MUTATIONAL ANALYSIS OF THE CYSTIC FIBROSIS GENE

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The cystic fibrosis (CF) gene codes for a protein that is part of a superfamily of membrane transport molecules that includes the multi-drug resistance genes. Analysis of the mutations in the CF gene in affected individuals has revealed that approximately 70% of CF chromosomes contains a deletion of 3 base pairs, resulting in the loss of a phenylalanine codon at amino acid position 508 (deltaF508). By employing sensitive methods for detecting mutations, we have been able to identify a number of alterations in the gene. CF patients display heterogeneity in the severity of their pancreatic and pulmonary symptoms. In some cases it could be shown that specific mutations give rise to milder pancreatic disease. The focus of this project is to identify the genetic basis of the heterogeneity in CF patients and to develop an animal model for the disorder. Virtually all males with CF are sterile because of an abnormal development of the vas deferens. Absence of the vas deferens is also seen in sterile males who have no symptoms characteristic of CF, a condition known as congenital bilateral absence of vas deferens (CBAVD). We have demonstrated that a large percentage (approximately half) of CBAVD patients are carriers for a severe CF mutation such as deltaF508. By screening these individuals for other mutations, we have identified eight patients that carry two CF mutations. Thus, CBAVD represents another disease caused by the CF gene, or can be thought of as a very mild form of CF. Heterogeneity of CF lung disease appears to be controlled by loci other than CF. This conclusion is based on the observation that individuals with the same CF genotype have great variability in their severity of lung disease. To test for the role of the immune system in the response to bacterial infections, we have typed genes from the HLA locus in CF patients with mild and severe lung disease. We have found a significant association between the DQA gene and severity of lung disease, suggesting that a gene in the HLA locus plays a role in CF pulmonary disease.