Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene which encodes a protein expressed in the apical membrane of exocrine epithelial cells. CFTR functions principally as a cAMP-induced chloride channel and appears capable of regulating other ion channels. Besides the most common mutation, ΔF508, accounting for about 70% of CF chromosomes worldwide, more than 850 mutant alleles have been reported to the CF Genetic Analysis Consortium. These mutations affect CFTR through a variety of molecular mechanisms which can produce little or no functional CFTR at the apical membrane. This genotypic variation provides a rationale for phenotypic effects of the specific mutations. The extent to which various CFTR alleles contribute to clinical variation in CF is evaluated by genotype-phenotype studies. These demonstrated that the degree of correlation between CFTR genotype and CF phenotype varies between its clinical components and is highest for the pancreatic status and lowest for pulmonary disease. The poor correlation between CFTR genotype and severity of lung disease strongly suggests an influence of environmental and secondary genetic factors (CF modifiers). Several candidate genes related to innate and adaptive immune response have been implicated as pulmonary CF modifiers. In addition, the presence of a genetic CF modifier for meconium ileus has been demonstrated on human chromosome 19q13.2. The phenotypic spectrum associated with mutations in the CFTR gene extends beyond the classically defined CF. Besides patients with atypical CF, there are large numbers of so-called monosymptomatic diseases such as various forms of obstructive azoospermia, idiopathic pancreatitis or disseminated bronchiectasis associated with CFTR mutations uncharacteristic for CF. The composition, frequency and type of CFTR mutations/variants parallel the spectrum of CFTR-associated phenotypes, from classic CF to mild monosymptomatic presentations. Expansion of the spectrum of disease associated with the CFTR mutant genes creates a need for revision of the diagnostic criteria for CF and a dilemma for setting nosologic boundaries between CF and other diseases with CFTR etiology.

Rosenstein BJ, Cutting GR: The diagnosis of cystic fibrosis: A consensus statement. Cystic Fibrosis Foundation Consensus Panel. J Pediatr 1998;132:589–595.
Welsh MJ, Tsui L-C, Boat TF, Beaudet AL: Cystic fibrosis; in Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic and Molecular Bases of Inherited Disease. New York, McGraw-Hill, 1995, vol III, pp 3799–3876.
Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, Rozmahel R, Cole JL, Kennedy D, Hidaka N: Identification of the cystic fibrosis gene: Chromosome walking and jumping. Science 1989;245:1059–1065.
Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou JL: Identification of the cystic fibrosis gene: Cloning and characterization of complementary DNA. Science 1989;245:1066–1073.
Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, Buchwald M, Tsui LC: Identification of the cystic fibrosis gene: Genetic analysis. Science 1989;245:1073–1080.
Zielenski J, Rozmahel R, Bozon D, Kerem B, Grzelczak Z, Riordan JR, Rommens J, Tsui LC: Genomic DNA sequence of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Genomics 1991;10:214–228.
Quinton PM: Physiological basis of cystic fibrosis: A historical perspective. Physiol Rev 1999;79:S3–S22.
Sheppard DN, Welsh MJ: Structure and function of the CFTR chloride channel. Physiol Rev 1999;79:S23–S45.
Dawson DC, Smith SS, Mansoura MK: CFTR: Mechanism of anion conduction. Physiol Rev 1999;79:S47–S75.
Gadsby DC, Nairn AC: Control of CFTR channel gating by phosphorylation and nucleotide hydrolysis. Physiol Rev 1999;79:S77–S107.
Schwiebert EM, Benos DJ, Egan ME, Stutts MJ, Guggino WB: CFTR is a conductance regulator as well as a chloride channel. Physiol Rev 1999;79:S145–S166.
Kopito RR: Biosynthesis and degradation of CFTR. Physiol Rev 1999;79:S167–S173.
Bradbury NA: Intracellular CFTR: Localization and function. Physiol Rev 1999;79:S175–S191.
The Cystic Fibrosis Genetic Analysis Consortium: Population variation of common cystic fibrosis mutations. The Cystic Fibrosis Genetic Analysis Consortium. Hum Mutat 1994;4:167–177.
Messaoud T, Verlingue C, Denamur E, Pascaud O, Quere I, Fattoum S, Elion J, Ferec C: Distribution of CFTR mutations in cystic fibrosis patients of Tunisian origin: Identification of two novel mutations. Eur J Hum Genet 1996;4:20–24.
