This article explores the role of the *TUBB4B* gene in ciliopathies, particularly in primary ciliary dyskinesia (PCD). The study identifies mutations in *TUBB4B* that disrupt centriole and cilium biogenesis, leading to distinct ciliopathic diseases. The *TUBB4B* isotype is essential for the formation of axonemal microtubules in motile cilia, and different mutations in this gene result in varying clinical presentations, including PCD-only, sensory ciliopathy (SND-only), and syndromic ciliopathy (PCD+SND). The study demonstrates that *TUBB4B* variants act in a dominant-negative manner, affecting microtubule dynamics and cilia formation. Structural and functional analyses show that different *TUBB4B* variants disrupt distinct tubulin interfaces, leading to different disease phenotypes. Mouse models and patient-derived cells confirm that *TUBB4B* is critical for motile cilia assembly in specific tissues. The study also reveals that *TUBB4B* is localized to centrioles and cilia, and its mutations have distinct effects on tubulin heterodimer assembly and microtubule dynamics. The findings highlight the importance of specific tubulin isotypes in ciliary function and establish a link between tubulinopathies and ciliopathies. The study provides insights into the molecular mechanisms underlying ciliopathies and underscores the role of *TUBB4B* in maintaining the structural integrity of cilia and centrioles.This article explores the role of the *TUBB4B* gene in ciliopathies, particularly in primary ciliary dyskinesia (PCD). The study identifies mutations in *TUBB4B* that disrupt centriole and cilium biogenesis, leading to distinct ciliopathic diseases. The *TUBB4B* isotype is essential for the formation of axonemal microtubules in motile cilia, and different mutations in this gene result in varying clinical presentations, including PCD-only, sensory ciliopathy (SND-only), and syndromic ciliopathy (PCD+SND). The study demonstrates that *TUBB4B* variants act in a dominant-negative manner, affecting microtubule dynamics and cilia formation. Structural and functional analyses show that different *TUBB4B* variants disrupt distinct tubulin interfaces, leading to different disease phenotypes. Mouse models and patient-derived cells confirm that *TUBB4B* is critical for motile cilia assembly in specific tissues. The study also reveals that *TUBB4B* is localized to centrioles and cilia, and its mutations have distinct effects on tubulin heterodimer assembly and microtubule dynamics. The findings highlight the importance of specific tubulin isotypes in ciliary function and establish a link between tubulinopathies and ciliopathies. The study provides insights into the molecular mechanisms underlying ciliopathies and underscores the role of *TUBB4B* in maintaining the structural integrity of cilia and centrioles.