Such basic science information should help improve treatments for children and adults with cystic fibrosis, the most common lethal genetic illness among Caucasians in the United States, the University of North Carolina at Chapel Hill scientists say.
People with that illness have a defective form of the CFTR gene that doesn’t allow their bodies to regulate water on their lung surfaces properly.
The result is excessively sticky mucous that traps disease-causing organisms but prevents the lungs from expelling them as they normally would. Chronic infections follow, along with lung damage that eventually leads to premature death.
A report on the findings appears online Tuesday (Nov. 13) in the Proceedings of the National Academy of Sciences, a top scientific journal. Authors, all at the UNC Cystic Fibrosis Center, are Drs. Pingbo Huang and Robert Tarran, research associates; Richard C. Boucher, professor and center director; Eduardo Lazerowski, research assistant professor; and M. Jackson Stutts, associate professor. Dr. Sharon L. Milgram, associate professor of cell and developmental biology at UNC, collaborated on the study.
Huang and colleagues employed a highly sophisticated patch clamp technique, which involves electrical and physical isolation of several CFTR ion channels, to remove tiny pieces of the membrane covering cells that line airway surfaces. Biochemical analyses followed.
“What was unique about this work was that Pingbo was able to use the activity of the chloride channel itself in conjunction with biochemical reagents as a readout of the signaling pathways that were present,” Stutts said. “He found that all the elements needed for physiologic regulation of the CFTR chloride channel were present in very small pieces of membrane with the CFTR molecule.”
The work suggests the presence of a highly ordered array of at least a half-dozen signaling molecules that in healthy people control the passage of chloride and other ions, he said.
“One of the reasons that it’s so important to understand how CFTR is regulated in normal.tissues is that we hope to be able to treat CF patients before long by restoring some of their CFTR function through genetic engineering,” Stutts said. “That’s going to be hard because the restored CFTR is unlikely to be at high levels so we’ll need to do everything we can to optimize its function. This could involve new drug therapy or other treatments.”
Besides the lungs, other organs strongly affected by CFTR gene mutations include the pancreas and skin. Often parents first suspect cystic fibrosis when their infants’ skin tastes salty following motherly kisses.
A child born to parents who each carry the defective CFTR gene faces a 25 percent risk of being born with cystic fibrosis. He or she has a 50-50 chance of being a carrier of CF and a 25 percent chance of being normal.
About one of every 20 Caucasians in the United States has the defective CFTR gene. Dr. Francis Collins, a UNC medical graduate who directs the Human Genome Project, helped identified the gene 12 years ago.
Among their contributions to research on cystic fibrosis, UNC scientists found strong evidence several years ago that the CF mutation was not eliminated from people of European ancestry because -- ironically -- it helped protect against cholera.
Note: Huang can be reached at (919) 966-7057. E-mail: huangp@med.unc.edu
Contact: David Williamson, (919) 962-8596
Journal
Proceedings of the National Academy of Sciences