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2. Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy

Author

Töpf, Ana, Cox, Dan, Zaharieva, Irina T., Di Leo, Valeria, Sarparanta, Jaakko, Jonson, Per Harald, Sealy, Ian M., Smolnikov, Andrei, White, Richard J., Vihola, Anna, Savarese, Marco, Merteroglu, Munise, Wali, Neha, Laricchia, Kristen M., Venturini, Cristina, Vroling, Bas, Stenton, Sarah L., Cummings, Beryl B., Harris, Elizabeth, Marini-Bettolo, Chiara, Diaz-Manera, Jordi, Henderson, Matt, Barresi, Rita, Duff, Jennifer, England, Eleina M., Patrick, Jane, Al-Husayni, Sundos, Biancalana, Valerie, Beggs, Alan H., Bodi, Istvan, Bommireddipalli, Shobhana, Bönnemann, Carsten G., Cairns, Anita, Chiew, Mei-Ting, Claeys, Kristl G., Cooper, Sandra T., Davis, Mark R., Donkervoort, Sandra, Erasmus, Corrie E., Fassad, Mahmoud R., Genetti, Casie A., Grosmann, Carla, Jungbluth, Heinz, Kamsteeg, Erik-Jan, Lornage, Xavière, Löscher, Wolfgang N., Malfatti, Edoardo, Manzur, Adnan, Martí, Pilar, Mongini, Tiziana E., Muelas, Nuria, Nishikawa, Atsuko, O’Donnell-Luria, Anne, Ogonuki, Narumi, O’Grady, Gina L., O’Heir, Emily, Paquay, Stéphanie, Phadke, Rahul, Pletcher, Beth A., Romero, Norma B., Schouten, Meyke, Shah, Snehal, Smuts, Izelle, Sznajer, Yves, Tasca, Giorgio, Taylor, Robert W., Tuite, Allysa, Van den Bergh, Peter, VanNoy, Grace, Voermans, Nicol C., Wanschitz, Julia V., Wraige, Elizabeth, Yoshimura, Kimihiko, Oates, Emily C., Nakagawa, Osamu, Nishino, Ichizo, Laporte, Jocelyn, Vilchez, Juan J., MacArthur, Daniel G., Sarkozy, Anna, Cordell, Heather J., Udd, Bjarne, Busch-Nentwich, Elisabeth M., Muntoni, Francesco, and Straub, Volker

Published
2024
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4. Clinical, biochemical, and genetic spectrum of MADD in a South African cohort: an ICGNMD study

Author

Bisschoff, Michelle, primary, Smuts, Izelle, additional, Dercksen, Marli, additional, Schoonen, Maryke, additional, Vorster, Barend Christiaan, additional, Watt, George van der, additional, Spencer, Careni, additional, Naidu, Kireshnee, additional, Henning, Franclo, additional, Meldau, Surita, additional, McFarland, Robert, additional, Taylor, Robert, additional, Patel, Krutik, additional, Fassad, Mahmoud R, additional, Vandrovcova, Jana, additional, Consortium, The ICGNMD, additional, Wanders, Ronald JA, additional, and Westhuizen, Francois Hendrikus van der, additional

Published
2023
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6. Neuromuscular disease genetics in under-represented populations: increasing data diversity

Author

Wilson, Lindsay A, primary, Macken, William L, additional, Perry, Luke D, additional, Record, Christopher J, additional, Schon, Katherine R, additional, Frezatti, Rodrigo S S, additional, Raga, Sharika, additional, Naidu, Kireshnee, additional, Köken, Özlem Yayıcı, additional, Polat, Ipek, additional, Kapapa, Musambo M, additional, Dominik, Natalia, additional, Efthymiou, Stephanie, additional, Morsy, Heba, additional, Nel, Melissa, additional, Fassad, Mahmoud R, additional, Gao, Fei, additional, Patel, Krutik, additional, Schoonen, Maryke, additional, Bisschoff, Michelle, additional, Vorster, Armand, additional, Jonvik, Hallgeir, additional, Human, Ronel, additional, Lubbe, Elsa, additional, Nonyane, Malebo, additional, Vengalil, Seena, additional, Nashi, Saraswati, additional, Srivastava, Kosha, additional, Lemmers, Richard J L F, additional, Reyaz, Alisha, additional, Mishra, Rinkle, additional, Töpf, Ana, additional, Trainor, Christina I, additional, Steyn, Elizabeth C, additional, Mahungu, Amokelani C, additional, van der Vliet, Patrick J, additional, Ceylan, Ahmet Cevdet, additional, Hiz, A Semra, additional, Çavdarlı, Büşranur, additional, Semerci Gündüz, C Nur, additional, Ceylan, Gülay Güleç, additional, Nagappa, Madhu, additional, Tallapaka, Karthik B, additional, Govindaraj, Periyasamy, additional, van der Maarel, Silvère M, additional, Narayanappa, Gayathri, additional, Nandeesh, Bevinahalli N, additional, Wa Somwe, Somwe, additional, Bearden, David R, additional, Kvalsund, Michelle P, additional, Ramdharry, Gita M, additional, Oktay, Yavuz, additional, Yiş, Uluç, additional, Topaloğlu, Haluk, additional, Sarkozy, Anna, additional, Bugiardini, Enrico, additional, Henning, Franclo, additional, Wilmshurst, Jo M, additional, Heckmann, Jeannine M, additional, McFarland, Robert, additional, Taylor, Robert W, additional, Smuts, Izelle, additional, van der Westhuizen, Francois H, additional, Sobreira, Claudia Ferreira da Rosa, additional, Tomaselli, Pedro J, additional, Marques, Wilson, additional, Bhatia, Rohit, additional, Dalal, Ashwin, additional, Srivastava, M V Padma, additional, Yareeda, Sireesha, additional, Nalini, Atchayaram, additional, Vishnu, Venugopalan Y, additional, Thangaraj, Kumarasamy, additional, Straub, Volker, additional, Horvath, Rita, additional, Chinnery, Patrick F, additional, Pitceathly, Robert D S, additional, Muntoni, Francesco, additional, Houlden, Henry, additional, Vandrovcova, Jana, additional, Reilly, Mary M, additional, and Hanna, Michael G, additional

Published
2023
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8. Axonemal structures reveal mechanoregulatory and disease mechanisms

Author

Walton, Travis, primary, Gui, Miao, additional, Velkova, Simona, additional, Fassad, Mahmoud R., additional, Hirst, Robert A., additional, Haarman, Eric, additional, O’Callaghan, Christopher, additional, Bottier, Mathieu, additional, Burgoyne, Thomas, additional, Mitchison, Hannah M., additional, and Brown, Alan, additional

Published
2023
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10. The Palestinian primary ciliary dyskinesia population: first results of the diagnostic and genetic spectrum