Schwartz M, Johansen HK, Koch C, Brandt NJ: Frequency of the delta F508 mutation on cystic fibrosis chromosomes in Denmark. Hum Genet 1990;85:427–428.
Tsui LC: The spectrum of cystic fibrosis mutations. Trends Genet 1992;8:392–398.
Welsh MJ, Smith AE: Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell 1993;73:1251–1254.
Zielenski J, Tsui LC: Cystic fibrosis: Genotypic and phenotypic variations. Annu Rev Genet 1995;29:777–807.
Kalin N, Claass A, Sommer M, Puchelle E, Tummler B: DeltaF508 CFTR protein expression in tissues from patients with cystic fibrosis. J Clin Invest 1999;103:1379–1389.
Fulmer SB, Schwiebert EM, Morales MM, Guggino WB, Cutting GR: Two cystic fibrosis transmembrane conductance regulator mutations have different effects on both pulmonary phenotype and regulation of outwardly rectified chloride currents. Proc Natl Acad Sci USA 1995;92:6832–6836.
McNicholas CM, Guggino WB, Schwiebert EM, Hebert SC, Giebisch G, Egan ME: Sensitivity of a renal K+ channel (ROMK2) to the inhibitory sulfonylurea compound glibenclamide is enhanced by coexpression with the ATP-binding cassette transporter cystic fibrosis transmembrane regulator. Proc Natl Acad Sci USA 1996;93:8083–8088.
Sheppard DN, Rich DP, Ostedgaard LS, Gregory RJ, Smith AE, Welsh MJ: Mutations in CFTR associated with mild-disease-form Cl–channels with altered pore properties. Nature 1993;362:160–164.
Akabas MH, Kaufmann C, Cook TA, Archdeacon P: Amino acid residues lining the chloride channel of the cystic fibrosis transmembrane conductance regulator. J Biol Chem 1994;269:14865–14868.
Highsmith WE, Burch LH, Zhou Z, Olsen JC, Boat TE, Spock A, Gorvoy JD, Quittel L, Friedman KJ, Silverman LM: A novel mutation in the cystic fibrosis gene in patients with pulmonary disease but normal sweat chloride concentrations. N Engl J Med 1994;331:974–980.
De Braekeleer M, Allard C, Leblanc JP, Simard F, Aubin G: Genotype-phenotype correlation in cystic fibrosis patients compound heterozygous for the A455E mutation. Hum Genet 1997;101:208–211.
Sheppard DN, Ostedgaard LS, Winter MC, Welsh MJ: Mechanism of dysfunction of two nucleotide binding domain mutations in cystic fibrosis transmembrane conductance regulator that are associated with pancreatic sufficiency. EMBO J 1995;14:876–883.
Haardt M, Benharouga M, Lechardeur D, Kartner N, Lukacs GL: C-terminal truncations destabilize the cystic fibrosis transmembrane conductance regulator without impairing its biogenesis. A novel class of mutation. J Biol Chem 1999;274:21873–21877.
Tizzano EF, Buchwald M: CFTR expression and organ damage in cystic fibrosis. Ann Intern Med 1995;123:305–308.
Kerem E, Kerem B: Genotype-phenotype correlations in cystic fibrosis. Pediatr Pulmonol 1996;22:387–395.
Kristidis P, Bozon D, Corey M, Markiewicz D, Rommens J, Tsui LC, Durie P: Genetic determination of exocrine pancreatic function in cystic fibrosis. Am J Hum Genet 1992;50:1178–1184.
Kerem E, Nissim-Rafinia M, Argaman Z, Augarten A, Bentur L, Klar A, Yahav Y, Szeinberg A, Hiba O, Branski D, Corey M, Kerem B: A missense cystic fibrosis transmembrane conductance regulator mutation with variable phenotype. Pediatrics 1997;100:E5.
Farrell PM, Kosorok MR, Laxova A, Shen G, Koscik RE, Bruns WT, Splaingard M, Mischler EH: Nutritional benefits of neonatal screening for cystic fibrosis. Wisconsin Cystic Fibrosis Neonatal Screening Study Group. N Engl J Med 1997;337:963–969.
