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

Male Mice, Knockout 570 0303 health sciences Axoneme 610 Article Mice 03 medical and health sciences name=General Tubulin /dk/atira/pure/subjectarea/asjc/1000 Mutation Animals Humans Protein Isoforms Female Cilia Centrioles Ciliary Motility Disorders
DOI: 10.1126/science.adf5489 Publication Date: 2024-04-25T18:00:04Z
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.
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