Author

Rumman, Nisreen, primary, Fassad, Mahmoud R., additional, Driessens, Corine, additional, Goggin, Patricia, additional, Abdelrahman, Nader, additional, Adwan, Adel, additional, Albakri, Mutaz, additional, Chopra, Jagrati, additional, Doherty, Regan, additional, Fashho, Bishara, additional, Freke, Grace M., additional, Hasaballah, Abdallah, additional, Jackson, Claire L., additional, Mohamed, Mai A., additional, Abu Nema, Reda, additional, Patel, Mitali P., additional, Pengelly, Reuben J., additional, Qaaqour, Ahmad, additional, Rubbo, Bruna, additional, Thomas, N. Simon, additional, Thompson, James, additional, Walker, Woolf T., additional, Wheway, Gabrielle, additional, Mitchison, Hannah M., additional, and Lucas, Jane S., additional

Published
2023
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11. TUBB4Bvariants specifically impact ciliary function, causing a ciliopathic spectrum

Author

Mechaussier, Sabrina, Dodd, Daniel O, Yeyati, Patricia L, McPhie, Fraser, Attard, Thomas, Shoemark, Amelia, Gupta, Deepesh K, Zariwala, Maimoona A, Legendre, Marie, Bracht, Diana, Wallmeier, Julia, Gui, Miao, Anderson, Jacob R, Fassad, Mahmoud R, Parry, David A, Tennant, Peter A, Meynert, Alison, Wheway, Gabrielle, Fares-Taie, Lucas, Black, Holly A, Mitri-Frangieh, Rana, Faucon, Catherine, Kaplan, Josseline, Patel, Mitali, McKie, Lisa, Megaw, Roly, Gatsogiannis, Christos, Mohamed, Mai A, Aitken, Stuart, Gautier, Philippe, Reinholt, Finn R, Hirst, Robert A, O’Callaghan, Chris, Heimdal, Ketil, Bottier, Mathieu, Escudier, Estelle, Crowley, Suzanne, Descartes, Maria, Jabs, Ethylin W, Kenia, Priti, Amiel, Jeanne, Blümlein, Ulrike, Rogers, Andrew, Wambach, Jennifer A, Wegner, Daniel J, Fulton, Anne B, Kenna, Margaret, Rosenfeld, Margaret, Holm, Ingrid A, Quigley, Alan, Cassidy, Diana M, von Kriegsheim, Alex, Papon, Jean-Francois, Pasquier, Laurent, Murris, Marlène S, Chalmers, James D, Hogg, Clare, Macleod, Kenneth, Urquhart, Don S, Unger, Stefan, Aitman, Timothy J, Amselem, Serge, Rozet, Jean-Michel, Leigh, Margaret W, Knowles, Michael R., Omran, Heymut, Mitchison, Hannah M, Brown, Alan, Marsh, Joseph A, Welburn, Julie P I, Horani, Amjad, Perrault, Isabelle, and Mill, Pleasantine

Abstract

Cilia are small microtubule-based structures found on the surface of most mammalian cells, which have key sensory and sometimes motile functions. Primary ciliary dyskinesia (PCD) is a type of ciliopathy caused by defects in motile cilia. The genetic basis of PCD is only partially understood. Studying a cohort of 11 human patients with PCD, we find thatde novomutations inTUBB4B, a beta tubulin isotype, cause three distinct classes of ciliopathic disease.In vivostudies in mice show thatTubb4bplays a specific role in cilia, building centrioles and axonemes in multiciliated cells. Examining the effects of specific TUBB4B variants in cells and in mice, we further demonstrate that distinctTUBB4Bmutations differentially affect microtubule dynamics and cilia formation in a dominant negative manner. Finally, structure-function studies reveal that different TUBB4B mutations disrupt distinct tubulin interfaces. Importantly, these molecular differences correlate with disease features. We show that tubulin heterodimer-impairing TUBB4B variants underlie nonsyndromic PCD, whilst additional renal and sensorineural ciliopathic features in a syndromic PCD subtype arise from microtubule lumenal interface-impaired TUBB4B variants. These findings suggest that specific tubulin isotypes have distinct and non-redundant subcellular functions, and demonstrate that human tubulinopathies can be drivers of ciliopathic syndromes.

Published
2022

12. CFAP300 mutation causing primary ciliary dyskinesia in Finland

Author

Schultz, Rüdiger, primary, Elenius, Varpu, additional, Fassad, Mahmoud R., additional, Freke, Grace, additional, Rogers, Andrew, additional, Shoemark, Amelia, additional, Koistinen, Tiina, additional, Mohamed, Mai A., additional, Lim, Jacqueline S. Y., additional, Mitchison, Hannah M., additional, and Sironen, Anu I., additional

Published
2022
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13. High prevalence of CCDC103 p.His154Pro mutation causing primary ciliary dyskinesia disrupts protein oligomerisation and is associated with normal diagnostic investigations

Author

Shoemark, Amelia, Moya, Eduardo, Hirst, Robert A, Patel, Mitali P, Robson, Evelyn A, Hayward, Jane, Scully, Juliet, Fassad, Mahmoud R, Lamb, William, Schmidts, Miriam, Dixon, Mellisa, Patel-King, Ramila S, Rogers, Andrew V, Rutman, Andrew, Jackson, Claire L, Goggin, Patricia, Rubbo, Bruna, Ollosson, Sarah, Carr, Siobhán, Walker, Woolf, Adler, Beryl, Loebinger, Michael R, Wilson, Robert, Bush, Andrew, Williams, Hywel, Boustred, Christopher, Jenkins, Lucy, Sheridan, Eamonn, Chung, Eddie M K, Watson, Christopher M, Cullup, Thomas, Lucas, Jane S, Kenia, Priti, OʼCallaghan, Christopher, King, Stephen M, Hogg, Claire, and Mitchison, Hannah M

Published
2018
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14. Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability.

