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Original Research: CYSTIC FIBROSIS |

Prospective Analysis of Cystic Fibrosis Transmembrane Regulator Mutations in Adults With Bronchiectasis or Pulmonary Nontuberculous Mycobacterial Infection* FREE TO VIEW

Tomasz M. Ziedalski, MD; Peter N. Kao, PhD, MD; Noreen R. Henig, MD, FCCP; Susan S. Jacobs, RN; Stephen J. Ruoss, MD
Author and Funding Information

*From the Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, Stanford, CA.

Correspondence to: Stephen J. Ruoss, MD, Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, 300 Pasteur Dr, Stanford, CA 94305-5236; e-mail: ruoss@stanford.edu



Chest. 2006;130(4):995-1002. doi:10.1378/chest.130.4.995
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Background: Bronchiectasis and pulmonary infection with nontuberculous mycobacteria (NTM) may be associated with disease-causing mutations in the cystic fibrosis transmembrane regulator (CFTR).

Methods: Fifty adult patients at Stanford University Medical Center with a diagnosis of bronchiectasis and/or pulmonary NTM infection were prospectively characterized by sweat chloride measurement, comprehensive mutational analysis of CFTR, and sputum culture results.

Results: A de novo diagnosis of cystic fibrosis (CF) was established in 10 patients (20%). Patients with CF were more likely than those without CF to have mucus plugging seen on chest high-resolution CT, and women with a CF diagnosis were thinner, with a significantly lower mean body mass index than the non-CF subjects. Thirty CFTR mutations were identified in 24 patients (50% prevalence). Sweat chloride concentration was elevated > 60 mEq/dL (diagnostic of CF) in seven patients (14%), and from 40 to 60 mEq/dL in eight patients (16%). The frequency of CFTR mutations was elevated above that expected in the general population: heterozygous ΔF508 (12% vs 3%), R75Q (14% vs 1%), and intron 8 5T (17% vs 5 to 10%). Other known CFTR mutations identified were V456A, G542X, R668C, I1027T, D1152, R1162L, W1282X, and L183I. Three novel CFTR mutations were identified: A394V, F650L, and C1344S.

Conclusions: Mutations in CFTR that alter RNA splicing and/or functional chloride conductance are common in this population, and are likely to contribute to the susceptibility and pathogenesis of adult bronchiectasis and pulmonary NTM infection. Careful clinical evaluation for disease cause should be undertaken in this clinical context.

Bronchiectasis is a disease of the airways characterized by luminal dilation that develops as a consequence of chronic mucosal and submucosal injury, inflammation, and remodeling. The clinical manifestations include chronic cough productive of purulent sputum and airflow obstruction.1 The epidemiology, genetics, and pathogenesis of bronchiectasis are complex and incompletely understood.

An intriguing and increasingly common clinical presentation of adult bronchiectasis involves women who have chronic cough and purulent sputum production associated with airway infection during the fifth to seventh decades of life.24 These women typically have no preexisting pulmonary disease, no smoking history, and no identified underlying immune deficiency. The reported ethnicity of affected individuals is most often white, although other ethnic groups are also affected.4 Bronchiectasis in these patients is typically anatomically diffuse, although the manifestations are often most prominent in the right middle lobe and/or lingula.45 A frequent distinguishing feature of these patients with adult onset of diffuse bronchiectasis is recurrent airway infection with nontuberculous mycobacteria (NTM) species, such as Mycobacterium avium.,24

Cystic fibrosis (CF) is an autosomal-recessive disease caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene.67 Certain CFTR mutations lead to a defective cyclic adenosine monophosphate-stimulated chloride channel in the plasma membrane of secretory epithelial cells. The presence of two allelic CFTR mutations is associated with classic CF phenotypes of progressive bronchiectasis leading to respiratory failure, pancreatic exocrine and endocrine insufficiency, chronic sinusitis and, in males, congenital bilateral absence of the vas deferens (CBAVD). Atypical or mild CF phenotypes have also been described in patients with two allelic mutations of CFTR and abnormal pilocarpine iontophoretic sweat chloride concentrations. Single mutations of CFTR have also been associated with diseases other than classic CF, including isolated CBAVD,9 cryptogenic pancreatitis,1011 allergic bronchopulmonary aspergillosis,12and chronic sinusitis.13

Given some of the shared clinical features of CF and adult idiopathic bronchiectasis, CFTR has been considered as a candidate genetic participant in the etiology of idiopathic bronchiectasis.1424 Three early studies2527 detected an increased frequency of ΔF508, the most common CFTR mutation, in patients with chronic bronchial hypersecretion, disseminated bronchiectasis, and bronchiectasis with increased sweat chloride concentrations. These studies were limited by both their sample size and the limited CFTR genetic analysis that was available. The continuing identification of new CFTR mutations (> 1,300) leaves the biological roles of a large number of CFTR mutations incompletely characterized (CFTR Mutation Database: http://www.genet.sickkids.on.ca/cftr/; latest database accession: June 5, 2006).

