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

Dodd DO; Mechaussier S; Yeyati PL; McPhie F; Anderson JR; Khoo CJ; Shoemark A; Gupta DK; Attard T; Zariwala MA; Legendre M; Bracht D; Wallmeier J; Gui M; Fassad MR; Parry DA; Tennant PA; Meynert A; Wheway G; Fares-Taie L; Black HA; Mitri-Frangieh R; Faucon C; Kaplan J; Patel M; McKie L; Megaw R; Gatsogiannis C; Mohamed MA; Aitken S; Gautier P; Reinholt FR; Hirst RA; O'Callaghan C; Heimdal K; Bottier M; Escudier E; Crowley S; Descartes M; Jabs EW; Kenia P; Amiel J; Bacci GM; Calogero C; Palazzo V; Tiberi L; Blümlein U; Rogers A; Wambach JA; Wegner DJ; Fulton AB; Kenna M; Rosenfeld M; Holm IA; Quigley A; Hall EA; Murphy LC; Cassidy DM; von Kriegsheim A; Scottish Genomes Partnership16; Genomics England Research Consortium45; Undiagnosed Diseases Network46; Papon JF; Pasquier L; Murris MS; Chalmers JD; Hogg C; Macleod KA; Urquhart DS; Unger S; Aitman TJ; Amselem S; Leigh MW; Knowles MR; Omran H; Mitchison HM; Brown A; Marsh JA; Welburn JPI; Ti SC; Horani A; Rozet JM; Perrault I; Mill P

Zusammenfassung

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.