Author

Erdinc, Direnis, Rodríguez‐Luis, Alejandro, Fassad, Mahmoud R, Mackenzie, Sarah, Watson, Christopher M, Valenzuela, Sebastian, Xie, Xie, Menger, Katja E, Sergeant, Kate, Craig, Kate, Hopton, Sila, Falkous, Gavin, Poulton, Joanna, Garcia‐Moreno, Hector, Giunti, Paola, de Moura Aschoff, Carlos A, Morales Saute, Jonas A, Kirby, Amelia J, Toro, Camilo, and Wolfe, Lynne

Abstract

Topoisomerase 3α (TOP3A) is an enzyme that removes torsional strain and interlinks between DNA molecules. TOP3A localises to both the nucleus and mitochondria, with the two isoforms playing specialised roles in DNA recombination and replication respectively. Pathogenic variants in TOP3A can cause a disorder similar to Bloom syndrome, which results from bi‐allelic pathogenic variants in BLM, encoding a nuclear‐binding partner of TOP3A. In this work, we describe 11 individuals from 9 families with an adult‐onset mitochondrial disease resulting from bi‐allelic TOP3A gene variants. The majority of patients have a consistent clinical phenotype characterised by bilateral ptosis, ophthalmoplegia, myopathy and axonal sensory‐motor neuropathy. We present a comprehensive characterisation of the effect of TOP3A variants, from individuals with mitochondrial disease and Bloom‐like syndrome, upon mtDNA maintenance and different aspects of enzyme function. Based on these results, we suggest a model whereby the overall severity of the TOP3A catalytic defect determines the clinical outcome, with milder variants causing adult‐onset mitochondrial disease and more severe variants causing a Bloom‐like syndrome with mitochondrial dysfunction in childhood. Synopsis: We report cases of adult‐onset mitochondrial disease causes by pathological variants in the topoisomerase TOP3A, which localises both to mitochondria and the nucleus. We propose that different variants result in different disease outcomes related to the mitochondrial or nuclear forms of the enzyme. Pathological variants in TOP3A cause adult‐onset mitochondrial disease.Pathological TOP3A variants cause mitochondrial genome instability and muscle mitochondrial dysfunction.TOP3A variants affect the DNA binding, relaxation and ssDNA decatenation functions of the protein, and impair mtDNA replication.The severity of the TOP3A catalytic defect determines the clinical outcome, with milder variants associated with mitochondrial disease and more severe variants associated with Bloom syndrome. [ABSTRACT FROM AUTHOR]

Published
2023
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15. Contributors

Author

Baek, Rena C., Bonardo, Pablo, Brady, Philip, Butterfield, Russell J., Calame, Daniel G., Chung, Wendy K., Cohen, Bernard A., Corvin, Aiden, Daich Varela, Malena, de Boer, Irene, Dyment, David A., Eratne, Dhamidhu, Fassad, Mahmoud R., Federico, Antonio, Fink, John K., Finn, Patrick F., Georgiou, Michalis, Gill, Pritmohinder S., Heron, Elizabeth, Huq, Aamira J., Jinnah, H.A., Kernohan, Kristin D., Kim, Jong-Won, Kinariwalla, Neha, Koleilat, Alaa, Lawrence, Chloe J., Lequin, Maarten, Li, Hong, Lin, Ava Yun, Lupski, James R., Lynch, David S., Manberg, Stephanie, Marafi, Dana, Martini, Paolo G.V., Matthews, Emma, McFarland, Robert, Menkovic, Iskren, Michaelides, Michel, Millington, David S., Muthusamy, Karthik, Oegema, Renske, Ormond, Cathal, Park, Helen H., Park, Kyung Sun, Pastores, Gregory M., Patel, Krutik, Porter-Gill, Patricia A., Reisin, Ricardo, Rule, Don, Ryan, Niamh, Scarpa, Maurizio, Schimmenti, Lisa A., Schottlaender, Lucía, Tay, Stacey K.H., Taylor, Robert W., Terwindt, Gisela M., van den Maagdenberg, Arn M.J.M., Velakoulis, Dennis, Vengoechea, Jaime, Wade, Charles, Wagner, Matias, Wang, Leo H., Wortmann, Saskia B., Younger, David S., Yu, Feliciano B., Jr., and Ziegler, Alban C.

Published
2024
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16. Development and first results of the BEAT-PCD international Primary Ciliary Dyskinesia gene variant database: CiliaVar

Author

Mani, Rahma, primary, Gomes, Mafalda, additional, González, Adrián Rodríguez, additional, Hogg, Claire, additional, Morris-Rosendahl, Deborah, additional, Maitre, Bernard, additional, Fassad, Mahmoud R, additional, Goutaki, Myrofora, additional, Lucas, Jane S, additional, Shoemark, Amelia, additional, Mitchison, Hannah M, additional, Legendre, Marie, additional, and Crowley, Suzanne, additional

Published
2021
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17. Higher throughput drug screening for rare respiratory diseases: readthrough therapy in primary ciliary dyskinesia

Author

Lee, Dani Do Hyang, primary, Cardinale, Daniela, additional, Nigro, Ersilia, additional, Butler, Colin R., additional, Rutman, Andrew, additional, Fassad, Mahmoud R., additional, Hirst, Robert A., additional, Moulding, Dale, additional, Agrotis, Alexander, additional, Forsythe, Elisabeth, additional, Peckham, Daniel, additional, Robson, Evie, additional, Smith, Claire M., additional, Somavarapu, Satyanarayana, additional, Beales, Philip L., additional, Hart, Stephen L., additional, Janes, Sam M., additional, Mitchison, Hannah M., additional, Ketteler, Robin, additional, Hynds, Robert E., additional, and O'Callaghan, Christopher, additional

Published
2021
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18. Topological data analysis reveals genotype–phenotype relationships in primary ciliary dyskinesia

Author

Shoemark, Amelia, primary, Rubbo, Bruna, additional, Legendre, Marie, additional, Fassad, Mahmoud R., additional, Haarman, Eric G., additional, Best, Sunayna, additional, Bon, Irma C.M., additional, Brandsma, Joost, additional, Burgel, Pierre-Regis, additional, Carlsson, Gunnar, additional, Carr, Siobhan B., additional, Carroll, Mary, additional, Edwards, Matt, additional, Escudier, Estelle, additional, Honoré, Isabelle, additional, Hunt, David, additional, Jouvion, Gregory, additional, Loebinger, Michel R., additional, Maitre, Bernard, additional, Morris-Rosendahl, Deborah, additional, Papon, Jean-Francois, additional, Parsons, Camille M., additional, Patel, Mitali P., additional, Thomas, N. Simon, additional, Thouvenin, Guillaume, additional, Walker, Woolf T., additional, Wilson, Robert, additional, Hogg, Claire, additional, Mitchison, Hannah M., additional, and Lucas, Jane S., additional

Published
2021
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19. Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules.

