPRESSION, Stable isotope labeling by amino acids in cell culture, Computational biology, Biology, Research and Analysis Methods, SOLUTE-CARRIER-PROTEIN, Model Organisms, medicine, Animals, data integration, 030304 developmental biology, Afferent Neurons, Reproducibility of Results, Cell Biology, zebrafish, biology.organism_classification, Ciliopathy, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Biological Databases, Cellular Neuroscience, RNA, OSCP1, CiliaCarta
Abstract

The cilium is an essential organelle at the surface of mammalian cells whose dysfunction causes a wide range of genetic diseases collectively called ciliopathies. The current rate at which new ciliopathy genes are identified suggests that many ciliary components remain undiscovered. We generated and rigorously analyzed genomic, proteomic, transcriptomic and evolutionary data and systematically integrated these using Bayesian statistics into a predictive score for ciliary function. This resulted in 285 candidate ciliary genes. We generated independent experimental evidence of ciliary associations for 24 out of 36 analyzed candidate proteins using multiple cell and animal model systems (mouse, zebrafish and nematode) and techniques. For example, we show that OSCP1, which has previously been implicated in two distinct non-ciliary processes, causes ciliogenic and ciliopathy-associated tissue phenotypes when depleted in zebrafish. The candidate list forms the basis of CiliaCarta, a comprehensive ciliary compendium covering 956 genes. The resource can be used to objectively prioritize candidate genes in whole exome or genome sequencing of ciliopathy patients and can be accessed at http://bioinformatics.bio.uu.nl/john/syscilia/ciliacarta/. This work was supported by the European Community’s Seventh Framework Programme [241955, 278568 to MU and KB, 602273 to RS]; the Virgo consortium, funded by the Dutch government [FES0908 to TvD, RvdL and MAH]; the Netherlands Genomics Initiative [050-060-452 to TvD, RvdL and MAH]; the Canadian Institutes of Health Research [MOP-142243, MOP-82870 and PJT-156042 to MRL]; Michael Smith Foundation for Health Research to MRL and VLJ; Kidney Research Scientist Core Education and National Training fellowship to VLJ; The Foundation Fighting Blindness [PPA-0717-0719-RAD to UW, RR, and MU]; the Dutch Kidney Foundation “KOUNCIL” consortium [CP11.18 to RHG, PLB and RR]; The Deutsche Forschungsgemeinschaft [Excellence grant CellNetworks to RBR and QL, CRC1140 “Kidney Disease – From Genes to Mechanisms” to MS, collaborative research center grant SFB-1411 KIDGEM to MS]; Metakids Foundation to RS; the National Institute for Health Research to PLB and VH-H. PLB is an NIHR Senior Investigator; Radboudumc Hypatia Tenure Track Fellowship, Radboud Universiteit excellence fellowship, ERC starting grant TREATCilia, grant agreement no. 716344 to MS; and the Netherlands Organization for Scientific Research [NWO Vici-865.12.005 to RR].

Published
2019

39. Mutations in C11orf70 Cause Primary Ciliary Dyskinesia with Randomization of Left/Right Body Asymmetry Due to Defects of Outer and Inner Dynein Arms

Author

Gerard W. Dougherty, Petra Pennekamp, Johanna Raidt, Inga M. Höben, Laura Venditto, Julia Wallmeier, Israel Amirav, Tabea Nöthe-Menchen, Heymut Omran, Diana Frank, Huda Mussaffi, Kaman Wu, Kim G. Nielsen, Niki T. Loges, Maria C. Philipsen, Bernd Dworniczak, Zeineb Bakey, Isabella Aprea, Francesca Santamaria, Miriam Schmidts, Freerk Prenzel, Rim Hjeij, Heike Olbrich, Höben, Inga M., Hjeij, Rim, Olbrich, Heike, Dougherty, Gerard W., Nöthe-Menchen, Tabea, Aprea, Isabella, Frank, Diana, Pennekamp, Petra, Dworniczak, Bernd, Wallmeier, Julia, Raidt, Johanna, Nielsen, Kim G., Philipsen, Maria C., Santamaria, Francesca, Venditto, Laura, Amirav, Israel, Mussaffi, Huda, Prenzel, Freerk, Wu, Kaman, Bakey, Zeineb, Schmidts, Miriam, Loges, Niki T., and Omran, Heymut

