This discovery builds on years of cystic fibrosis (CF) research at The Hospital for Sick Children (HSC), including the discovery of the CF gene in 1989. After the discovery of the gene, research focused on determining the function of the protein that the gene encodes. Each gene in the human genome codes for a unique protein. The gene is the molecule of information, but the protein that is then biosynthesized in the cell actually carries out the bodily function. In the case of the CF gene, the protein (named CFTR) regulates the necessary balance of sodium chloride (salt) across the cell membranes in the lungs and pancreas.
"We now have a clearer picture of why the protein doesn't function properly in the milder form of cystic fibrosis - segments of the protein are sticking together, interfering with the flow of chloride in and out of the cell," said Dr. Charles Deber, the study's principal investigator, a senior scientist in the HSC Research Institute and a professor of Biochemistry at the University of Toronto.
Cystic fibrosis is not just one distinct phenotype, as researchers have found hundreds of different mutations in the CF gene and the corresponding protein. The milder form of cystic fibrosis, also known as pancreatic sufficient CF, occurs in 10-15 per cent of CF patients. In this form of the disease, which often manifests as lung disease and male infertility, CFTR is able to carry out partial function. In the more severe forms of cystic fibrosis, the protein never assembles properly and no chloride can be transported.
"This opens the door for new avenues of research in terms of rational drug design," added Dr. Deber. "We will look for molecules that could possibly break up the abnormal bond that is causing the protein strands to stick together."
CFTR is a membrane protein with a massive and complicated structure. Membrane proteins, which regulate the stable internal physiological conditions of the cell in a controlled way, allowing for such things as intracellular communication, are very difficult to study.
"We had to develop and refine molecular biological techniques in order to accurately study this membrane protein. This research will add to the body of knowledge about membrane proteins, which are also implicated in other diseases such as cancer, diabetes, and hypertension," said Dr. Alex Therien, the study's lead author and a Canadian Institutes of Health Research (CIHR) postdoctoral fellow in Dr. Deber's lab. The other author on this paper is Fiona Grant, who was student in Dr. Deber's lab as part of the Samuel Lunenfeld Research Summer Student Program in the HSC Research Institute.
This research was supported by the Canadian Cystic Fibrosis Foundation, CIHR, and the National Institutes of Health in the United States.
The Hospital for Sick Children is a health care, teaching and research centre dedicated exclusively to children; affiliated with the University of Toronto. Its mission is to provide the best in family-centred, compassionate care, to lead in scientific and clinical advancement, and to prepare the next generation of leaders in child health. For more information, please visit www.sickkids.ca.
Journal
Nature Structural & Molecular Biology