Author

Dodd, Daniel O., Mechaussier, Sabrina, Yeyati, Patricia L., McPhie, Fraser, Anderson, Jacob R., Khoo, Chen Jing, Shoemark, Amelia, Gupta, Deepesh K., Attard, Thomas, Zariwala, Maimoona A., Legendre, Marie, Bracht, Diana, Wallmeier, Julia, Gui, Miao, Fassad, Mahmoud R., Parry, David A., Tennant, Peter A., Meynert, Alison, Wheway, Gabrielle, and Fares-Taie, Lucas

Published
2024
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20. High-content screening for rare respiratory diseases: readthrough therapy in primary ciliary dyskinesia

Author

Lee, Dani Do Hyang, primary, Cardinale, Daniela, additional, Nigro, Ersilia, additional, Butler, Colin R., additional, Rutman, Andrew, additional, Fassad, Mahmoud R., additional, Hirst, Robert A., additional, Moulding, Dale, additional, Agrotis, Alexander, additional, Forsythe, Elisabeth, additional, Peckham, Daniel, additional, Robson, Evie, additional, Smith, Claire M., additional, Somavarapu, Satyanarayana, additional, Beales, Philip L., additional, Hart, Stephen L., additional, Janes, Sam M., additional, Mitchison, Hannah M., additional, Ketteler, Robin, additional, Hynds, Robert E., additional, and O’Callaghan, Christopher, additional

Published
2020
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21. Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort

Author

Fassad, Mahmoud R., primary, Patel, Mitali P., additional, Shoemark, Amelia, additional, Cullup, Thomas, additional, Hayward, Jane, additional, Dixon, Mellisa, additional, Rogers, Andrew V., additional, Ollosson, Sarah, additional, Jackson, Claire, additional, Goggin, Patricia, additional, Hirst, Robert A., additional, Rutman, Andrew, additional, Thompson, James, additional, Jenkins, Lucy, additional, Aurora, Paul, additional, Moya, Eduardo, additional, Chetcuti, Philip, additional, O'Callaghan, Chris, additional, Morris-Rosendahl, Deborah J, additional, Watson, Christopher M., additional, Wilson, Robert, additional, Carr, Siobhan, additional, Walker, Woolf, additional, Pitno, Andreia, additional, Lopes, Susana, additional, Morsy, Heba, additional, Shoman, Walaa, additional, Pereira, Luisa, additional, Constant, Carolina, additional, Loebinger, Michael R., additional, Chung, Eddie M.K., additional, Kenia, Priti, additional, Rumman, Nisreen, additional, Fasseeh, Nader, additional, Lucas, Jane S., additional, Hogg, Claire, additional, and Mitchison, Hannah M., additional

Published
2019
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23. X-linked primary ciliary dyskinesia due to mutations in the cytoplasmic axonemal dynein assembly factor PIH1D3

Author

Olcese, Chiara, Patel, Mitali P., Shoemark, Amelia, Kiviluoto, Santeri, Legendre, Marie, Williams, Hywel J., Vaughan, Cara K., Hayward, Jane, Goldenberg, Alice, Emes, Richard D., Munye, Mustafa M., Dyer, Laura, Cahill, Thomas, Bevillard, Jeremy, Gehrig, Corinne, Guipponi, Michel, Chantot, Sandra, Duquesnoy, Philippe, Thomas, Lucie, Jeanson, Ludovic, Copin, Bruno, Tamalet, Aline, Thauvin-Robinet, Christel, Papon, Jean-Francois, Garin, Antoine, Pin, Isabelle, Vera, Gabriella, Aurora, Paul, Fassad, Mahmoud R., Jenkins, Lucy, Boustred, Christopher, Cullup, Thomas, Dixon, Mellisa, Onoufriadis, Alexandros, Bush, Andrew, Chung, Eddie M. K., Antonarakis, Stylianos E., Loebinger, Michael R., Wilson, Robert, Armengot, Miguel, Escudier, Estelle, Hogg, Claire, Amselem, Serge, Sun, Zhaoxia, Bartoloni, Lucia, Blouin, Jean-Louis, Mitchison, Hannah M., and UK10K Rare Grp

Subjects
Science, PROTEIN, DEFECTS, VARIANTS, R2TP COMPLEX, respiratory tract diseases, ARMS, IDENTIFIES MUTATIONS, MOTILITY, OF-FUNCTION MUTATIONS, otorhinolaryngologic diseases, INNER, OUTER
Abstract

By moving essential body fluids and molecules, motile cilia and flagella govern respiratory mucociliary clearance, laterality determination and the transport of gametes and cerebrospinal fluid. Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder frequently caused by non-assembly of dynein arm motors into cilia and flagella axonemes. Before their import into cilia and flagella, multi-subunit axonemal dynein arms are thought to be stabilized and pre-assembled in the cytoplasm through a DNAAF2DNAAF4- HSP90 complex akin to the HSP90 co-chaperone R2TP complex. Here, we demonstrate that large genomic deletions as well as point mutations involving PIH1D3 are responsible for an X-linked form of PCD causing disruption of early axonemal dynein assembly. We propose that PIH1D3, a protein that emerges as a new player of the cytoplasmic pre-assembly pathway, is part of a complementary conserved R2TP-like HSP90 co-chaperone complex, the loss of which affects assembly of a subset of inner arm dyneins.

Published
2017

24. Proceedings from the 3rd BEAT-PCD Conference and 4th PCD Training School

Author

Hannah, Farley, Rubbo, Bruna, Bukowy-Bieryllo, Zuzanna, Fassad, Mahmoud R., Goutaki, Myrofora, Harman, Katherine, Hogg, Claire, Kuehni, Claudia E., Lopes, Susana P., Nielsen, Kim G., Norris, Dominic P., Reula, Ana, Rumman, Nisreen, Shoemark, Amelia, Wilkins, Hannah, Wisse, Agatha, Lucas, Jane, and Marthin, June K.

Subjects
education, otorhinolaryngologic diseases
Abstract

Primary ciliary dyskinesia (PCD) is a chronic suppurative airways disease that is usually recessively inherited and has marked clinical phenotypic heterogeneity. Classic symptoms include neonatal respiratory distress, chronic rhinitis since early childhood, chronic otitis media, recurrent airway infections leading to bronchiectasis, chronic sinusitis, laterality defects with and without congenital heart disease including abnormal situs in approximately 50% of the cases, and male infertility. Lung function deteriorates progressively from childhood throughout life. ‘Better Experimental Approaches to Treat Primary Ciliary Dyskinesia’ (BEAT-PCD) is a network of scientists and clinicians coordinating research from basic science through to clinical care with the intention of developing treatments and diagnostics that lead to improved long-term outcomes for patients. BEAT-PCD activities are supported by EU funded COST Action (BM1407). The third BEAT-PCD conference and fourth PCD training school were held jointly in February 2018 in Lisbon, Portugal. Presentations and workshops focussed on advancing the knowledge and skills relating to PCD in: basic science, epidemiology, diagnostic testing, clinical management and clinical trials. The multidisciplinary conference provided an interactive platform for exchanging ideas through a program of lectures, poster presentations, breakout sessions and workshops. Three working groups met to plan consensus statements. Progress with BEAT-PCD projects was shared and new collaborations were fostered. In this report, we summarize the meeting, highlighting developments made during the meeting.

