article · Science
Microtubules are essential structural components of cells built from tubulin proteins, which exist in multiple forms known as isotypes. Examining twelve human patients with primary ciliary dyskinesia alongside mouse models reveals that genetic variations in the tubulin isotype TUBB4B directly impair the formation of centrioles and cilia. These variants act in a dominant-negative manner, meaning the altered protein actively interferes with normal microtubule dynamics and assembly. Detailed structure-function investigations demonstrate that different mutations disrupt distinct interfaces of the tubulin molecule. Consequently, these molecular alterations allow the division of affected individuals into three separate disease classes. The findings demonstrate that individual tubulin isotypes perform unique, nonredundant roles within specific cellular structures, establishing a direct biological connection between tubulin-related disorders and ciliopathies.
Cilia are hair-like cellular structures vital for organ development, fluid movement, and sensory perception. When they fail, severe inherited conditions called ciliopathies occur. Demonstrating that a specific tubulin building block is necessary for cilia formation explains how subtle genetic variations cause distinct human disorders, improving our understanding of cellular architecture and inherited disease mechanisms.
This early-stage research provides a biological basis for diagnostic developers to design targeted genetic screening tools and biomarker panels. Clinical geneticists could use the identified TUBB4B variant interfaces to stratify ciliopathy patients into three distinct disease classes. However, because the findings remain at the stage of patient cohort analysis and mouse models, translation into clinical diagnostic assays or therapies will require further development and validation.
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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> 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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DOI: 10.1126/science.adf5489
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