'CFTR-opathies': disease phenotypes associated with cystic fibrosis transmembrane regulator gene mutations

Respiratory Research

Michael R Knowles¹  Peadar G Noone¹ 

[1] Pulmonary Research and Treatment Center, Department of Medicine, University of North Carolina at Chapel Hill, North Carolina, USA

关键词: phenotype;    pancreatitis;    mutations;    cystic fibrosis transmembrane regulator (CFTR);    cystic fibrosis (CF);    asthma;   

Others  :  1227432
DOI  :  10.1186/rr82

 received in 2001-06-18, accepted in 2001-07-17,  发布年份 2001

【 摘 要 】

Cystic fibrosis is a genetic disease that is associated with abnormal sweat electrolytes, sino-pulmonary disease, exocrine pancreatic insufficiency, and male infertility. Insights into genotype/phenotype relations have recently been gained in this disorder. The strongest relationship exists between 'severe' mutations in the gene that encodes the cystic fibrosis transmembrane regulator (CFTR) and pancreatic insufficiency. The relationship between 'mild' mutations, associated with residual CFTR function, and expression of disease is less precise. Atypical 'mild' mutations in the CFTR gene have been linked to late-onset pulmonary disease, congenital bilateral absence of the vas deferens, and idiopathic pancreatitis. Less commonly, sinusitis, allergic bronchopulmonary aspergillosis, and possibly even asthma may also be associated with mutations in the CFTR gene, but those syndromes predominantly reflect non-CFTR gene modifiers and environmental influences.

【 授权许可】

   
2001 BioMed Central Ltd

【 参考文献 】

• [1]Welsh MJ, Tsui L-C, Boat TF, Beaudet AL: Cystic fibrosis. In The Metabolic and Molecular Basis of Inherited Diseases. 7th edn. Edited by Scriver CR, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill; 1996, 3799-3876.
• [2]Stutts MJ, Boucher RC: Cystic fibrosis gene and functions of CFTR. In Cystic Fibrosis in Adults. Edited by Yankaskas JR, Knowles MR. Philadelphia: Lippincott-Raven Publishers; 1999, 3-25.
• [3]Rosenstein BJ, Cutting GR, Boat TF, Cantin A, Dorkin HL, Durie P, FitzSimmons S, Knowles MR, Saiman L, Tullis E: The diagnosis of cystic fibrosis: a consensus statement. J Pediatr 1998, 132:589-595.
• [4]Knowles MR, Friedman KJ, Silverman LM: Genetics, diagnosis and clinical phenotype. In: Cystic Fibrosis in Adults. Edited by Yankaskas JR, Knowles MR. Philadelphia: Lippincott-Raven; 1999, 27-42.
• [5]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.
• [6]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.
• [7]Matsui H, Grubb BR, Tarran R, Randell SH, Gatzy JT, Davis CW, Boucher RC: Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease. Cell 1998, 95:1-20.
• [8]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.
• [9]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.
• [10]Noone PG, Pue CA, Zhou Z, Friedman KJ, Wakeling EL, Ganeshananthan M, Simon RH, Silverman LM, Knowles MR: Lung disease associated with the IVS8 5T allele of the CFTR gene. Am J Respir Crit Care Med 2000, 162:1919-1924.
• [11]Osborne LR, Lynch M, Middleton PG, Alton EWFW, Geddes DM, Pryor JP, Hodson ME, Santis GK: Nasal epithelial ion transport and genetic analysis of infertile men with congenital absence of the vas deferens. Hum Mol Genet 1993, 2:1605-1609.
• [12]Delmarco A, Pradal U, Cabrini G, Bonizzato A, Mastella G: Nasal potential difference in cystic fibrosis patients presenting borderline sweat test. Eur Respir J 1997, 10:1145-1149.
• [13]Pignatti PF, Bombieri C, Benetazzo M, Casartelli A, Trabetti E, Gile LS, Martinati LC, Boner AL, Luisetti M: CFTR gene variant ICS8-5T in disseminated bronciectasis. Am J Hum Genet 1996, 58:889-892.
• [14]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.
• [15]Ockenga J, Stuhrmann M, Ballmann M, Teich N, Keim V, Dork T, Manns MP: Mutations of the cystic fibrosis gene, but not cationic trypsinogen gene, are associated with recurrent or chronic idiopathic pancreatitis. Am J Gastroenterol 2000, 95:2061-2067.
• [16]Castellani C, Bonizzato A, Rolfini R, Frulloni L, Cavallini GC, Mastella G: Increased prevalence of mutations of the cystic fibrosis gene in idiopathic chronic and recurrent pancreatitis. Am J Gastroenterol 1999, 94:1993-1995.
• [17]Noone PG, Zhou Z, Pace RG, Silverman LM, Knowles MR, Cohn JA: Molecular, cell physiologic and clinical characteristics of patients with idiopathic pancreatitis with and without mutations in the CFTR gene [abstract]. Pediatr Pulmonol 1999, suppl 19:A166.
• [18]Cohn JA, Bornstein JD, Jowell PS: Cystic fibrosis mutations and genetic predisposition to idiopathic chronic pancreatitis. Med Clin North Am 2000, 84:621-631.
• [19]Wang X, Moylan B, Leopold DA, Kim J, Rubenstein RC, Togias A, Proud D, Zeitlin PL, Cutting GR: Mutation in the gene responsible for cystic fibrosis and predisposition to chronic rhinosinusitis in the general population. JAMA 2000, 284:1814-1819.
• [20]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.
• [21]Dahl M, Tybjaerg-Hansen A, Lange P, Nordestgaard BG: DeltaF508 heterozygosity in cystic fibrosis and susceptibility to asthma. Lancet 1998, 351:1911-1913.
• [22]Lazaro C, de Cid R, Sunyer J, Soriano J, Gimenez J, Alvarez 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.
• [23]Schroeder SA, Gaughan DM, Swift M: Protection aganist bronchial asthma by CFTR DeltaF508 mutation: a heterozygote advantage in cystic fibrosis. Nat Med 1995, 1:703-705.
• [24]Swift M, Su Y: DeltaF508 heterozygosity and asthma. Lancet 1998, 352:984-987.