CFTR mutations and polymorphisms in adults with disseminated bronchiectasis: a controversial issue
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《胸》
Institute of Molecular Genetics and Genetic Engineering, Belgrade, Serbia and Montenegro
Correspondence to:
Dr D Radojkovic
Institute of Molecular Genetics and Genetic Engineering,P O Box 23, Belgrade 11010, Serbia and Montenegro;dada@eunet.yu
Keywords: disseminated bronchiectasis; CFTR; genetics
The recently published paper by King et al1 prompted us to report the results of our study of 19 Serbian patients with disseminated bronchiectasis (DB) of unknown cause for whom complete screening of the CFTR gene was performed. Our patients consisted of four men and 15 women of mean age 54.5 years (range 24–79); the mean age at onset of the disease was 38.8 years. The diagnosis was based on high resolution computed tomographic (HRCT) scanning. Known and common causes of bronchiectasis such as primary ciliary dyskinesia, immunodeficiency, and 1--antytripsin deficiency were excluded. Most of the patients had Pseudomonas aeruginosa isolated from their sputum. Pulmonary function tests were performed in 16 of the 19 patients. The remaining three were unable to undergo these tests because of the severity of their disease. Mean (SD) forced vital capacity (FVC) was 66.6 (20.5)% of predicted and mean (SD) forced expiratory volume in 1 second (FEV1) was 55.3 (24.0)% of predicted.
The whole coding region and intronic boundaries of the CFTR gene were analysed by denaturing gradient gel electrophoresis (DGGE) and subsequent DNA sequencing.2 The IVS8-5T, IVS8-7T, and IVS8-9T alleles of polymorphic Tn locus in intron 8 of the CFTR gene were detected using the PSM method.3 CFTR mutations were detected in two of the 19 patients with DB. The cumulative allelic frequency of mutations in this group of patients was 7.9% (3/38 chromosomes). The IVS8-5T allele was not found in any of the patients. Controversial data on the role of the 5T variant in patients with bronchiectasis have been reported. Pignatti and coworkers4 analysed 16 patients with bronchiectasis and suggested that the 5T variant had a similar role to that described in the congenital bilateral absence of vas deferens (CBAVD) phenotype. However, later studies1,5–7 did not find a higher frequency of the 5T variant in patients with bronchiectasis.
The incidence of the M470 allele in our patients was 28.9% (11/38 alleles). M470V (nucleotide change 1540A/G) is a common change known to affect the functionality and maturation of the CFTR protein. In addition, several common silent mutations (1716G/A, 2694T/G, 4002A/G, 4404C/T) and nucleotide changes in non-coding regions (875+40A/G, GATT6/7, 1011+11C/T) were identified. One of the patients with DB was a compound heterozygote (V920L/R75Q) and one was heterozygous for R75Q. Several groups have reported R75Q in patients with DB, CBAVD, chronic pancreatitis, asthma and chronic obstructive pulmonary disease.5,6,8,9,10,11
In contrast to previous reports,4–7 the frequency of CFTR mutations in patients with DB was not significantly higher than in our general population (2.17%, unpublished data, 2003). Because of the small sample size, these results are preliminary and need to be confirmed in a large study, but the strength of our study lies in the strict clinical selection of patients and the fact that the complete coding region of the CFTR gene was screened.
Our results support the recently published data by King et al1 whose findings also do not indicate a major role for CFTR gene mutations in the aetiology of DB. On the other hand, a recently published paper by Casals and coworkers7 suggests that heterozygosity for CFTR mutations has pathogenic consequences which contribute to the development of bronchiectasis in adult patients. Further multicentre studies on a larger cohort of clinically well defined DB patients are needed to resolve these conflicting results.
References
King PT, Freezer NJ, Holmes PW, et al. Role of CFTR mutations in adult bronchiectasis. Thorax 2004;59:357–8.[
Fanen P , Ghanem N, Vidaud M, et al. Molecular characterization of cystic fibrosis: 16 novel mutations identified by analysis of the whole cystic fibrosis conductance transmembrane regulator (CFTR) coding regions and splice site junctions. Genomics 1992;13:770–6.
