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

TitleCiliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules
Authors
Issue Date26-Apr-2024
PublisherAmerican Association for the Advancement of Science
Citation
Science, 2024, v. 384, n. 6694 How to Cite?
Abstract

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.


Persistent Identifierhttp://hdl.handle.net/10722/347629
ISSN
2023 Impact Factor: 44.7
2023 SCImago Journal Rankings: 11.902

 

DC FieldValueLanguage
dc.contributor.authorDodd, Daniel O.-
dc.contributor.authorMechaussier, Sabrina-
dc.contributor.authorYeyati, Patricia L.-
dc.contributor.authorMcPhie, Fraser-
dc.contributor.authorAnderson, Jacob R.-
dc.contributor.authorKhoo, Chen Jing-
dc.contributor.authorShoemark, Amelia-
dc.contributor.authorGupta, Deepesh K.-
dc.contributor.authorAttard, Thomas-
dc.contributor.authorZariwala, Maimoona A.-
dc.contributor.authorLegendre, Marie-
dc.contributor.authorBracht, Diana-
dc.contributor.authorWallmeier, Julia-
dc.contributor.authorGui, Miao-
dc.contributor.authorFassad, Mahmoud R.-
dc.contributor.authorParry, David A.-
dc.contributor.authorTennant, Peter A.-
dc.contributor.authorMeynert, Alison-
dc.contributor.authorWheway, Gabrielle-
dc.contributor.authorFares-Taie, Lucas-
dc.contributor.authorBlack, Holly A.-
dc.contributor.authorMitri-Frangieh, Rana-
dc.contributor.authorFaucon, Catherine-
dc.contributor.authorKaplan, Josseline-
dc.contributor.authorPatel, Mitali-
dc.contributor.authorMcKie, Lisa-
dc.contributor.authorMegaw, Roly-
dc.contributor.authorGatsogiannis, Christos-
dc.contributor.authorMohamed, Mai A.-
dc.contributor.authorAitken, Stuart-
dc.contributor.authorGautier, Philippe-
dc.contributor.authorReinholt, Finn R.-
dc.contributor.authorHirst, Robert A.-
dc.contributor.authorO’Callaghan, Chris-
dc.contributor.authorHeimdal, Ketil-
dc.contributor.authorBottier, Mathieu-
dc.contributor.authorEscudier, Estelle-
dc.contributor.authorCrowley, Suzanne-
dc.contributor.authorDescartes, Maria-
dc.contributor.authorJabs, Ethylin W.-
dc.contributor.authorKenia, Priti-
dc.contributor.authorAmiel, Jeanne-
dc.contributor.authorBacci, Giacomo Maria-
dc.contributor.authorCalogero, Claudia-
dc.contributor.authorPalazzo, Viviana-
dc.contributor.authorTiberi, Lucia-
dc.contributor.authorBlümlein, Ulrike-
dc.contributor.authorRogers, Andrew-
dc.contributor.authorWambach, Jennifer A.-
dc.contributor.authorWegner, Daniel J.-
dc.contributor.authorFulton, Anne B.-
dc.contributor.authorKenna, Margaret-
dc.contributor.authorRosenfeld, Margaret-
dc.contributor.authorHolm, Ingrid A.-
dc.contributor.authorQuigley, Alan-
dc.contributor.authorHall, Emma A.-
dc.contributor.authorMurphy, Laura C.-
dc.contributor.authorCassidy, Diane M.-
dc.contributor.authorvon Kriegsheim, Alex-
dc.contributor.authorPartnership, Scottish Genomes-
dc.contributor.authorNetwork, Undiagnosed Diseases-
dc.contributor.authorPapon, Jean François-
dc.contributor.authorPasquier, Laurent-
dc.contributor.authorMurris, Marlène S.-
dc.contributor.authorChalmers, James D.-
dc.contributor.authorHogg, Claire-
dc.contributor.authorMacleod, Kenneth A.-
dc.contributor.authorUrquhart, Don S.-
dc.contributor.authorUnger, Stefan-
dc.contributor.authorAitman, Timothy J.-
dc.contributor.authorAmselem, Serge-
dc.contributor.authorLeigh, Margaret W.-
dc.contributor.authorKnowles, Michael R.-
dc.contributor.authorOmran, Heymut-
dc.contributor.authorMitchison, Hannah M.-
dc.contributor.authorBrown, Alan-
dc.contributor.authorMarsh, Joseph A.-
dc.contributor.authorWelburn, Julie P.I.-
dc.contributor.authorTi, Shih Chieh-
dc.contributor.authorHorani, Amjad-
dc.contributor.authorRozet, Jean Michel-
dc.contributor.authorPerrault, Isabelle-
dc.contributor.authorMill, Pleasantine-
dc.date.accessioned2024-09-26T00:30:14Z-
dc.date.available2024-09-26T00:30:14Z-
dc.date.issued2024-04-26-
dc.identifier.citationScience, 2024, v. 384, n. 6694-
dc.identifier.issn0036-8075-
dc.identifier.urihttp://hdl.handle.net/10722/347629-
dc.description.abstract<p>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.</p>-
dc.languageeng-
dc.publisherAmerican Association for the Advancement of Science-
dc.relation.ispartofScience-
dc.titleCiliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules-
dc.typeArticle-
dc.identifier.doi10.1126/science.adf5489-
dc.identifier.pmid38662826-
dc.identifier.scopuseid_2-s2.0-85191476815-
dc.identifier.volume384-
dc.identifier.issue6694-
dc.identifier.eissn1095-9203-
dc.identifier.issnl0036-8075-

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