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

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.

SUBMITTER: Dodd DO 

PROVIDER: S-EPMC7616230 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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

Dodd Daniel O DO   Mechaussier Sabrina S   Yeyati Patricia L PL   McPhie Fraser F   Anderson Jacob R JR   Khoo Chen Jing CJ   Shoemark Amelia A   Gupta Deepesh K DK   Attard Thomas T   Zariwala Maimoona A MA   Legendre Marie M   Bracht Diana D   Wallmeier Julia J   Gui Miao M   Fassad Mahmoud R MR   Parry David A DA   Tennant Peter A PA   Meynert Alison A   Wheway Gabrielle G   Fares-Taie Lucas L   Black Holly A HA   Mitri-Frangieh Rana R   Faucon Catherine C   Kaplan Josseline J   Patel Mitali M   McKie Lisa L   Megaw Roly R   Gatsogiannis Christos C   Mohamed Mai A MA   Aitken Stuart S   Gautier Philippe P   Reinholt Finn R FR   Hirst Robert A RA   O'Callaghan Chris C   Heimdal Ketil K   Bottier Mathieu M   Escudier Estelle E   Crowley Suzanne S   Descartes Maria M   Jabs Ethylin W EW   Kenia Priti P   Amiel Jeanne J   Bacci Giacomo Maria GM   Calogero Claudia C   Palazzo Viviana V   Tiberi Lucia L   Blümlein Ulrike U   Rogers Andrew A   Wambach Jennifer A JA   Wegner Daniel J DJ   Fulton Anne B AB   Kenna Margaret M   Rosenfeld Margaret M   Holm Ingrid A IA   Quigley Alan A   Hall Emma A EA   Murphy Laura C LC   Cassidy Diane M DM   von Kriegsheim Alex A   Papon Jean-François JF   Pasquier Laurent L   Murris Marlène S MS   Chalmers James D JD   Hogg Claire C   Macleod Kenneth A KA   Urquhart Don S DS   Unger Stefan S   Aitman Timothy J TJ   Amselem Serge S   Leigh Margaret W MW   Knowles Michael R MR   Omran Heymut H   Mitchison Hannah M HM   Brown Alan A   Marsh Joseph A JA   Welburn Julie P I JPI   Ti Shih-Chieh SC   Horani Amjad A   Rozet Jean-Michel JM   Perrault Isabelle I   Mill Pleasantine P  

Science (New York, N.Y.) 20240426 6694

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 <i>TUBB4B</i> isotype that specifically perturbed centriole and cilium biogenesis. Distinct <i>TUBB4B</i> vari  ...[more]

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