Shrimpton AE. R117H and IVS8-5T cystic fibrosis mutation detection by restriction enzyme digestion. Mol Diagn 2000;5:235–8.
Pignatti PF, Bombieri C, Marigo C, et al. Increased incidence of cystic fibrosis gene mutations in adults with disseminated bronchiectasis. Hum Mol Genet 1995;4:635–9.
Girodon E , Cazeneuve C, Lebargy F, et al. CFTR gene mutations in adults with disseminated bronchiectasis. Eur J Hum Genet 1997;5:149–55.
Tzetis M , Efthymiadou A, Strofalis S, et al. CFTR gene mutations—including three novel nucleotide substitutions—and haplotype background in patients with asthma, disseminated bronchiectasis and chronic obstructive pulmonary disease. Hum Genet 2001;108:216–21.
Casals T , De-Gracia J, Gallego M, et al. Bronchiectasis in adult patients: an expression of heterozigosity for CFTR gene mutations? Clin Genet 2004;65:490–5.
Bombieri C , Benetazzo M, Saccomani A, et al. Complete mutational screening of the CFTR gene in 120 patients with pulmonary disease. Hum Genet 1998;103:718–22.
Ravnik-Glavac M , Dean M, Glavac D. Study of mutant and polyvariant mutant CFTR genes in patients with congenital absence of the vas deferens. Pflugers Arch-Eur J Physiol 2000;439 (Suppl 3) :R53–5.
Ockenga J , Sthrumann M, Ballmann M, et al. Mutations of the CFTR gene, but not cationic trypsinogen gene, are associated with recurrent or chronic pancreatitis. Am J Gastroenterol 2000;95:2061–7.
Divac A , Nikolic A, Mitic-Milikic M, et al. High frequency of the R75Q CFTR variation in patients with chronic obstructive pulmonary disease. J Cystic Fibrosis 2004;3:189–91.(A Divac, A Nikolic, M Mit)
Correspondence to:
Dr D Radojkovic
Institute of Molecular Genetics and Genetic Engineering,P O Box 23, Belgrade 11010, Serbia and Montenegro;dada@eunet.yu
Keywords: disseminated bronchiectasis; CFTR; genetics
The recently published paper by King et al1 prompted us to report the results of our study of 19 Serbian patients with disseminated bronchiectasis (DB) of unknown cause for whom complete screening of the CFTR gene was performed. Our patients consisted of four men and 15 women of mean age 54.5 years (range 24–79); the mean age at onset of the disease was 38.8 years. The diagnosis was based on high resolution computed tomographic (HRCT) scanning. Known and common causes of bronchiectasis such as primary ciliary dyskinesia, immunodeficiency, and 1--antytripsin deficiency were excluded. Most of the patients had Pseudomonas aeruginosa isolated from their sputum. Pulmonary function tests were performed in 16 of the 19 patients. The remaining three were unable to undergo these tests because of the severity of their disease. Mean (SD) forced vital capacity (FVC) was 66.6 (20.5)% of predicted and mean (SD) forced expiratory volume in 1 second (FEV1) was 55.3 (24.0)% of predicted.
The whole coding region and intronic boundaries of the CFTR gene were analysed by denaturing gradient gel electrophoresis (DGGE) and subsequent DNA sequencing.2 The IVS8-5T, IVS8-7T, and IVS8-9T alleles of polymorphic Tn locus in intron 8 of the CFTR gene were detected using the PSM method.3 CFTR mutations were detected in two of the 19 patients with DB. The cumulative allelic frequency of mutations in this group of patients was 7.9% (3/38 chromosomes). The IVS8-5T allele was not found in any of the patients. Controversial data on the role of the 5T variant in patients with bronchiectasis have been reported. Pignatti and coworkers4 analysed 16 patients with bronchiectasis and suggested that the 5T variant had a similar role to that described in the congenital bilateral absence of vas deferens (CBAVD) phenotype. However, later studies1,5–7 did not find a higher frequency of the 5T variant in patients with bronchiectasis.