Rosenecker J, Eichler I, Kuhn L, Harms HK, von der Hardt H: Genetic determination of diabetes mellitus in patients with cystic fibrosis. Multicenter Cystic Fibrosis Study Group. J Pediatr 1995;127:441–443.
De Braekeleer M, Allard C, Leblanc JP, Aubin G, Simard F: Is meconium ileus genetically determined or associated with a more severe evolution of cystic fibrosis? J Med Genet 1998;35:262–263.
Wilschanski M, Rivlin J, Cohen S, Augarten A, Blau H, Aviram M, Bentur L, Springer C, Vila Y, Branski D, Kerem B, Kerem E: Clinical and genetic risk factors for cystic fibrosis-related liver disease. Pediatrics 1999;103:52–57.
Kerem E, Corey M, Kerem BS, Rommens J, Markiewicz D, Levison H, Tsui LC, Durie P: The relation between genotype and phenotype in cystic fibrosis – analysis of the most common mutation (delta F508). N Engl J Med 1990;323:1517–1522.
Santis G, Osborne L, Knight R, Hodson ME, Ramsay M: Genetic influences on pulmonary severity in cystic fibrosis. Lancet 1990;335:294.
Johansen HK, Nir M, Hoiby N, Koch C, Schwartz M: Severity of cystic fibrosis in patients homozygous and heterozygous for delta F508 mutation. Lancet 1991;337:631–634.
Campbell PW III, Phillips JA III, Krishnamani MR, Maness KJ, Hazinski TA: Cystic fibrosis: Relationship between clinical status and F508 deletion. J Pediatr 1991;118:239–241.
Burke W, Aitken ML, Chen SH, Scott CR: Variable severity of pulmonary disease in adults with identical cystic fibrosis mutations. Chest 1992;102:506–509.
Liechti-Gallati S, Bonsall I, Malik N, Schneider V, Kraemer LG, Ruedeberg A, Moser H, Kraemer R: Genotype/phenotype association in cystic fibrosis: Analyses of the delta F508, R553X, and 3905insT mutations. Pediatr Res 1992;32:175–178.
Correlation between genotype and phenotype in patients with cystic fibrosis. The Cystic Fibrosis Genotype-Phenotype Consortium. N Engl J Med 1993;329:1308–1313.
Borgo G, Gasparini P, Bonizzato A, Cabrini G, Mastella G, Pignatti PF: Cystic fibrosis: The delta F508 mutation does not lead to an exceptionally severe phenotype. A cohort study. Eur J Pediatr 1993;152:1006–1011.
Kubesch P, Dork T, Wulbrand U, Kalin N, Neumann T, Wulf B, Geerlings H, Weissbrodt H, von der Hardt H, Tummler B: Genetic determinants of airways’ colonisation with Pseudomonas aeruginosa in cystic fibrosis. Lancet 1993;341:189–193.
Mohon RT, Wagener JS, Abman SH, Seltzer WK, Accurso FJ: Relationship of genotype to early pulmonary function in infants with cystic fibrosis identified through neonatal screening. J Pediatr 1993;122:550–555.
Lester LA, Kraut J, Lloyd-Still J, Karrison T, Mott C, Billstrand C, Lemke A, Ober C: Delta F508 genotype does not predict disease severity in an ethnically diverse cystic fibrosis population. Pediatrics 1994;93:114–118.
Khan TZ, Wagener JS, Bost T, Martinez J, Accurso FJ, Riches DW: Early pulmonary inflammation in infants with cystic fibrosis. Am J Respir Crit Care Med 1995;151:1075–1082.
Gan KH, Geus WP, Bakker W, Lamers CB, Heijerman HG: Genetic and clinical features of patients with cystic fibrosis diagnosed after the age of 16 years. Thorax 1995;50:1301–1304.
Hubert D, Bienvenu T, Desmazes-Dufeu N, Fajac I, Lacronique J, Matran R, Kaplan JC, Dusser DJ: Genotype-phenotype relationships in a cohort of adult cystic fibrosis patients. Eur Respir J 1996;9:2207–2214.
Marostica PJ, Raskin S, Abreu-e-Silva FA: Analysis of the delta F508 mutation in a Brazilian cystic fibrosis population: Comparison of pulmonary status of homozygotes with other patients. Braz J Med Biol Res 1998;31:529–532.
