MUTATIONAL ANALYSIS OF THE CYSTIC FIBROSIS GENE

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Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR encodes a protein that is part of a superfamily of membrane transport molecules, and CF patients display abnormalities in many secretory organs, particularly the lungs and pancreas. Over 250 different mutations have been identified in the gene, the most common being a deletion of 3 base pairs, resulting in the loss of a phenylalanine codon at amino acid position 508 (deltaF508). The severity of symptoms in CF patients is highly heterogeneous. Although some mutations appear only in patients with mild pancreatic disease, the severity of pulmonary symptoms does not show a correlation with the patients genotype. The focus of this project is to identify the genetic basis of the heterogeneity in CF patients and to characterize other genetic disorders that may be caused by CFTR. In addition to the pulmonary and pancreatic defects in CF patients, nearly all CF males are infertile. We have previously shown that sterile males with a condition known as congenital bilateral absence of vas deferens (CBAVD) have mutations in the CF gene. In other words, CBAVD may represent a milder form of CF. By collecting a larger sample of CBAVD patients we have been able to extend and confirm this finding. Another symptom that is associated with CF is pancreatitis, a disorder of the pancreas associated with severe abdominal pain, abnormal serum enzyme levels, and pancreatic fibrosis. Although there are many causes of pancreatitis, at least one form is hereditary. Hereditary pancreatitis (HP) is an autosomal dominant disorder with onset of the disease in childhood. To investigate the possibility that HP could be caused by alterations in the CF gene, we have analyzed an HP family for CFTR gene alterations. A mutation in the gene was identified in this family that was present in both the affected mother and her son. This mutation occurs in a residue of the protein which shows conservation between the CFTR genes of many species, suggesting that it is important for the function of the gene.