The incidence of the M470 allele in our patients was 28.9% (11/38 alleles). M470V (nucleotide change 1540A/G) is a common change known to affect the functionality and maturation of the CFTR protein. In addition, several common silent mutations (1716G/A, 2694T/G, 4002A/G, 4404C/T) and nucleotide changes in non-coding regions (875+40A/G, GATT6/7, 1011+11C/T) were identified. One of the patients with DB was a compound heterozygote (V920L/R75Q) and one was heterozygous for R75Q. Several groups have reported R75Q in patients with DB, CBAVD, chronic pancreatitis, asthma and chronic obstructive pulmonary disease.5,6,8,9,10,11
In contrast to previous reports,4–7 the frequency of CFTR mutations in patients with DB was not significantly higher than in our general population (2.17%, unpublished data, 2003). Because of the small sample size, these results are preliminary and need to be confirmed in a large study, but the strength of our study lies in the strict clinical selection of patients and the fact that the complete coding region of the CFTR gene was screened.
Our results support the recently published data by King et al1 whose findings also do not indicate a major role for CFTR gene mutations in the aetiology of DB. On the other hand, a recently published paper by Casals and coworkers7 suggests that heterozygosity for CFTR mutations has pathogenic consequences which contribute to the development of bronchiectasis in adult patients. Further multicentre studies on a larger cohort of clinically well defined DB patients are needed to resolve these conflicting results.
References
King PT, Freezer NJ, Holmes PW, et al. Role of CFTR mutations in adult bronchiectasis. Thorax 2004;59:357–8.[
Fanen P , Ghanem N, Vidaud M, et al. Molecular characterization of cystic fibrosis: 16 novel mutations identified by analysis of the whole cystic fibrosis conductance transmembrane regulator (CFTR) coding regions and splice site junctions. Genomics 1992;13:770–6.
Shrimpton AE. R117H and IVS8-5T cystic fibrosis mutation detection by restriction enzyme digestion. Mol Diagn 2000;5:235–8.
Pignatti PF, Bombieri C, Marigo C, et al. Increased incidence of cystic fibrosis gene mutations in adults with disseminated bronchiectasis. Hum Mol Genet 1995;4:635–9.
Girodon E , Cazeneuve C, Lebargy F, et al. CFTR gene mutations in adults with disseminated bronchiectasis. Eur J Hum Genet 1997;5:149–55.
Tzetis M , Efthymiadou A, Strofalis S, et al. CFTR gene mutations—including three novel nucleotide substitutions—and haplotype background in patients with asthma, disseminated bronchiectasis and chronic obstructive pulmonary disease. Hum Genet 2001;108:216–21.
Casals T , De-Gracia J, Gallego M, et al. Bronchiectasis in adult patients: an expression of heterozigosity for CFTR gene mutations? Clin Genet 2004;65:490–5.
Bombieri C , Benetazzo M, Saccomani A, et al. Complete mutational screening of the CFTR gene in 120 patients with pulmonary disease. Hum Genet 1998;103:718–22.
Ravnik-Glavac M , Dean M, Glavac D. Study of mutant and polyvariant mutant CFTR genes in patients with congenital absence of the vas deferens. Pflugers Arch-Eur J Physiol 2000;439 (Suppl 3) :R53–5.
Ockenga J , Sthrumann M, Ballmann M, et al. Mutations of the CFTR gene, but not cationic trypsinogen gene, are associated with recurrent or chronic pancreatitis. Am J Gastroenterol 2000;95:2061–7.
Divac A , Nikolic A, Mitic-Milikic M, et al. High frequency of the R75Q CFTR variation in patients with chronic obstructive pulmonary disease. J Cystic Fibrosis 2004;3:189–91.(A Divac, A Nikolic, M Mit)