Gaskin K, Gurwitz D, Durie P, Corey M, Levison H, Forstner G: Improved respiratory prognosis in patients with cystic fibrosis with normal fat absorption. J Pediatr 1982;100:857–862.
Corey M, Gaskin K, Durie P, Levison H, Forstner G: Improved prognosis in CF patients with normal fat absorption. J Pediatr Gastroenterol Nutr 1984;3(suppl 1):S99–105.
Corey M, Edwards L, Levison H, Knowles M: Longitudinal analysis of pulmonary function decline in patients with cystic fibrosis. J Pediatr 1997;131:809–814.
Strong TV, Smit LS, Turpin SV, Cole JL, Hon CT, Markiewicz D, Petty TL, Craig MW, Rosenow EC III, Tsui LC: Cystic fibrosis gene mutation in two sisters with mild disease and normal sweat electrolyte levels. N Engl J Med 1991;325:1630–1634.
Augarten A, Kerem BS, Yahav Y, Noiman S, Rivlin Y, Tal A, Blau H, Ben-Tur L, Szeinberg A, Kerem E: Mild cystic fibrosis and normal or borderline sweat test in patients with the 3849 + 10 kb C→T mutation. Lancet 1993;342:25–26.
Gan KH, Veeze HJ, van den Ouweland AM, Halley DJ, Scheffer H, van der Hout A, Overbeek SE, de Jongste JC, Bakker W, Heijerman HG: A cystic fibrosis mutation associated with mild lung disease. N Engl J Med 1995;333:95–99.
Orozco L, Lezana JL, Villarreal MT, Chavez M, Carnevale A: Mild cystic fibrosis disease in three Mexican delta-F508/G551S compound heterozygous siblings. Clin Genet 1995;47:96–98.
The Cystic Fibrosis Genotype-Phenotype Consortium: Variable phenotypes for nine CFTR mutations associated with pancreatic sufficiency in CF patients. Pediatr Pulmonol 1996;(suppl 13):245.
De Braekeleer M, Mari G, Verlingue C, Allard C, Leblanc JP, Simard F, Aubin G, Ferec C: Clinical features of cystic fibrosis patients with rare genotypes in Saguenay Lac-Saint-Jean (Quebec, Canada). Ann Genet 1997;40:205–208.
Gilfillan A, Warner JP, Kirk JM, Marshall T, Greening A, Ho LP, Hargreave T, Stack B, McIntyre D, Davidson R, Dean JC, Middleton W, Brock DJ: P67L: A cystic fibrosis allele with mild effects found at high frequency in the Scottish population. J Med Genet 1998;35:122–125.
De Braekeleer M, Allard C, Leblanc JP, Aubin G, Simard F: Genetic determinants of Pseudomonas aeruginosa colonization in cystic fibrosis patients in Canada. Eur J Clin Microbiol Infect Dis 1998;17:269–271.
Walker LC, Venglarik CJ, Aubin G, Weatherly MR, McCarty NA, Lesnick B, Ruiz F, Clancy JP, Sorscher EJ: Relationship between airway ion transport and a mild pulmonary disease mutation in CFTR. Am J Respir Crit Care Med 1997;155:1684–1689.
Sharma GD, Tosi MF, Stern RC, Davis PB: Progression of pulmonary disease after disappearance of Pseudomonas in cystic fibrosis. Am J Respir Crit Care Med 1995;152:169–173.
Drittanti L, Masciovecchio MV, Gabbarini J, Vega M: Cystic fibrosis: Gene therapy or preventive gene transfer? Gene Ther 1997;4:1001–1003.
Davidson DJ, Porteous DJ: Genetics and pulmonary medicine. 1. The genetics of cystic fibrosis lung disease. Thorax 1998;53:389–397.
Kraemer R, Birrer P, Liechti-Gallati S: Genotype-phenotype association in infants with cystic fibrosis at the time of diagnosis. Pediatr Res 1998;44:920–926.
Wilschanski M, Zielenski J, Markiewicz D, Tsui LC, Corey M, Levison H, Durie PR: Correlation of sweat chloride concentration with classes of the cystic fibrosis transmembrane conductance regulator gene mutations. J Pediatr 1995;127:705–710.
