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

• DOI: 10.1126/science.adf5489
• Publication Date: 2024-04-25T18:00:04Z
• Authors: Daniel O. Dodd; Sabrina Mechaussier; Patricia L. Yeyati; Fraser McPhie; Jacob R. Anderson; Chen Jing Khoo; Amelia Shoemark; Deepesh K. Gupta; Thomas Attard; Maimoona A. Zariwala; Marie Legendre; Diana Bracht; Julia Wallmeier; Miao Gui; Mahmoud R. Fassad; David A. Parry; Peter A. Tennant; Alison Meynert; Gabrielle Wheway; Lucas Fares-Taie; Holly A. Black; Rana Mitri-Frangieh; Catherine Faucon; Josseline Kaplan; Mitali Patel; Lisa McKie; Roly Megaw; Christos Gatsogia...; Mai A. Mohamed; Stuart Aitken; Philippe Gautier; Finn R. Reinholt; Robert A. Hirst; Chris O’Callaghan; Ketil Heimdal; Mathieu Bottier; Estelle Escudier; Suzanne Crowley; Maria Descartes; Ethylin W. Jabs; Priti Kenia; Jeanne Amiel; Giacomo Maria Bacci; Claudia Calogero; Viviana Palazzo; Lucia Tiberi; Ulrike Blümlein; Andrew Rogers; Jennifer A. Wambach; Daniel J. Wegner; Anne B. Fulton; Margaret Kenna; Margaret Rosenfeld; Ingrid A. Holm; Alan Quigley; Emma A. Hall; Laura C. Murphy; Diane M. Cassidy; Alex von Kriegsheim; ; ; ; Jean-François Papon; Laurent Pasquier; Marlène S. Murris; James D Chalmers; Claire Hogg; Kenneth A. Macleod; Don S. Urquhart; Stefan Unger; Timothy J. Aitman; Serge Amselem; Margaret W. Leigh; Michael R. Knowles; Heymut Omran; Hannah M. Mitchison; Alan Brown; Joseph A. Marsh; Julie P. I. Welburn; Shih-Chieh Ti; Amjad Horani; Jean-Michel Rozet; Isabelle Perrault; Pleasantine Mill
• Keywords: Ciliopathies; Centriole; Ciliopathy; Ciliogenesis; Basal body; Intraflagellar Transport; Organelle

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