CF is an inherited disorder which occurs in 1/2000 births. The gene responsible for this disease produces the Cystic Fibrosis Transmembrane Regulator (CFTR) protein. This protein is thought to regulate passage of chloride ions through cell membranes. Different mutations in the CFTR gene may potentially lead to different phenotypes, as demonstrated by the variability in organ involvement and severity of CF. A sweat chloride value greater than 70 mEq/L has been the gold standard for diagnosis in CF. """"""""Borderline"""""""" (40-70 mEq/L) values are often associated with mild CF symptoms but not tied to a CF diagnosis. Many patients with a mild pulmonary phenotype similar to that observed in this borderline population are adults who have never had sweat tests performed. Based on the hypotheses that a mild, pancreatic sufficient, chronic obstructive pulmonary disease phenotype with """"""""borderline"""""""" sweat chloride is linked to mutation(s) in the CFTR gene, the applicant will characterize the phenotypes of 1) a large population of borderlines and 2) subjects with chronic respiratory disorders from several well defined longitudinal study populations. The CFTR genotypes will then be characterized in these populations by ASO, SSCP and DNA sequencing, and based on preliminary data that suggests unique CFTR genotypes are presented in these populations, develop a molecular genetic screening panel for appropriate mutations. The significance of associating chronic debilitating pulmonary disorders other than CF (such as chronic bronchitis and chronic obstructive pulmonary disease) with CFTR gene abnormalIties would improve insight into the pathophysiology and potential therapy of those disorders.
| Parad, R B; Gerard, C J; Zurakowski, D et al. (1999) Pulmonary outcome in cystic fibrosis is influenced primarily by mucoid Pseudomonas aeruginosa infection and immune status and only modestly by genotype. Infect Immun 67:4744-50 |
| Chiba-Falek, O; Parad, R B; Kerem, E et al. (1999) Variable levels of normal RNA in different fetal organs carrying a cystic fibrosis transmembrane conductance regulator splicing mutation. Am J Respir Crit Care Med 159:1998-2002 |
| Parad, R B (1998) Buccal cell DNA mutation analysis for diagnosis of cystic fibrosis in newborns and infants inaccessible to sweat chloride measurement. Pediatrics 101:851-5 |
| Parad, R B (1996) Heterogeneity of phenotype in two cystic fibrosis patients homozygous for the CFTR exon 11 mutation G551D. J Med Genet 33:711-3 |
| Parad, R B; Applegate, K; Doubilet, P M et al. (1995) Occult fetal bowel obstruction: ileal atresia presenting in a newborn infant after normal antenatal sonography. J Ultrasound Med 14:161-3 |
