6.6 Biological Mechanism Underlying CFTR Variants ...
In the human exocrine pancreas，CFTR is predominantly expressed in the apical plasma membrane of the ductal and centroacinar cells，wherein its major function is thought to prevent the formation of protein plugs that predispose to pancreatic injury via dilution and alkalinisation of the protein-rich acinar secretions（Chen and Férec 2009）.A diverse range of CFTR variants have been associated with idiopathic and alcoholic chronic pancreatitis，but the underlying biological mechanisms are unclear in most cases.The risk of pancreatitis in patients with cystic fibrosis appears to be determined by the type of CFTR mutation；somewhat paradoxically，it is the mild genotypes that confer an increased risk of pancreatitis as compared with the moderate-severe genotypes（Ooi et al.2011）.A recent study has shed light on this paradox.LaRusch and colleagues identified several CFTR variants in patients with chronic pancreatitis（and often sinus infections）and male infertility，but not other symptoms of cystic fibrosis（LaRusch et al.2014）.These mutant CFTR channels were shown to secrete chloride，which is important in the sweat glands，lung and intestine，but not bicarbonate，which is important in the pancreas，sinuses and male reproductive tract（LaRusch et al.2014）.In other words，these CFTR variants cause a selective bicarbonate defect in channel function，affecting organs that utilize CFTR for bicarbonate secretion but sparing organs that utilize CFTR for chloride secretion.Presumably，some CFTR variants may affect both channel functions but their respective effects may differ between variants.(https://www.daowen.com)