De Braekeleer M, Allard C, Leblanc JP, Aubin G, Simard F: Correlation of sweat chloride concentration with genotypes in cystic fibrosis patients in Saguenay Lac-Saint-Jean, Quebec, Canada. Clin Biochem 1998;31:33–36.
Chiba-Falek O, Parad RB, Kerem E, Kerem B: Variable levels of normal RNA in different fetal organs carrying a cystic fibrosis transmembrane conductance regulator splicing mutation. Am J Respir Crit Care Med 1999;159:1998–2002.
Schellen TM, van Straaten A: Autosomal recessive hereditary congenital aplasia of the vasa deferentia in four siblings. Fertil Steril 1980;34:401–404.
Dumur V, Gervais R, Rigot JM, Lafitte JJ, Manouvrier S, Biserte J, Mazeman E, Roussel P: Abnormal distribution of CF delta F508 allele in azoospermic men with congenital aplasia of epididymis and vas deferens. Lancet 1990;336:512.
Sharer N, Schwartz M: Mutations of the cystic fibrosis gene and pancreatitis. N Engl J Med 1999;340:238–239.
Friedman KJ, Silverman LM: Cystic fibrosis syndrome: A new paradigm for inherited disorders and implications for molecular diagnostics. Clin Chem 1999;45:929–931.
Jequier A, Ansell ID, Bullimore NJ: Congenital absence of the vasa deferentia presenting with infertility. J Androl 1985;6:15–19.
De Braekeleer M, Ferec C: Mutations in the cystic fibrosis gene in men with congenital bilateral absence of the vas deferens. Mol Hum Reprod 1996;2:669–677.
Patrizio P, Zielenski J: Congenital absence of the vas deferens: A mild form of cystic fibrosis. Mol Med Today 1996;2:24–31.
Lissens W, Mercier B, Tournaye H, Bonduelle M, Ferec C, Seneca S, Devroey P, Silber S, Van Steirteghem A, Liebaers I: Cystic fibrosis and infertility caused by congenital bilateral absence of the vas deferens and related clinical entities. Hum Reprod 1996;11(suppl 4):55–78.
Phillipson G: Cystic fibrosis and reproduction. Reprod Fertil Dev 1998;10:113–119.
Chu CS, Trapnell BC, Curristin S, Cutting GR, Crystal RG: Genetic basis of variable exon 9 skipping in cystic fibrosis transmembrane conductance regulator mRNA. Nat Genet 1993;3:151–156.
Strong TV, Wilkinson DJ, Mansoura MK, Devor DC, Henze K, Yang Y, Wilson JM, Cohn JA, Dawson DC, Frizzell RA: Expression of an abundant alternatively spliced form of the cystic fibrosis transmembrane conductance regulator (CFTR) gene is not associated with a cAMP-activated chloride conductance. Hum Mol Genet 1993;2:225–230.
Chillon M, Casals T, Mercier B, Bassas L, Lissens W, Silber S, Romey MC, Ruiz-Romero J, Verlingue C, Claustres M: Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med 1995;332:1475–1480.
Zielenski J, Patrizio P, Corey M, Handelin B, Markiewicz D, Asch R, Tsui LC: CFTR gene variant for patients with congenital absence of vas deferens. Am J Hum Genet 1995;57:958–960.
Kiesewetter S, Macek M Jr, Davis C, Curristin SM, Chu CS, Graham C, Shrimpton AE, Cashman SM, Tsui LC, Mickle J: A mutation in CFTR produces different phenotypes depending on chromosomal background. Nat Genet 1993;5:274–278.
Mak V, Jarvi KA, Zielenski J, Durie P, Tsui LC: Higher proportion of intact exon 9 CFTR mRNA in nasal epithelium compared with vas deferens. Hum Mol Genet 1997;6:2099–2107.
Jarvi K, Zielenski J, Wilschanski M, Durie P, Buckspan M, Tullis E, Markiewicz D, Tsui LC: Cystic fibrosis transmembrane conductance regulator and obstructive azoospermia. Lancet 1995;345:1578.
Cuppens H, Lin W, Jaspers M, Costes B, Teng H, Vankeerberghen A, Jorissen M, Droogmans G, Reynaert I, Goossens M, Nilius B, Cassiman JJ: Polyvariant mutant cystic fibrosis transmembrane conductance regulator genes. The polymorphic (Tg)m locus explains the partial penetrance of the T5 polymorphism as a disease mutation. J Clin Invest 1998;101:487–496.
