Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules.
Daniel O DoddSabrina MechaussierPatricia L YeyatiFraser McPhieJacob R AndersonChen Jing KhooAmelia ShoemarkDeepesh Kumar GuptaThomas AttardMaimoona A ZariwalaMarie LegendreDiana BrachtJulia WallmeierMiao GuiMahmoud R FassadDavid A ParryPeter A TennantAlison M MeynertGabrielle WhewayLucas Fares-TaieHolly A BlackRana Mitri-FrangiehCatherine FauconJosseline KaplanMitali P PatelLisa McKieRoly MegawChristos GatsogiannisMai A MohamedStuart AitkenPhilippe GautierFinn R ReinholtRobert A HirstChris O'CallaghanKetil HeimdalMathieu BottierEstelle EscudierSuzanne CrowleyMaria DescartesEthylin Wang JabsPriti KeniaJeanne AmielGiacomo Maria BacciClaudia CalogeroViviana PalazzoLucia TiberiUlrike BlümleinAndrew RogersJennifer A WambachDaniel J WegnerAnne B FultonMargaret A KennaMargaret RosenfeldIngrid A HolmAlan QuigleyEmma A HallLaura C MurphyDiane M CassidyAlexander von Kriegsheimnull nullnull nullnull nullJean-François PaponLaurent PasquierMarlène S MurrisJames D ChalmersClaire HoggKenneth A MacLeodDonald S UrquhartStefan A UngerTimothy J AitmanSerge AmselemMargaret W LeighMichael R KnowlesHeymut OmranHannah M MitchisonAlan BrownJoseph A MarshJulie P I WelburnShih-Chieh TiAmjad HoraniJean-Michel RozetIsabelle PerraultPleasantine MillPublished in: Science (New York, N.Y.) (2024)
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.