Article Dans Une Revue (Data Paper) Science Année : 2024

Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules

Daniel O Dodd (1) , Sabrina Mechaussier (2) , Patricia L Yeyati (1) , Fraser Mcphie (1) , Jacob R Anderson (3) , Chen Jing Khoo (4) , Amelia Shoemark (5, 6) , Deepesh K Gupta (7) , Thomas Attard (1) , Maimoona A Zariwala (8) , Marie Legendre (9, 10) , Diana Bracht (11) , Julia Wallmeier (11) , Miao Gui (3) , Mahmoud R Fassad (12, 13) , David A Parry (1) , Peter A Tennant (1) , Alison Meynert (1) , Gabrielle Wheway (14) , Lucas Fares-Taie (2) , Holly A Black (1, 15) , Rana Mitri-Frangieh (16, 17) , Catherine Faucon (16) , Josseline Kaplan (2) , Mitali Patel (12) , Lisa Mckie (1) , Roly Megaw (1) , Christos Gatsogiannis (18) , Mai A Mohamed (12, 19) , Stuart Aitken (1) , Philippe Gautier (1) , Finn R Reinholt (20) , Robert A Hirst (21) , Chris O'Callaghan (21) , Ketil Heimdal (20) , Mathieu Bottier (5) , Estelle Escudier (9, 16) , Suzanne Crowley (20) , Maria Descartes (22) , Ethylin Jabs (23, 24) , Priti Kenia (25) , Jeanne Amiel (26, 2) , Giacomo Maria Bacci (27) , Claudia Calogero (27) , Viviana Palazzo (27) , Lucia Tiberi (27) , Ulrike Blümlein (28) , Andrew Rogers (6) , Jennifer A Wambach (7) , Daniel J Wegner (7) , Anne B Fulton (29) , Margaret Kenna (29) , Margaret Rosenfeld (30, 31) , Ingrid A Holm (29, 3) , Alan Quigley (32) , Emma A Hall (1) , Laura C Murphy (1) , Diane M Cassidy (5) , Alex von Kriegsheim (1) , Jean-François Papon (9) , Laurent Pasquier (33) , Marlène S Murris (34) , James D Chalmers (5) , Claire Hogg (6) , Kenneth A Macleod (32) , Don S Urquhart (32, 1) , Stefan Unger (32, 1) , Timothy J Aitman (1) , Serge Amselem (9, 10) , Margaret W Leigh (35) , Michael R Knowles (35) , Heymut Omran (11) , Hannah M Mitchison (12) , Alan Brown (3) , Joseph A Marsh (1) , Julie P I Welburn (1) , Shih-Chieh Ti (4) , Amjad Horani (7) , Jean-Michel Rozet (2) , Isabelle Perrault (2) , Pleasantine Mill (1)
1 Edin. - University of Edinburgh
2 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
3 HMS - Harvard Medical School [Boston]
4 HKU - The University of Hong Kong
5 University of Dundee
6 Royal Brompton Hospital
7 Washington University School of Medicine [Saint Louis, MO]
8 UNC - University of North Carolina [Chapel Hill]
9 U933 - Maladies génétiques d'expression pédiatrique
10 CHU Trousseau [APHP]
11 UKM - University Hospital Münster - Universitaetsklinikum Muenster [Germany]
12 UCL - University College of London [London]
13 Alexandria University [Alexandrie]
14 University of Southampton
15 Western General Hospital [Edinburgh, UK]
16 CHIC - Centre Hospitalier Intercommunal de Créteil
17 IMRB - Institut Mondor de Recherche Biomédicale
18 IM2P - Institute of Medical Physics and Biophysics [Münster, Germany]
19 Zagazig University
20 Oslo University Hospital [Oslo]
21 University of Leicester
22 UAB - University of Alabama at Birmingham [ Birmingham]
23 MSSM - Icahn School of Medicine at Mount Sinai [New York]
24 Mayo Clinic [Rochester]
25 Birmingham Women's and Children's NHS Foundation Trust
26 Hôpital Necker - Enfants Malades [AP-HP]
27 AOU Meyer - Azienda Ospedaliero Universitaria Meyer [Firenze] = Meyer Children's University Hospital [Florence]
28 MUL - Medizinische Universität Lausitz - Carl Thiem [Cottbus, Germany]
29 Boston Children's Hospital
30 University of Washington [Seattle]
31 Seattle Children's Research Institute [Seattle, WA, USA]
32 RHCYP - Royal Hospital for Children and Young People [Edinburgh, UK]
33 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Pontchaillou]
34 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
35 UNC - University of North Carolina at Chapel Hill [NC, USA]
Daniel O Dodd
Sabrina Mechaussier
Patricia L Yeyati
Fraser Mcphie
Jacob R Anderson
Chen Jing Khoo
Peter A Tennant
Alison Meynert
Gabrielle Wheway
Mitali Patel
Lisa Mckie
Roly Megaw
Stuart Aitken
Philippe Gautier
Ketil Heimdal
Mathieu Bottier
Suzanne Crowley
Anne B Fulton
Margaret Kenna
Emma A Hall
Laura C Murphy
Diane M Cassidy
Alex von Kriegsheim
James D Chalmers
Claire Hogg
Timothy J Aitman
Alan Brown
Joseph A Marsh
Shih-Chieh Ti
Pleasantine Mill

Résumé

Tubulin, one of the most abundant cytoskeletal building blocks, has numerous isotypes in metazoans encoded by different conserved genes. Whether these distinct isotypes form cell type– and context-specific microtubule structures is poorly understood. Based on a cohort of 12 patients with primary ciliary dyskinesia as well as mouse mutants, we identified and characterized variants in the TUBB4B isotype that specifically perturbed centriole and cilium biogenesis. Distinct TUBB4B variants differentially affected microtubule dynamics and cilia formation in a dominant-negative manner. Structure-function studies revealed that different TUBB4B variants disrupted distinct tubulin interfaces, thereby enabling stratification of patients into three classes of ciliopathic diseases. These findings show that specific tubulin isotypes have distinct and nonredundant subcellular functions and establish a link between tubulinopathies and ciliopathies.
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Dates et versions

inserm-04804407 , version 1 (26-11-2024)

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Daniel O Dodd, Sabrina Mechaussier, Patricia L Yeyati, Fraser Mcphie, Jacob R Anderson, et al.. Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules. Science, 2024, 384 (6694), pp.eadf5489. ⟨10.1126/science.adf5489⟩. ⟨inserm-04804407⟩
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