Concomitant airway infection plays an active and important role in the pathogenesis and progression of bronchiectasis.1 The substantial frequency of NTM infections in adult-onset diffuse bronchiectasis raises an important question about the etiologic contribution of these pathogens to the progression of disease. This same question is of current importance in CF, in which studies2829 have highlighted a significant incidence (13%) of chronic NTM infections in patients with documented CF and bronchiectasis. Given the high degree of concordance between NTM infection and bronchiectasis, we investigated potential underlying causes for both pulmonary NTM infection and bronchiectasis.

Studies3035 seeking to identify subtle immune deficiencies that might confer susceptibility to pulmonary NTM infection demonstrated genetic mutations in a few patients in the interferon-γ, interleukin-12, and nuclear factor-κB essential modulator pathways. However, the limited numbers of patients and the phenotypic manifestations at young ages make these genetic mutations insufficient to account for the majority of cases of adult-onset pulmonary NTM infection.

The present study explores the hypothesis that adult-onset diffuse bronchiectasis and pulmonary NTM infection may result from abnormal CFTR gene expression. Implicit in this hypothesis is a need to consider a broader range of abnormalities of CFTR gene expression or function as important contributing factors in the pathogenesis of pulmonary NTM infection and bronchiectasis in adults.

Patient Population

The study was approved by the Stanford University Institutional Review Board, and all subjects provided written informed consent to participate. Fifty patients with bronchiectasis and/or symptomatic NTM infection were prospectively enrolled through the Stanford University Medical Center adult pulmonary medicine clinic from January 2003 through April 2004. Some of these patients (n = 7) had been seen previously at Stanford University Medical Center but had not undergone evaluation for the cause of the bronchiectasis. Following institutional review board approval, any new or returning patient with a diagnosis of bronchiectasis and/or pulmonary NTM infection was approached during their next chest clinic visit and invited to participate in the study. Subjects with a prior known cause for their bronchiectasis were excluded from this study. Subjects with known immune compromised states, current therapy with immune modulating therapies, known malignancy, or inability to follow instructions were excluded. A diagnosis of bronchiectasis was established by high-resolution CT (HRCT) of the chest and, as outlined above, a specific etiology of the bronchiectasis was undetermined at study entry. All diagnoses of pulmonary NTM infection were established in accordance with standard published diagnostic criteria.36 Respiratory specimen cultures were obtained with the following guidelines: bronchoscopy and lavage were offered to the patient if the patient was unable to expectorate adequate quality sputum samples (defined as samples with polymorphonuclear leukocytes present and with < 10 epithelial cells per low power field). Additionally, if nodular pulmonary infiltrates with a “tree-in-bud” pattern were observed on HRCT (suggesting the presence of mycobacterial infection), study subjects were also offered bronchoscopy with lavage if they did not have a prior NTM infection diagnosis.

CFTR Genotyping

Peripheral blood samples were obtained by routine venopuncture. Genetic testing of subject DNA for > 1,300 CFTR mutations was performed by Ambry Genetics (Aliso Viejo, CA). From genomic DNA, all CFTR exons as well as relevant intronic regions were amplified by polymerase chain reaction using proprietary genomic DNA primers. Polymerase chain reaction products were processed by modified temporal temperature gradient electrophoresis analysis (DCode gels; BioRad; Hercules, CA). Regions indicating the presence of a mutation were subsequently sequenced. Exons were sequenced in both sense and antisense directions because, in rare instances, only one direction may give adequate sequence due to repeat regions such as the polyT site upstream of CFTR exon 9. This genetic assay screens all CFTR exons (OMIM 602421), at least 20 bases 5′ and 3′ into each intron, and selected deep intronic mutations.

