Cystic fibrosis could be considered two diseases—one that can affect multiple organs, including the lungs—and one that doesn’t affect the lungs at all, a new study shows.
Research published online in PLOS Genetics shows that nine variants in the gene associated with cystic fibrosis (CF) can lead to pancreatitis, sinusitis, and male infertility, but has no impact on lung function.
People with CF inherit from each parent a severely mutated copy of a gene called CFTR, which makes a protein that forms a channel for the movement of chloride molecules in and out of cells that produce sweat, mucus, tears, semen, and digestive enzymes, says David Whitcomb, chief of gastroenterology, hepatology, and nutrition at University of Pittsburgh School of Medicine.
Without functional CFTR channels, secretions become thick and sticky, causing problems such as the chronic lung congestion associated with CF.
PANCREAS IS THE TARGET
“There are other kinds of mutations of CFTR, but these were deemed to be harmless because they didn’t cause lung problems,” Whitcomb says. “We examined whether these variants could be related to disorders of the pancreas and other organs that use CFTR channels.”
Min Goo Lee, of Yonsei University College of Medicine, in Seoul, Korea, conducted careful tests of CFTR in pancreatic cell models and determined that a molecular switch inside the cell called WINK1 made CFTR channels secrete bicarbonate rather than chloride molecules.
“Pancreas cells use CFTR to secrete bicarbonate to neutralize gastric acids,” Whitcomb says. “When that doesn’t happen, the acids cause the inflammation, cyst formation, and scarring of severe pancreatitis.”
Researchers found nine CFTR gene variants associated with pancreatitis after testing nearly 1,000 patients with the disease and a comparable number of healthy volunteers. They also learned that each variant could impair the WINK1 switch to prevent CFTR from becoming a bicarbonate-secreting channel.
Ivet Bahar, professor of computational biology at the University of Pittsburgh School of Medicine, built a computer model of the CFTR protein’s structure and determined that all the nine variants alter the area that forms the bicarbonate transport channel, thus impairing secretion of the molecule.
“It turns out that CFTR-mediated bicarbonate transport is critical to thin mucus in the sinuses and for proper sperm function,” Whitcomb says. “When we surveyed pancreatitis patients, there was a subset who said they had problems with chronic sinusitis. Of men over 30 who said they had tried to have children and were infertile, nearly all had one of these nine CFTR mutations.”
Identification of the mechanisms that cause the conditions make it possible to develop treatments, as well as to launch trials to determine if medications that are used by CF patients might have some benefit for those who do not have lung disease, but who carry the other mutations.
The team includes researchers from the University of Pittsburgh, the Mayo Clinic, Brigham and Women’s Hospital, and other institutions that are part of the North American Pancreatitis Study Group.
The National Institutes of Health, the Ministry for Health & Welfare of the Republic of Korea, and Brain Korea 21 Project for Medical Sciences in Seoul funded the study.
《Mechanisms of CFTR Functional Variants That Impair Regulated Bicarbonate Permeation and Increase Risk for Pancreatitis but Not for Cystic Fibrosis》, Published on Journal 《Plos Genetics》in July 17, 2014.