Published
2018

25. Expanding the phenome and variome of skeletal dysplasia

Author

Maddirevula, Sateesh, primary, Alsahli, Saud, additional, Alhabeeb, Lamees, additional, Patel, Nisha, additional, Alzahrani, Fatema, additional, Shamseldin, Hanan E., additional, Anazi, Shams, additional, Ewida, Nour, additional, Alsaif, Hessa S., additional, Mohamed, Jawahir Y., additional, Alazami, Anas M., additional, Ibrahim, Niema, additional, Abdulwahab, Firdous, additional, Hashem, Mais, additional, Abouelhoda, Mohamed, additional, Monies, Dorota, additional, Al Tassan, Nada, additional, Alshammari, Muneera, additional, Alsagheir, Afaf, additional, Seidahmed, Mohammed Zain, additional, Sogati, Samira, additional, Aglan, Mona S, additional, Hamad, Muddathir H., additional, Salih, Mustafa A., additional, Hamed, Ahlam A., additional, Alhashmi, Nadia, additional, Nabil, Amira, additional, Alfadli, Fatima, additional, Abdel-Salam, Ghada M.H., additional, Alkuraya, Hisham, additional, Peitee, Winnie Ong, additional, Keng, W.T., additional, Qasem, Abdullah, additional, Mushiba, Aziza M., additional, Zaki, Maha S, additional, Fassad, Mahmoud R., additional, Alfadhel, Majid, additional, Alexander, Saji, additional, Sabr, Yasser, additional, Temtamy, Samia, additional, Ekbote, Alka V, additional, Ismail, Samira, additional, Hosny, Gamal Ahmed, additional, Otaify, Ghada A., additional, Amr, Khalda, additional, Al Tala, Saeed, additional, Khan, Arif O., additional, Rizk, Tamer, additional, Alaqeel, Aida, additional, Alsiddiky, Abdulmonem, additional, Singh, Ankur, additional, Kapoor, Seema, additional, Alhashem, Amal, additional, Faqeih, Eissa, additional, Shaheen, Ranad, additional, and Alkuraya, Fowzan S., additional

Published
2018
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26. Mutations in Outer Dynein Arm Heavy Chain DNAH9 Cause Motile Cilia Defects and Situs Inversus

Author

Fassad, Mahmoud R., primary, Shoemark, Amelia, additional, Legendre, Marie, additional, Hirst, Robert A., additional, Koll, France, additional, le Borgne, Pierrick, additional, Louis, Bruno, additional, Daudvohra, Farheen, additional, Patel, Mitali P., additional, Thomas, Lucie, additional, Dixon, Mellisa, additional, Burgoyne, Thomas, additional, Hayes, Joseph, additional, Nicholson, Andrew G., additional, Cullup, Thomas, additional, Jenkins, Lucy, additional, Carr, Siobhán B., additional, Aurora, Paul, additional, Lemullois, Michel, additional, Aubusson-Fleury, Anne, additional, Papon, Jean-François, additional, O’Callaghan, Christopher, additional, Amselem, Serge, additional, Hogg, Claire, additional, Escudier, Estelle, additional, Tassin, Anne-Marie, additional, and Mitchison, Hannah M., additional

Published
2018
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27. Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort.

Author

Fassad, Mahmoud R., Patel, Mitali P., Shoemark, Amelia, Cullup, Thomas, Hayward, Jane, Dixon, Mellisa, Rogers, Andrew V., Ollosson, Sarah, Jackson, Claire, Goggin, Patricia, Hirst, Robert A., Rutman, Andrew, Thompson, James, Jenkins, Lucy, Aurora, Paul, Moya, Eduardo, Chetcuti, Philip, O'Callaghan, Chris, Morris-Rosendahl, Deborah J., and Watson, Christopher M.

Abstract

Background Primary ciliary dyskinesia (PcD), a genetically heterogeneous condition enriched in some consanguineous populations, results from recessive mutations affecting cilia biogenesis and motility. currently, diagnosis requires multiple expert tests. Methods The diagnostic utility of multigene panel next- generation sequencing (ngs) was evaluated in 161 unrelated families from multiple population ancestries. Results Most (82%) families had affected individuals with biallelic or hemizygous (75%) or single (7%) pathogenic causal alleles in known PcD genes. loss-of-function alleles dominate (73% frameshift, stop- gain, splice site), most (58%) being homozygous, even in non- consanguineous families. although 57% (88) of the total 155 diagnostic disease variants were novel, recurrent mutations and mutated genes were detected. These differed markedly between white european (52% of families carry DNAH5 or DNAH11 mutations), arab (42% of families carry CCDC39 or CCDC40 mutations) and south asian (single LRRC6 or CCDC103 mutations carried in 36% of families) patients, revealing a striking genetic stratification according to population of origin in PcD. genetics facilitated successful diagnosis of 81% of families with normal or inconclusive ultrastructure and 67% missing prior ultrastructure results. Conclusions This study shows the added value of high-throughput targeted ngs in expediting PcD diagnosis. Therefore, there is potential significant patient benefit in wider and/or earlier implementation of genetic screening. [ABSTRACT FROM AUTHOR]

Published
2020
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28. Clinical and genetic spectrum in 33 Egyptian families with suspected primary ciliary dyskinesia.

Author

Fassad, Mahmoud R., Shoman, Walaa I., Morsy, Heba, Patel, Mitali P., Radwan, Nesrine, Jenkins, Lucy, Cullup, Thomas, Fouda, Eman, Mitchison, Hannah M., and Fasseeh, Nader

Subjects
*GENETIC testing, *GENETIC disorder diagnosis, *GENETIC disorders, *NUCLEOTIDE sequencing, *CILIA & ciliary motion, DEVELOPING countries
Abstract

Primary ciliary dyskinesia (PCD) is a rare genetic disorder of motile cilia dysfunction generally inherited as an autosomal recessive disease. Genetic testing is increasingly considered an early step in the PCD diagnostic workflow. We used targeted panel next‐generation sequencing (NGS) for genetic screening of 33 Egyptian families with clinically highly suspected PCD. All variants prioritized were Sanger confirmed in the affected individuals and correctly segregated within the family. Targeted NGS yielded a high diagnostic output (70%) with biallelic mutations identified in known PCD genes. Mutations were identified in 13 genes overall, with CCDC40 and CCDC39 the most frequently mutated genes among Egyptian patients. Most identified mutations were predicted null effect variants (79%) and not reported before (85%). This study reveals that the genetic landscape of PCD among Egyptians is highly heterogeneous, indicating that a targeted NGS approach covering multiple genes will provide a superior diagnostic yield compared to Sanger sequencing for genetic diagnosis. The high diagnostic output achieved here highlights the potential of placing genetic testing early within the diagnostic workflow for PCD, in particular in developing countries where other diagnostic tests can be less available. [ABSTRACT FROM AUTHOR]

