A tale of tubulins: how different tubulin isotypes are essential to centriole and cilia biogenesis

We are thrilled to share our latest team science pre-print now online! This is about tubulin, one of the most abundant molecules in ou bodies. It a tale about rare disease genetics, tubulin code and how isotypes can have organelle-specific functions. Specifically, everyone’s favorite centrioles and cilia! A tale about the power of patient-led functional genomics- variants to unpick fundamental biology… Check the pre-print

Prepare to be swept away... https://www.medrxiv.org/content/10.1101/2022.10.19.22280748v1

Humans have multiple #tubulin isotypes- different genes encoding highly similar proteins. The question remains is it just down to expression- is all tubulin equal? Biophysical properties, such as dynamics, of microtubules they make up could come down to PTMs? Human disease genetics tells us otherwise…

We start with a cohort of 11 patients with the motile ciliopathy primary ciliary dyskinesia (PCD). Structure/function defects of motile #cilia which line our airways, brain & reproductive tracts lead to chronic airway disease, bronchiectasis, #hydrocephaly & infertility

50+ causal genes identified to date, PCD is mostly recessive, meaning 2 defective copies of the same gene are found in a patient. Using next gen sequencing, we identified de novo, meaning not inherited from either parent, variants in beta-tubulin TUBB4B.

All patients have striking cellular phenotypes in airway epithelial cells. Few short cilia with disorganized microtubule-based axonemes, disrupted MT doublets and centriole MT triplets. The patients have PCD because they cannot build centrioles and axonemes, hence have no effective mucociliary clearance.

To address if TUBB4B is essential for development, we knocked out TUBB4B in mice. Tubb4b KOs died perinatally with similar cellular & physiological defects to our PCD patients. TUBB4B is essential to build cilia & centrioles.

It is PCD awareness month- and there is no bigger way to mark it that a new PCD disease gene, disease mechanism and already thinking new #therapies! We are very grateful to the patients and their families, and patient advocacy groups @PCD_UK @PCDFoundation for their support, as well as @beatpcd that supports our community.