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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; 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; Bacci, Giacomo Maria; Calogero, Claudia; Palazzo, Viviana; Tiberi, Lucia; Blümlein, Ulrike; Rogers, Andrew; Wambach, Jennifer A; Wegner, Daniel J; Fulton, Anne B; Kenna, Margaret; Rosenfeld, Margaret; Holm, Ingrid A; Quigley, Alan; Hall, Emma A; Murphy, Laura C; Cassidy, Diane M; von Kriegsheim, Alex; Papon, Jean-François; Pasquier, Laurent; Murris, Marlène S; Chalmers, James D; Hogg, Claire; Macleod, Kenneth A; Urquhart, Don S; Unger, Stefan; Aitman, Timothy J; Amselem, Serge; Leigh, Margaret W; Knowles, Michael R; Omran, Heymut; Mitchison, Hannah M; Brown, Alan; Marsh, Joseph A; Welburn, Julie P I; Ti, Shih-Chieh; Horani, Amjad; Rozet, Jean-Michel; Perrault, Isabelle; Mill, Pleasantine
Science (American Association for the Advancement of Science), 2024-Apr-26, 2024-04-26, 20240426, Letnik: 384, Številka: 6694Journal Article
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 isotype that specifically perturbed centriole and cilium biogenesis. Distinct 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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