Published
2020
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29. Motile cilia structure and function in patients with mutations in the outer dynein arm heavy chain DNAH9

Author

Shoemark, Amelia, primary, Fassad, Mahmoud R, additional, Daudvohra, Farheen, additional, Burgoyne, Tom, additional, Hirst, Robert A, additional, Hayes, Joe, additional, Dixon, Mellisa, additional, Rogers, Andrew, additional, Loebinger, Micheal, additional, O'Callaghan, Christopher, additional, Hogg, Claire, additional, and Mitchison, Hannah, additional

Published
2018
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30. Risk factors for situs defects and congenital heart disease in primary ciliary dyskinesia

Author

Best, Sunayna, primary, Shoemark, Amelia, additional, Rubbo, Bruna, additional, Patel, Mitali P, additional, Fassad, Mahmoud R, additional, Dixon, Mellisa, additional, Rogers, Andrew V, additional, Hirst, Robert A, additional, Rutman, Andrew, additional, Ollosson, Sarah, additional, Jackson, Claire L, additional, Goggin, Patricia, additional, Thomas, Simon, additional, Pengelly, Reuben, additional, Cullup, Thomas, additional, Pissaridou, Eleni, additional, Hayward, Jane, additional, Onoufriadis, Alexandros, additional, O’Callaghan, Christopher, additional, Loebinger, Michael R, additional, Wilson, Robert, additional, Chung, Eddie MK, additional, Kenia, Priti, additional, Doughty, Victoria L, additional, Carvalho, Julene S, additional, Lucas, Jane S, additional, Mitchison, Hannah M, additional, and Hogg, Claire, additional

Published
2018
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31. C11orf70 Mutations Disrupting the Intraflagellar Transport-Dependent Assembly of Multiple Axonemal Dyneins Cause Primary Ciliary Dyskinesia

Author

Fassad, Mahmoud R., primary, Shoemark, Amelia, additional, le Borgne, Pierrick, additional, Koll, France, additional, Patel, Mitali, additional, Dixon, Mellisa, additional, Hayward, Jane, additional, Richardson, Charlotte, additional, Frost, Emily, additional, Jenkins, Lucy, additional, Cullup, Thomas, additional, Chung, Eddie M.K., additional, Lemullois, Michel, additional, Aubusson-Fleury, Anne, additional, Hogg, Claire, additional, Mitchell, David R., additional, Tassin, Anne-Marie, additional, and Mitchison, Hannah M., additional

Published
2018
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32. C11orf70 mutations causing primary ciliary dyskinesia disrupt a conserved step in the intraflagellar transport-dependent assembly of multiple axonemal dyneins

Author

Fassad, Mahmoud R., primary, Shoemark, Amelia, additional, Borgne, Pierrick le, additional, Koll, France, additional, Patel, Mitali, additional, Dixon, Mellisa, additional, Hayward, Jane, additional, Richardson, Charlotte, additional, Frost, Emily, additional, Jenkins, Lucy, additional, Cullup, Thomas, additional, Chung, Eddie MK, additional, Lemullois, Michel, additional, Aubusson-Fleury, Anne, additional, Hogg, Claire, additional, Mitchell, David R., additional, Tassin, Anne-Marie, additional, and Mitchison, Hannah M., additional

Published
2017
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33. A high prevalence CCDC103 p.His154Pro mutation causing primary ciliary dyskinesia is associated with normal diagnostic investigations

Author

Shoemark, Amelia, primary, Moya, Eduardo, additional, Hirst, Robert A, additional, Patel, Mitali P, additional, Robson, Evelyn, additional, Hayward, Jane, additional, Scully, Juliet, additional, Fassad, Mahmoud R, additional, Schmidts, Miriam, additional, Dixon, Mellisa, additional, Patel-King, Ramila S, additional, Rogers, Andrew, additional, Rutman, Andrew, additional, Jackson, Claire L, additional, Goggin, Patricia, additional, Ollosson, Sarah, additional, Carr, Siobhán, additional, Walker, Woolf, additional, Adler, Beryl, additional, Loebinger, Michael R, additional, Wilson, Robert, additional, Bush, Andrew, additional, Williams, Hywel, additional, Boustred, Christopher, additional, Jenkins, Lucy, additional, Sheridan, Eamonn, additional, Chung, Eddie M. K., additional, Watson, Christopher M., additional, Cullup, Thomas, additional, Lucas, Jane S, additional, Kenia, Priti, additional, O’Callaghan, Christopher, additional, King, Stephen M., additional, Hogg, Claire, additional, and Mitchison, Hannah M., additional

Published
2017
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34. High prevalence of CCDC103 p.His154Pro mutation causing primary ciliary dyskinesia disrupts protein oligomerisation and is associated with normal diagnostic investigations

Author

Shoemark, Amelia, primary, Moya, Eduardo, additional, Hirst, Robert A, additional, Patel, Mitali P, additional, Robson, Evelyn A, additional, Hayward, Jane, additional, Scully, Juliet, additional, Fassad, Mahmoud R, additional, Lamb, William, additional, Schmidts, Miriam, additional, Dixon, Mellisa, additional, Patel-King, Ramila S, additional, Rogers, Andrew V, additional, Rutman, Andrew, additional, Jackson, Claire L, additional, Goggin, Patricia, additional, Rubbo, Bruna, additional, Ollosson, Sarah, additional, Carr, Siobhán, additional, Walker, Woolf, additional, Adler, Beryl, additional, Loebinger, Michael R, additional, Wilson, Robert, additional, Bush, Andrew, additional, Williams, Hywel, additional, Boustred, Christopher, additional, Jenkins, Lucy, additional, Sheridan, Eamonn, additional, Chung, Eddie M K, additional, Watson, Christopher M, additional, Cullup, Thomas, additional, Lucas, Jane S, additional, Kenia, Priti, additional, O’Callaghan, Christopher, additional, King, Stephen M, additional, Hogg, Claire, additional, and Mitchison, Hannah M, additional

Published
2017
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35. Screening for the mitochondrial A1555G mutation among Egyptian patients with non-syndromic, sensorineural hearing loss

