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Study Suggests Cystic Fibrosis May Be Two Diseases

One affects the lungs, and the other doesn’t

Cystic fibrosis (CF) could be considered two diseases — one that affects multiple organs, including the lungs, and one that doesn’t affect the lungs at all — according to researchers at the University of Pittsburgh School of Medicine.

The new findings, published online July 17 in PLOS Genetics, showed that nine variants in the gene associated with CF can lead to pancreatitis, sinusitis, and male infertility, but can leave the lungs unharmed.

People with CF inherit from each parent a mutated copy of the CFTR gene. This gene makes a protein that forms a channel for the movement of chloride molecules in and out of cells; this activity produces sweat, mucus, tears, semen, and digestive enzymes. Without functional CFTR channels, secretions become thick and sticky, causing problems, such as the chronic lung congestion associated with CF.

“There are other kinds of mutations of CFTR, but these were deemed to be harmless because they didn’t cause lung problems,” said co-senior investigator David Whitcomb, MD, PhD. “We examined whether these variants could be related to disorders of the pancreas and other organs that use CFTR channels.”

Co-senior author Min Goo Lee, MD, PhD, conducted tests of CFTR proteins in pancreatic cell models and determined that a molecular switch inside the cell — called WINK1 — caused CFTR channels to secrete bicarbonate rather than chloride molecules.

“Pancreas cells use CFTR to secrete bicarbonate to neutralize gastric acids,” Whitcomb said. “When that doesn’t happen, the acids cause the inflammation, cyst formation, and scarring of severe pancreatitis.”

The research team found that nine CFTR gene variants were associated with pancreatitis after testing nearly 1,000 patients with CF and a comparable number of healthy volunteers. They also learned that each variant could impair the WINK1 switch to prevent CFTR proteins from becoming a bicarbonate-secreting channel.

Co-senior author Ivet Bahar, PhD, built a computer model of the CFTR protein’s structure and determined that all of the nine variants alter the area that forms the bicarbonate transport channel, thereby 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 said. “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.”

Whitcomb added that identification of the mechanisms that cause the conditions makes it possible to develop treatments, as well as to launch trials to determine whether 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.

Sources: UPMC; July 17, 2014; and PLOS Genetics; July 17, 2014.

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