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
AUTHORS (84)
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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CITATIONS (15)
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