Author

Fassad, Mahmoud R, Desouky, Lubna M, Asal, Samir, and Abdalla, Ebtesam M

Subjects
otorhinolaryngologic diseases, Original Article
Abstract

Background & Aim: Hearing loss is the most frequent form of neurosensory deficit in humans. Although the majority of hereditary hearing loss is due to nuclear gene mutations, it has become clear the significant contribution of mitochondrial genes. The first mitochondrial mutation shown to cause non-syndromic hearing loss in humans was the A1555G mutation in the small ribosomal RNA gene (12S rRNA). It has been detected in hundreds of families of different ethnic backgrounds, making it one of the prevalent genetic causes of hearing loss currently identified. However, there are major differences between ethnic groups regarding the frequency of this mutation. Few studies have been made in Arab countries, especially in Egypt. Here we report the prevalence of the mitochondrial mutation A1555G among patients with non-syndromic hearing loss (NSHL) and in healthy individuals with normal hearing in the Egyptian population. Subjects & Methods: The study was conducted on 97 patients with SNHL and 300 unrelated healthy Egyptian individuals, with normal hearing, as normal control subjects. Polymerase chain reaction followed by restriction enzyme digestion was used to screen the DNA samples of all subjects for the A1555G mutation. Results: Participants included 97 cases with SNHL, 46 males and 51 females. Their ages ranged from 1 month to 65 years with the mean age 6.2 years (SD ± 8.2). Paternal consanguinity was reported in 46% (35/76) of the studied families. The A1555G mutation was found in one of the 97 patients (1.3%), while it has not been detected in the 300 control samples. Conclusion: Our findings indicate that, even in absence of exposure to aminoglycosides, the mitochondrial A1555G mutation is one of the potential causes of non-syndromic SNHL in the Egyptian population.

Published
2014

36. High prevalence of p.His154Pro mutation causing primary ciliary dyskinesia disrupts protein oligomerisation and is associated with normal diagnostic investigations.

Author

Shoemark, Amelia, Moya, Eduardo, Hirst, Robert A., Patel, Mitali P., Robson, Evelyn A., Hayward, Jane, Scully, Juliet, Fassad, Mahmoud R., Lamb, William, Schmidts, Miriam, Dixon, Mellisa, Patel-King, Ramila S., Rogers, Andrew V., Rutman, Andrew, Jackson, Claire L., Goggin, Patricia, Rubbo, Bruna, Ollosson, Sarah, Carr, Siobhán, and Walker, Woolf

Subjects
RARE diseases, DISEASE prevalence, GENETIC mutation, ETIOLOGY of diseases, CLINICAL trials, ASIANS, COMPARATIVE studies, LONGITUDINAL method, RESEARCH methodology, MEDICAL cooperation, NERVE tissue proteins, RESEARCH, EVALUATION research, RESPIRATORY organ abnormalities
Abstract

Rationale: Primary ciliary dyskinesia is a genetically heterogeneous inherited condition characterised by progressive lung disease arising from abnormal cilia function. Approximately half of patients have situs inversus. The estimated prevalence of primary ciliary dyskinesia in the UK South Asian population is 1:2265. Early, accurate diagnosis is key to implementing appropriate management but clinical diagnostic tests can be equivocal.Objectives: To determine the importance of genetic screening for primary ciliary dyskinesia in a UK South Asian population with a typical clinical phenotype, where standard testing is inconclusive.Methods: Next-generation sequencing was used to screen 86 South Asian patients who had a clinical history consistent with primary ciliary dyskinesia. The effect of a CCDC103 p.His154Pro missense variant compared with other dynein arm-associated gene mutations on diagnostic/phenotypic variability was tested. CCDC103 p.His154Pro variant pathogenicity was assessed by oligomerisation assay.Results: Sixteen of 86 (19%) patients carried a homozygous CCDC103 p.His154Pro mutation which was found to disrupt protein oligomerisation. Variable diagnostic test results were obtained including normal nasal nitric oxide levels, normal ciliary beat pattern and frequency and a spectrum of partial and normal dynein arm retention. Fifteen (94%) patients or their sibling(s) had situs inversus suggesting CCDC103 p.His154Pro patients without situs inversus are missed.Conclusions: The CCDC103 p.His154Pro mutation is more prevalent than previously thought in the South Asian community and causes primary ciliary dyskinesia that can be difficult to diagnose using pathology-based clinical tests. Genetic testing is critical when there is a strong clinical phenotype with inconclusive standard diagnostic tests. [ABSTRACT FROM AUTHOR]

Published
2018
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37. Risk factors for situs defects and congenital heart disease in primary ciliary dyskinesia.

Author

Best, Sunayna, Shoemark, Amelia, Rubbo, Bruna, Patel, Mitali P., Fassad, Mahmoud R., Dixon, Mellisa, Rogers, Andrew V., Hirst, Robert A., Rutman, Andrew, Ollosson, Sarah, Jackson, Claire L., Goggin, Patricia, Thomas, Simon, Pengelly, Reuben, Cullup, Thomas, Pissaridou, Eleni, Hayward, Jane, Onoufriadis, Alexandros, O'Callaghan, Christopher, and Loebinger, Michael R.

Subjects
CILIARY motility disorders, CONGENITAL heart disease, SITUS inversus, CONGENITAL disorders, HEART diseases, COMPARATIVE studies, CONSANGUINITY, DISEASE susceptibility, RESEARCH methodology, MEDICAL cooperation, GENETIC mutation, RESEARCH, RESEARCH funding, PHENOTYPES, EVALUATION research, DISEASE prevalence, RETROSPECTIVE studies, MULTIPLE human abnormalities, GENOTYPES
Abstract

Primary ciliary dyskinesia (PCD) is associated with abnormal organ positioning (situs) and congenital heart disease (CHD). This study investigated genotype-phenotype associations in PCD to facilitate risk predictions for cardiac and laterality defects. This retrospective cohort study of 389 UK patients with PCD found 51% had abnormal situs and 25% had CHD and/or laterality defects other than situs inversus totalis. Patients with biallelic mutations in a subset of nine PCD genes had normal situs. Patients with consanguineous parents had higher odds of situs abnormalities than patients with non-consanguineous parents. Patients with abnormal situs had higher odds of CHD and/or laterality defects. [ABSTRACT FROM AUTHOR]

Published
2019
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38. High prevalence of CCDC103p.His154Pro mutation causing primary ciliary dyskinesia disrupts protein oligomerisation and is associated with normal diagnostic investigations

Author

Shoemark, Amelia, Moya, Eduardo, Hirst, Robert A, Patel, Mitali P, Robson, Evelyn A, Hayward, Jane, Scully, Juliet, Fassad, Mahmoud R, Lamb, William, Schmidts, Miriam, Dixon, Mellisa, Patel-King, Ramila S, Rogers, Andrew V, Rutman, Andrew, Jackson, Claire L, Goggin, Patricia, Rubbo, Bruna, Ollosson, Sarah, Carr, Siobhán, Walker, Woolf, Adler, Beryl, Loebinger, Michael R, Wilson, Robert, Bush, Andrew, Williams, Hywel, Boustred, Christopher, Jenkins, Lucy, Sheridan, Eamonn, Chung, Eddie M K, Watson, Christopher M, Cullup, Thomas, Lucas, Jane S, Kenia, Priti, O’Callaghan, Christopher, King, Stephen M, Hogg, Claire, and Mitchison, Hannah M