Subjects
Male, 0301 basic medicine, primary ciliary dyskinesia, Genes, Recessive, Flagellum, Biology, Male infertility, Pathogenesis, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, dynein arm, Genetic, Loss of Function Mutation, Report, Ciliogenesis, preassembly, Genetics, medicine, Humans, Genetics (clinical), Nuclear Protein, Body Patterning, Primary ciliary dyskinesia, Kartagener Syndrome, Cilium, cilia, Dynein, Dyneins, Nuclear Proteins, C11ORF70, medicine.disease, Sperm, sperm flagella, 3. Good health, Cell biology, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], 030104 developmental biology, Sperm Tail, Mutation, Motile cilium, Female, Human
Abstract

Primary ciliary dyskinesia (PCD) is characterized by chronic airway disease, male infertility, and randomization of the left/right body axis as a result of defects of motile cilia and sperm flagella. We identified loss-of-function mutations in the open-reading frame C11orf70 in PCD individuals from five distinct families. Transmission electron microscopy analyses and high-resolution immunofluorescence microscopy demonstrate that loss-of-function mutations in C11orf70 cause immotility of respiratory cilia and sperm flagella, respectively, as a result of the loss of axonemal outer (ODAs) and inner dynein arms (IDAs), indicating that C11orf70 is involved in cytoplasmic assembly of dynein arms. Expression analyses of C11orf70 showed that C11orf70 is expressed in ciliated respiratory cells and that the expression of C11orf70 is upregulated during ciliogenesis, similar to other previously described cytoplasmic dynein-arm assembly factors. Furthermore, C11orf70 shows an interaction with cytoplasmic ODA/IDA assembly factor DNAAF2, supporting our hypothesis that C11orf70 is a preassembly factor involved in the pathogenesis of PCD. The identification of additional genetic defects that cause PCD and male infertility is of great importance for the clinic as well as for genetic counselling.

Published
2018

40. Randomization of Left-right Asymmetry and Congenital Heart Defects: The Role of DNAH5 in Humans and Mice.

Author

Nöthe-Menchen T, Wallmeier J, Pennekamp P, Höben IM, Olbrich H, Loges NT, Raidt J, Dougherty GW, Hjeij R, Dworniczak B, and Omran H

Abstract

Background - Nearly one in 100 live births presents with congenital heart defects (CHD). CHD are frequently associated with laterality defects, such as situs inversus totalis (SIT), a mirrored positioning of internal organs. Body laterality is established by a complex process: monocilia at the embryonic left-right organizer (LRO) facilitate both the generation and sensing of a leftward fluid flow. This induces the conserved left-sided Nodal signaling cascade to initiate asymmetric organogenesis. Primary ciliary dyskinesia (PCD) originates from dysfunction of motile cilia, causing symptoms such as chronic sinusitis, bronchiectasis and frequently SIT. The most frequently mutated gene in PCD, DNAH5 is associated with randomization of body asymmetry resulting in SIT in half of the patients; however, its relation to CHD occurrence in humans has not been investigated in detail so far. Methods - We performed genotype / phenotype correlations in 132 PCD patients carrying disease-causing DNAH5 mutations, focusing on situs defects and CHD. Using high speed video microscopy-, immunofluorescence-, and in situ hybridization analyses, we investigated the initial steps of left-right axis establishment in embryos of a Dnah5 mutant mouse model. Results - 65.9% (87 / 132) of the PCD patients carrying disease-causing DNAH5 mutations had laterality defects: 88.5% (77 / 87) presented with SIT, 11.5% (10 / 87) presented with situs ambiguus ; and 6.1% (8 / 132) presented with CHD. In Dnah5 mut/mut mice, embryonic LRO monocilia lack outer dynein arms resulting in immotile cilia, impaired flow at the LRO, and randomization of Nodal signaling with normal, reversed or bilateral expression of key molecules. Conclusions - For the first time, we directly demonstrate the disease-mechanism of laterality defects linked to DNAH5 deficiency at the molecular level during embryogenesis. We highlight that mutations in DNAH5 are not only associated with classical randomization of left-right body asymmetry but also with severe laterality defects including CHD.

Published
2019
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