Sweat Chloride Measurements

Pilocarpine iontophoresis sweat chloride tests were performed at Lucile Packard Children’s Hospital, Stanford, CA, in compliance with Cystic Fibrosis Foundation guidelines. This sweat chloride testing laboratory is regularly reviewed and accredited by the Cystic Fibrosis Foundation. In accordance with consensus criteria, a sweat chloride concentration > 60 mEq/dL was considered diagnostic of CF; a concentration of 40 to 60 mEq/dL was considered indeterminate; and a sweat chloride concentration < 40 mEq/dL was considered to not support a diagnosis of CF.37

Pulmonary Function Testing

The evaluation and interpretation of spirometry, lung volumes, and diffusion capacity of the lung for carbon monoxide (Dlco) were conducted in accordance with American Thoracic Society guidelines.38

Microbiology

Sputum samples from all subjects were processed by the Stanford University Medical Center clinical microbiology laboratory for routine bacterial, mycobacterial, and fungal cultures.

Statistical Analysis

Subjects were classified into groups based on sweat chloride test results: group 1, sweat chloride concentration < 40 mEq/dL; group 2, an indeterminate sweat chloride concentration of 40 to 60 mEq/dL; and group 3, sweat chloride concentration > 60 mEq/dL. Differences in the prevalence of CFTR mutations in these three groups were analyzed using the χ2 method. A two-sided Student t test was used to compare differences between continuous phenotypic variables including FEV1, FVC, and Dlco. Chest CT results were compared by the Fisher Exact Test, and the body mass index (BMI) data were analyzed using analysis of variance.

Fifty subjects (42 women and 8 men) aged 28 to 82 years (mean, 61.4 years) were enrolled. Thirty subjects (60%) had both bronchiectasis and pulmonary NTM, while 17 subjects (34%) had bronchiectasis alone without NTM infection. Three subjects (6%) had a pulmonary NTM infection without evidence of bronchiectasis on HRCT studies. There was no apparent association between specific pulmonary pathogens recovered and particular CFTR mutations or sweat chloride measurements.

Mean BMI was 22.1 ± 3.40 for the 42 subjects with available data. Using Centers for Disease Control and Prevention standard criteria, BMI < 18.5 is considered “underweight” and BMI from 18.5 to 24.9 is considered “normal.” In our population, 45% of subjects were either underweight or at the low normal range according to their BMI. When all subjects with a CF diagnosis were compared with non-CF subjects, there was a nonsignificant (p = 0.09 by single-factor analysis of variance analysis) difference in BMI, with BMI (mean ± SE) of 20.4 ± 3.6 and 22.6 ± 3.2 for the CF and non-CF subjects, respectively. If only the women in the study (84% of the study population) are included in a BMI analysis, the differences in mean BMI are significant: 19.7 ± 3.43 vs 22.6 ± 2.94 (p = 0.02) for women with CF and without CF, respectively.

In this population, there was no difference in the prevalence of sinusitis when comparing subjects who were found to have CF with those who did not have a new CF diagnosis. Of note, only 3 of 10 subjects with a CF diagnosis had any history of sinusitis.

Examination of chest HRCT findings in this study population found that the anatomic distribution and pattern of bronchiectasis did not correlate with the presence or absence of CF. However, there was a substantial trend toward finding mucus plugging more frequently in CF subjects as compared with non-CF subjects. Review of HRCT interpretations by radiologists (who were blinded to the cause of bronchiectasis in study subjects) demonstrated mucus plugging on HRCT scans for 3 of 10 subjects (30%) with CF, compared with mucus plugging seen in only 3 of 40 non-CF subjects (7.5%) [p = 0.085, Fisher exact test]. Of the eight men, one was separately found to be infertile due to primary ciliary dyskinesia.

Ten subjects (20%) had sweat chloride concentrations > 60 mEq/dL and/or two known pathologic CFTR mutations (Table 1 ). Of these 10 subjects who met diagnostic criteria for CF, 3 had both two established pathologic CFTR mutations and a sweat chloride concentration > 60 mEq/dL, and 5 had sweat chloride concentrations > 60 mEq/dL but 0 to one CFTR mutations. Importantly, while the remaining two subjects in this group did not have diagnostic sweat chloride concentrations > 60 mEq/dL, each was found to carry two pathologic CFTR mutations, including both common and rare mutations. The most common CFTR mutation identified was ΔF508, which occurred in 3 of the 10 subjects. Other identified mutations included R75Q, G542X, V4566A, D1152H, F650L, I1027T, W1282X, and the intron 8 polymorphism IVS 8 5T.

Eight subjects (16%) had indeterminate sweat chloride concentrations of 40 to 60 mEq/dL (Table 2 ). Only two subjects had a known pathologic CFTR mutation (patient 15, R75Q; patient 18, IVS8 5T).