Abstract

RationalePrimary ciliary dyskinesia is a genetically heterogeneous inherited condition characterised by progressive lung disease arising from abnormal cilia function. Approximately half of patients have situs inversus. The estimated prevalence of primary ciliary dyskinesia in the UK South Asian population is 1:2265. Early, accurate diagnosis is key to implementing appropriate management but clinical diagnostic tests can be equivocal.ObjectivesTo determine the importance of genetic screening for primary ciliary dyskinesia in a UK South Asian population with a typical clinical phenotype, where standard testing is inconclusive.MethodsNext-generation sequencing was used to screen 86 South Asian patients who had a clinical history consistent with primary ciliary dyskinesia. The effect of a CCDC103p.His154Pro missense variant compared with other dynein arm-associated gene mutations on diagnostic/phenotypic variability was tested. CCDC103 p.His154Pro variant pathogenicity was assessed by oligomerisation assay.ResultsSixteen of 86 (19%) patients carried a homozygous CCDC103p.His154Pro mutation which was found to disrupt protein oligomerisation. Variable diagnostic test results were obtained including normal nasal nitric oxide levels, normal ciliary beat pattern and frequency and a spectrum of partial and normal dynein arm retention. Fifteen (94%) patients or their sibling(s) had situs inversus suggesting CCDC103p.His154Pro patients without situs inversus are missed.ConclusionsThe CCDC103p.His154Pro mutation is more prevalent than previously thought in the South Asian community and causes primary ciliary dyskinesia that can be difficult to diagnose using pathology-based clinical tests. Genetic testing is critical when there is a strong clinical phenotype with inconclusive standard diagnostic tests.

Published
2018
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39. X-linked primary ciliary dyskinesia due to mutations in the cytoplasmic axonemal dynein assembly factor PIH1D3

Author

Olcese, Chiara, Patel, Mitali P., Shoemark, Amelia, Kiviluoto, Santeri, Legendre, Marie, Williams, Hywel J., Vaughan, Cara K., Hayward, Jane, Goldenberg, Alice, Emes, Richard D., Munye, Mustafa M., Dyer, Laura, Cahill, Thomas, Bevillard, Jeremy, Gehrig, Corinne, Guipponi, Michel, Chantot, Sandra, Duquesnoy, Philippe, Thomas, Lucie, Jeanson, Ludovic, Copin, Bruno, Tamalet, Aline, Thauvin-Robinet, Christel, Garin, Antoine, Pin, Isabelle, Vera, Gabriella, Aurora, Paul, Fassad, Mahmoud R., Jenkins, Lucy, Boustred, Christopher, Cullup, Thomas, Dixon, Mellisa, Onoufriadis, Alexandros, Bush, Andrew, Chung, Eddie M. K., Antonarakis, Stylianos E., Loebinger, Michael R., Wilson, Robert, Armengot, Miguel, Escudier, Estelle, Hogg, Claire, Al-Turki, Saeed, Anderson, Carl, Antony, Dinu, Beales, Philip L., Bentham, Jamie, Bhattacharya, Shoumo, Carss, Keren, Chatterjee, Krishna, Cirak, Sebahattin, Cosgrove, Catherine, Allan, Daly, Durbin, Richard, Fitzpatrick, David, Floyd, Jamie, Foley, A. Reghan, Franklin, Chris, Futema, Marta, Humphries, Steve E., Hurles, Matt, McCarthy, Shane, Muddyman, Dawn, Muntoni, Francesco, Parker, Victoria, Payne, Felicity, Plagnol, Vincent, Raymond, Lucy, Savage, David B., Scambler, Peter J., Schmidts, Miriam, Semple, Robert, Serra, Eva, Stalker, Jim, van Kogelenberg, Margriet, Vijayarangakannan, Parthiban, Walter, Klaudia, Amselem, Serge, Sun, Zhaoxia, Bartoloni, Lucia, Blouin, Jean-Louis, and Mitchison, Hannah M.

Abstract

By moving essential body fluids and molecules, motile cilia and flagella govern respiratory mucociliary clearance, laterality determination and the transport of gametes and cerebrospinal fluid. Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder frequently caused by non-assembly of dynein arm motors into cilia and flagella axonemes. Before their import into cilia and flagella, multi-subunit axonemal dynein arms are thought to be stabilized and pre-assembled in the cytoplasm through a DNAAF2–DNAAF4–HSP90 complex akin to the HSP90 co-chaperone R2TP complex. Here, we demonstrate that large genomic deletions as well as point mutations involving PIH1D3 are responsible for an X-linked form of PCD causing disruption of early axonemal dynein assembly. We propose that PIH1D3, a protein that emerges as a new player of the cytoplasmic pre-assembly pathway, is part of a complementary conserved R2TP-like HSP90 co-chaperone complex, the loss of which affects assembly of a subset of inner arm dyneins.

40. Screening for the mitochondrial A1555G mutation among Egyptian patients with non-syndromic, sensorineural hearing loss.

Author

Fassad MR, Desouky LM, Asal S, and Abdalla EM

Abstract

Background & Aim: Hearing loss is the most frequent form of neurosensory deficit in humans. Although the majority of hereditary hearing loss is due to nuclear gene mutations, it has become clear the significant contribution of mitochondrial genes. The first mitochondrial mutation shown to cause non-syndromic hearing loss in humans was the A1555G mutation in the small ribosomal RNA gene (12S rRNA). It has been detected in hundreds of families of different ethnic backgrounds, making it one of the prevalent genetic causes of hearing loss currently identified. However, there are major differences between ethnic groups regarding the frequency of this mutation. Few studies have been made in Arab countries, especially in Egypt. Here we report the prevalence of the mitochondrial mutation A1555G among patients with non-syndromic hearing loss (NSHL) and in healthy individuals with normal hearing in the Egyptian population., Subjects & Methods: The study was conducted on 97 patients with SNHL and 300 unrelated healthy Egyptian individuals, with normal hearing, as normal control subjects. Polymerase chain reaction followed by restriction enzyme digestion was used to screen the DNA samples of all subjects for the A1555G mutation., Results: Participants included 97 cases with SNHL, 46 males and 51 females. Their ages ranged from 1 month to 65 years with the mean age 6.2 years (SD ± 8.2). Paternal consanguinity was reported in 46% (35/76) of the studied families. The A1555G mutation was found in one of the 97 patients (1.3%), while it has not been detected in the 300 control samples., Conclusion: Our findings indicate that, even in absence of exposure to aminoglycosides, the mitochondrial A1555G mutation is one of the potential causes of non-syndromic SNHL in the Egyptian population.

Published
2014

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