Discovery of a new gene enables the diagnosis for patients with rare lung disease

As part of a large international research collaboration, scientists at the University of Leicester have helped identify a new candidate gene involved in the development of primary ciliary dyskinesia (PCD).

PCD is a rare inherited condition which affects several organs in the body and can lead to inflammation of the airways and infections in the lungs, nose, sinuses and ears.

Now, in a ground-breaking discovery, scientists have found that mutations in a tubulin (TUBB4B) affect cilia and cause PCD. The findings have now been published in Science.

The study, which was led by Professor Pleasantine Mill from the MRC Human Genetics Unit at the University of Edinburgh, identified different mutations in the tubulin TUBB4B gene in patients with PCD, sometimes with other presentations like vision loss and kidney disease. 

She said: “These exciting and unexpected insights into ciliopathies were only possible due to the collaborative partnership between the patients in our studies, their clinicians and researchers with interdisciplinary expertise from across the world.” 

Functional studies revealed how these mutations had different effects on functions of the tubulin protein, each resulting in different clinical presentations in patients.

Researchers were able to show that one mutant copy of TUBB4B was capable of over-riding the healthy copy to disrupt microtubule and cilia formation, a phenomenon called the ‘dominant negative’ effect, previously not observed in PCD. 

In addition to improving the diagnosis and genetic counselling of PCD patients and their families, this novel disease mechanism will require different therapeutic strategies to treat these patients.

Dr Robert Hirst, Principal Scientist at the Centre for PCD Diagnosis and Research in the Department of Respiratory Sciences – part of the Institute for Precision Health at the University of Leicester - conducted advanced imaging analysis on airway samples taken from some of the patients with PCD.  

He said: “These findings open up the use of rapid diagnosis techniques for affected people with this form of PCD and it will inform us on the wider implications of TUBB4B mutations in lung disease.

The University’s Centre for PCD Diagnosis collaborates with the National Institute for Health and Care Research (NIHR) Leicester Biomedical Research Centre (BRC). Dr Hirst and his team have diagnosed hundreds of PCD cases that are handed over to the NHS for their clinical management.

He added: “This study expands our understanding of tubulinopathies outside of classical neurological conditions. We continue to discover more how different genes and mutations in patients with PCD may influence clinical presentation and disease progression.”