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

• Published in: Science (American Association for the Advancement of Science) Vol. 384; no. 6694; p. eadf5489
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 26.04.2024
• Subjects: Age; Animals; Auditory defects; Axoneme - metabolism; Basal bodies; Biology; Biosynthesis; Blindness; Bones; Cellular structure; Centrioles; Centrioles - metabolism; Cilia; Cilia - metabolism; Ciliary Motility Disorders - genetics; Ciliary Motility Disorders - metabolism; Cytology; Cytoplasmic organelles; Disease; Electron microscopy; Female; Fluid flow; Genes; Genetic disorders; Genetics; Genomes; Hearing; Hearing loss; Humans; Immunofluorescence; Isotypes; Lung diseases; Male; Mice; Mice, Knockout; Microtubules; Mutation; Next-generation sequencing; Organelles; Patients; Phenotypes; Poisons; Polymers; Primary ciliary dyskinesia; Protein Isoforms - genetics; Protein Isoforms - metabolism; Proteins; Proteomics; Questions; Rare diseases; Respiratory function; Sequencing; Structural analysis; Structural Analysis (Linguistics); Structural Analysis (Science); Tissue; Tubulin; Tubulin - genetics; Tubulin - metabolism
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.adf5489

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.