Zielenski J, Jarvi K, Ray P, Tzountzouris J, Corey M, Durie PR, Tsui L-C: Increased risk of infertility associated with specific DNA marker haplotypes in the CFTR locus. Pediatr Pulmonol 1998;(suppl 17):297.
Larriba S, Bassas L, Gimenez J, Ramos MD, Segura A, Nunes V, Estivill X, Casals T: Testicular CFTR splice variants in patients with congenital absence of the vas deferens. Hum Mol Genet 1998;7:1739–1743.
Durieu I, Bey-Omar F, Rollet J, Calemard L, Boggio D, Lejeune H, Gilly R, Morel Y, Durand DV: Diagnostic criteria for cystic fibrosis in men with congenital absence of the vas deferens. Medicine (Baltimore) 1995;74:42–47.
Tullis DE, Jarvi K, Martin S, Ellis L, Zielenski J, Wilschanski M, Corey M, Tsui LC, Durie PR: CF genotype and phenotype in males with congenital absence of the vas deferens (CBAVD). Pediatr Pulmonol 1998;(suppl 17):294–295.
Mak V, Zielenski J, Tsui LC, Durie P, Zini A, Martin S, Longley TB, Jarvi KA: Proportion of cystic fibrosis gene mutations not detected by routine testing in men with obstructive azoospermia. JAMA 1999;281:2217–2224.
Durno C, Corey M, Tullis E, Tsui L-C, Zielenski J, Durie P: Retrospective analysis of pancreatic sufficient patients with cystic fibrosis with and without pancreatitis. Pediatr Pulmonol 1998;(suppl 14):247.
Sharer N, Schwarz M, Malone G, Howarth A, Painter J, Super M, Braganza J: Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N Engl J Med 1998;339:645–652.
Cohn JA, Friedman KJ, Noone PG, Knowles MR, Silverman LM, Jowell PS: Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med 1998;339:653–658.
Poller W, Faber JP, Scholz S, Olek K, Muller KM: Sequence analysis of the cystic fibrosis gene in patients with disseminated bronchiectatic lung disease. Application in the identification of a cystic fibrosis patient with atypical clinical course. Klin Wochenschr 1991;69:657–663.
Pignatti PF, Bombieri C, Marigo C, Benetazzo M, Luisetti M: Increased incidence of cystic fibrosis gene mutations in adults with disseminated bronchiectasis. Hum Mol Genet 1995;4:635–639.
Pignatti PF, Bombieri C, Benetazzo M, Casartelli A, Trabetti E, Gile LS, Martinati LC, Boner AL, Luisetti M: CFTR gene variant IVS8-5T in disseminated bronchiectasis. Am J Hum Genet 1996;58:889–892.
Girodon E, Cazeneuve C, Lebargy F, Chinet T, Costes B, Ghanem N, Martin J, Lemay S, Scheid P, Housset B, Bignon J, Goossens M: CFTR gene mutations in adults with disseminated bronchiectasis. Eur J Hum Genet 1997;5:149–155.
Bombieri C, Benetazzo M, Saccomani A, Belpinati F, Gile LS, Luisetti M, Pignatti PF: Complete mutational screening of the CFTR gene in 120 patients with pulmonary disease. Hum Genet 1998;103:718–722.
Puechal X, Fajac I, Bienvenu T, Desmazes-Dufeu N, Hubert D, Kaplan JC, Menkes CJ, Dusser DJ: Increased frequency of cystic fibrosis deltaF508 mutation in bronchiectasis associated with rheumatoid arthritis. Eur Respir J 1999;13:1281–1287.
Geller DE, Kaplowitz H, Light MJ, Colin AA: Allergic bronchopulmonary aspergillosis in cystic fibrosis: Reported prevalence, regional distribution, and patient characteristics. Scientific Advisory Group, Investigators, and Coordinators of the Epidemiologic Study of Cystic Fibrosis. Chest 1999;116:639–646.
Miller PW, Hamosh A, Macek M Jr, Greenberger PA, MacLean J, Walden SM, Slavin RG, Cutting GR: Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in allergic bronchopulmonary aspergillosis. Am J Hum Genet 1996;59:45–51.
