Cystic fibrosis genetics: from molecular understanding to clinical application

The availability of human genome sequences and tools to examine individual genomes provides an unprecedented opportunity to apply genetics to medicine. The Mendelian condition caused by a single genetic dysfunction provides a powerful example of how genetics provides insight into disease. As an example, cystic fibrosis is a more common deadly autosomal recessive Mendelian disease. Recent advances in pathogenesis mechanisms and causal elucidation of phenotypic variants and development of therapeutic approaches suggest that genetics 25 years after discovery of causative genes continues to play an important role in cystic fibrosis research doing.

Studies on pathogenic manifolds such as F508del are addressing the folding mechanism of cystic fibrosis transmembrane conductance regulator (CFTR) and will correct the folding of mutant CFTR by rational design of compounds.

The new tissue culture method helps to evaluate molecular target therapy for a wide range of CFTR genotypes and new animal models should be able to evaluate treatment early in the disease.

Analysis of the affected twin and sibling pair quantifies the contribution of genetic and non-genetic modifiers to variants of important features of cystic fibrosis.

Candidate and genome-wide methods have identified biologically significant genetic alteration factors for severity of lung disease, neonatal ileus and cystic fibrosis diabetes

Mutant annotation in CFTR increases the usefulness of genetic testing in neonatal screening, vehicle testing and diagnostic settings. Assignment of mutation as a causative factor verifies the purpose of mutants for molecular therapy

Small molecule therapy for cystic fibrosis has been successfully used in patients with some of the CFTR variants. Classifying mutations based on responses (ie types) in cell based assays can accelerate the treatment of affected individuals with rare CFTR genotypes

For example, Andrew Fraser, a professor of molecular genetics at the University of Toronto, studied cystic fibrosis. Even though all patients share mutations in the same gene, the incidence and severity of cystic fibrosis may be significantly different. However, some patients are diagnosed as neonates, others do not show symptoms before adulthood. The same idea, collaborators Brenda Andrews, Charles Boone, and Frederick Cross are looking for genes that suppress disease-causing mutations. They are also professors of molecular genetics at the University of Toronto and are members of the Canadian Institute of Advanced Studies, which cooperates with Professor Chad Myers of the University of Minnesota Twins to systematically search for yeast protective genes.

Cystic fibrosis is a recessive genetic disease that is the most common life-threatening genetic disease in most Caucasians. If both parents are carriers of the defective cystic fibrosis gene, their children will inherit both genes and have a 25% chance of developing the disease. If only one abnormal gene has been inherited (ie from only one parent), the child will not have the symptoms of the disease, but it will be able to pass the defective gene to the next generation. One in 40 Caucasians is a healthy carrier of the cystic fibrosis gene. Thirty years ago, most of the infant with cystic fibrosis died early in childhood, but survival opportunities were greatly improved by progress of diagnosis and treatment of the disease.