Thirty-two subjects (62%) had sweat chloride concentrations < 40 mEq/dL. A sweat chloride measurement could not be obtained for one subject despite three attempts. Of note, 14 subjects in this subgroup were heterozygotes for CFTR mutations (Table 3 ). R75Q was the most prevalent mutation (n = 5), followed by the IVS 8 5T polymorphism (n = 5) and ΔF508 (n = 2). We also identified three novel CFTR mutations, each in a separate patient with a normal sweat chloride concentration: A394V, C1344S, and F650L. A fourth mutation (L183I) was found that was thought to be novel, but in the course of manuscript preparation and review this mutation was found to have been previously reported.

Of the 50 subjects in the study, 24 subjects (50%) had pathologic CFTR mutations identified. Of interest, the R75Q mutation was detected in seven subjects (frequency, 14%), while ΔF508 mutations were found in six subjects (frequency, 12%). The intron 8 5T polymorphism was found in nine subjects (frequency, 17%). There were no significant differences in the distribution and number of mutations among the three sweat chloride diagnostic groups. The groups also did not differ with respect to HRCT bronchiectasis or type of chronic infection. There also appears to be no clear association between the presence of particular NTM species, or specific bacterial pathogens, and a specific CFTR genotype. Comparison of pulmonary function test data did not demonstrate significant differences between the three groups for either FEV1 or FVC. There was a trend toward lower Dlco among patients with sweat chloride levels > 40 mEq/dL (Table 4 ), but this difference did not reach statistical significance (p = 0.058).

This prospective study revealed that 20% of patients presenting to an adult pulmonary clinic with bronchiectasis and/or pulmonary NTM infection were conferred a de novo diagnosis of CF based on sweat chloride concentration or identification of two CFTR gene mutations. The study illuminates a number of important clinical points. First, the presence of bronchiectasis and/or pulmonary NTM infection in adults can be associated with a significant risk for the presence of occult CF. Second, a diagnosis of CF in adult years is associated with a broader variety of CFTR mutations than are typically encountered in a younger CF population. Third, we have identified added novel CFTR mutations in this adult population, as well as an unusually high prevalence of typically infrequent mutations (eg, R75Q) in this population. This finding is in part the consequence of our more exhaustive search for CFTR mutations than the screening undertaken in most of the prior studies in adult populations.

This study also identifies some clinical characteristics that suggest a diagnosis of CF in adults presenting for evaluation of bronchiectasis. A low BMI appears to correlate with the presence of CF, particularly in women. The finding of mucus plugging on chest HRCT is also suggestive of a CF diagnosis from our data. The difference in prevalence of mucus plugging between CF and non-CF subjects (30% vs 7.5%) did not reach statistical significance, but that may be due to the relatively small numbers in this study. In contrast to the above clinical clues to the presence of CF, sinusitis was not useful as a predictive parameter for a CF diagnosis, this despite a more common finding of sinusitis in typical CF populations.

The use of a more extensive screen for CFTR mutations resulted in additional diagnoses that would not have been found if we had used as our CFTR genetic screen the more commonly used commercially available 97-mutation screen. Use of the 97-mutation CFTR screen as the genetic analysis method in this study would have missed one of the 10 confirmed CF cases in this study. Additionally, it would not have identified the heterozygous state for CFTR in 7 of the 32 subjects with normal sweat chloride concentrations, some of whom also have other CFTR abnormalities, including M470V and 5T IVS8. These apparent CFTR heterozygotes may yet be shown to have clinically relevant abnormalities in CFTR function despite their normal sweat chloride concentrations.

The increased number of CFTR gene mutations present in this study population was greater than would be expected in the general population. Altogether, 33 pathologic CFTR mutations were identified in 26 of 50 prospective study patients. The most phenotypically severe CFTR mutation, ΔF508, was present in 12% of subjects in this study, compared to the general frequency of 3% in the white population in the United States.3940 The R75Q mutation frequency was 14% in this study, compared to the general frequency of 1% in Northern Europeans.41The intron 8 5T polymorphism was present in 17% of subjects in this study, compared to 5 to 10% in the general population.4243CFTR mutations identified in this study, including ΔF508, R75Q, R117H, S1235R, D1152, L183I, and IVS8 5T, have been associated with mild symptoms of CF41,4446 or with atypical manifestations of CF, such as isolated bronchiectasis1417,1920,2223,2527 and CBAVD.4243,47 This study also reports three novel CFTR mutations, each in a separate patient with normal sweat chloride level: A394V, C1344S, and F650L. Our results lend further support to the emerging perception that simple heterozygote carriers of CFTR mutations may be at risk for evolution of disease related to abnormal function of this gene product.,23,48

