Hereditary Mucin Deficiency Caused by Biallelic Loss-of-Function of MUC5B Defines a Novel Category of Lung Disease

Airway mucus is composed principally of the mucin glycoproteins MUC5AC and MUC5B. Dysregulation of MUC5B is observed in diverse common lung diseases and represents a potential therapeutic target. In mice, Muc5b (but not Muc5ac) is required for mucociliary clearance and limiting infections in the lower and upper airways. The consequences of loss of MUC5B in humans remain unknown. Methods: Whole genome sequencing was performed on blood-derived DNA from the proband with idiopathic bronchiectasis, using established methods and a bioinformatics pipeline for clinical genome annotation. A multimodal experimental approach was applied to characterize the clinical and cellular phenotype. Results: A 17-year-old female with bronchiectasis, moderate impairment of pulmonary function (FEV1 59%), and recurrent bacterial pneumonia (Staphylococcus aureus) was found to be apparently homozygous for a rare loss-of-function variant in MUC5B (NM_002458.2: c.1938+1G>A). Targeted familial testing revealed that her 25-year-old female sibling with chronic nonproductive cough, recurrent lung infections, impaired pulmonary function (FEV1 70%), and a history of bilateral nasal polypectomy in childhood, was also homozygous for the MUC5B variant. We observed an absence of the MUC5B protein in all samples examined (saliva, sputum and nasal) by mass spectrometry and immunostaining, and evidence of compensatory upregulation of MUC5AC. In vivo and ex vivo experiments in the proband revealed evidence of disrupted local airway defences, but intact mucociliary clearance in proximal airways. Conclusions: While lung growth and ventilation can be achieved in humans in the absence of MUC5B, hereditary mucin deficiency defines a novel category of inherited lung disease distinct from cystic fibrosis and primary ciliary dyskinesia.