Dahl M, Tybjaerg-Hansen A, Lange P, Nordestgaard BG: DeltaF508 heterozygosity in cystic fibrosis and susceptibility to asthma. Lancet 1998;351:1911–1913.
Schroeder SA, Gaughan DM, Swift M: Protection against bronchial asthma by CFTR delta F508 mutation: A heterozygote advantage in cystic fibrosis. Nat Med 1995;1:703–705.
Mennie M, Gilfillan A, Brock DJ, Liston WA: Heterozygotes for the delta F508 cystic fibrosis allele are not protected against bronchial asthma. Nat Med 1995;1:978–979.
Lazaro C, de Cid R, Sunyer J, Soriano J, Gimenez J, lvarez M, Casals T, Anto JM, Estivill X: Missense mutations in the cystic fibrosis gene in adult patients with asthma. Hum Mutat 1999;14:510–519.
Aznarez I, Zielenski J, Siminovitch K, Tsui LC: Increased frequency of CFTR mutations and variants among asthma patients. Pediatr Pulmonol 1999;(suppl 19):208.
Mickle JE, Macek M Jr, Fulmer-Smentek SB, Egan MM, Schwiebert E, Guggino W, Moss R, Cutting GR: A mutation in the cystic fibrosis transmembrane conductance regulator gene associated with elevated sweat chloride concentrations in the absence of cystic fibrosis. Hum Mol Genet 1998;7:729–735.
Campbell PW III, Parker RA, Roberts BT, Krishnamani MR, Phillips JA III: Association of poor clinical status and heavy exposure to tobacco smoke in patients with cystic fibrosis who are homozygous for the F508 deletion. J Pediatr 1992;120:261–264.
Rozmahel R, Wilschanski M, Matin A, Plyte S, Oliver M, Auerbach W, Moore A, Forstner J, Durie P, Nadeau J, Bear C, Tsui LC: Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor. Nat Genet 1996;12:280–287.
Zielenski J, Corey M, Rozmahel R, Markiewicz D, Aznarez I, Casals T, Larriba S, Mercier B, Cutting GR, Krebsova A, Macek M Jr, Langfelder-Schwind E, Marshall BC, DeCelie-Germana J, Claustres M, Palacio A, Bal J, Nowakowska A, Ferec C, Estivill X, Durie P, Tsui LC: Detection of a cystic fibrosis modifier locus for meconium ileus on human chromosome 19q13. Nat Genet 1999;22:128–129.
Rohlfs EM, Shaheen NJ, Silverman LM: Is the hemochromatosis gene a modifier locus for cystic fibrosis? Genet Test 1998;2:85–88.
Garred P, Pressler T, Madsen HO, Frederiksen B, Svejgaard A, Hoiby N, Schwartz M, Koch C: Association of mannose-binding lectin gene heterogeneity with severity of lung disease and survival in cystic fibrosis. J Clin Invest 1999;104:431–437.
Hull J, Thomson AH: Contribution of genetic factors other than CFTR to disease severity in cystic fibrosis. Thorax 1998;53:1018–1021.
Aron Y, Polla BS, Bienvenu T, Dall’Ava J, Dusser D, Hubert D: HLA class II polymorphism in cystic fibrosis. A possible modifier of pulmonary phenotype. Am J Respir Crit Care Med 1999;159:1464–1468.
Kent G, Iles R, Bear CE, Huan LJ, Griesenbach U, McKerlie C, Frndova H, Ackerley C, Gosselin D, Radzioch D, O’Brodovich H, Tsui LC, Buchwald M, Tanswell AK: Lung disease in mice with cystic fibrosis. J Clin Invest 1997;100:3060–3069.
Haston CK, McKerlie C, Corey M, Budisin B, Samanta T, Kent G, Tsui L-C, Rozmahel R: Detection of modifier loci influencing the lung phenotype of cystic fibrosis knockout mice. Pediatr Pulmonol 1999;(suppl 19):217.
Scheele GA, Fukuoka SI, Kern HF, Freedman SD: Pancreatic dysfunction in cystic fibrosis occurs as a result of impairments in luminal pH, apical trafficking of zymogen granule membranes, and solubilization of secretory enzymes. Pancreas 1996;12:1–9.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.