The slow, or late, development of bronchiectasis and pulmonary NTM infection predominantly in postmenopausal white women has suggested the possible presence of a subtle immune deficiency in these patients that might be modulated by age and/or hormonal status.31 Whether immune dysfunction is present, and whether (if present) it might be directly influenced by CFTR genotype, remain intriguing and unanswered questions. The expression of functional CFTR protein may be modulated at the level of RNA splicing.39 The intron 8 5T mutation increases the likelihood that exon 9 is aberrantly spliced and deleted during messenger RNA processing in bronchial epithelium.4950 The CFTR exon 9− protein does not form a functional chloride channel.51 Chu et al50 characterized four individuals homozygous for the CFTR IVS8 5T mutation whose levels of exon 9+ CFTR transcripts in bronchial epithelial cells ranged from 10 and 27%, yet each showed normal sweat chloride concentration.

Linkage disequilibrium between the intron 8 5T polymorphism and the M470V polymorphism was present in a cohort of patients with CBAVD compared to normal subjects, and this result suggested that the M470V allele contributed to lower expression of exon 9+ CFTR transcripts.52 The 5T-M470V haplotype was also present at a significantly higher frequency in Korean patients with bronchiectasis than normal subjects.20 Expression of M470V CFTR transcripts produced chloride channels with lower conductance and decreased open-channel probability than wild-type CFTR.53 An increased incidence of M470V heterozygotes as well as homozygotes has been reported in a study population with chronic rhinosinusitis,48 suggesting a significant role for this polymorphism in CFTR dysfunction and the evolution of upper airways disease. Four of the subjects in this study were found to be heterozygous for both M470V and the 5T intron 8 sequence. Although these four subjects all had sweat chloride concentrations < 40 mEq/dL, it is not known whether any of these individuals have cis orientation and a 5T-M470V haplotype, nor how these polymorphisms affect their chloride channel function or clinical status.

The CFTR exon 9 splicing associated with IVS8 5T mutation is also modulated by the number of TG repeats upstream from the polyT domain in intron 8.53Analysis of the IVS8 TG repeat sequences may provide important additional insight into CFTR expression and function in patients such as this cohort, but is beyond the scope of the current study. The efficiency of CFTR RNA splicing and production of nonfunctional CFTR proteins may be modulated by the levels of host cellular RNA splicing factors, the serine-arginine-rich proteins, and heteronuclear ribonucleoproteins and their viral analogs.5455 Further studies on the expression and regulation of aberrant CFTR transcripts in these patients are warranted.

Tissue-specific differences in RNA splicing and functional expression of CFTR protein may account for the presence of pulmonary disease in our study patients, even in the presence of indeterminate or normal sweat chloride results. Of the eight subjects with indeterminate sweat chloride results (40 to 60 mEq/dL), only two subjects had an identifiable CFTR mutation. Nasal potential differences may be useful in this study population to help confirm a diagnosis of CF and characterize functional chloride conductance.56Interactions between CFTR and the epithelial Na+ channels contribute to the regulation of mucosal chloride conductance.57 This will be further explored in a subsequent study.

Our demonstration of a 50% prevalence of CFTR mutations in 50 prospective patients with adult bronchiectasis and/or pulmonary NTM infection strongly supports an important role for CFTR dysfunction in the pathogenesis of these concurrent diseases. In summary, clinicians should maintain a high index of suspicion for CF as a cause of bronchiectasis in adults. Clinical presentation with low BMI and/or mucus plugging on HRCT should, from these data, increase the suspicion for the presence of CF. In cases with equivocal sweat chloride concentrations (approximately 40 to 59 mEq/dL), our data support undertaking a more exhaustive genetic search for CFTR mutations, including in noncoding regions (eg, IVS8) that can significantly affect the expression and function of CFTR and alter airways biology.

Abbreviations: BMI = body mass index; CBAVD = congenital bilateral absence of the vas deferens; CF = cystic fibrosis; CFTR = cystic fibrosis transmembrane regulator; Dlco = diffusion capacity of the lung for carbon monoxide; HRCT = high-resolution CT; NTM = nontuberculous mycobacteria

The authors have no conflicts of interest with respect to this article.

Table Graphic Jump Location
Table 1. Subjects With Diagnosis of CF*
* 

Bronch = bronchiectasis (Bronch); F = female; M = male; Y = yes; N = no.

 

NTM infection includes M avium complex (MAC), Mycobacterium chelonae (MCh), Mycobacterium fortuitum, Mycobacterium simiae (Msi), Mycobacterium kansasii (Mka), Mycobacterium gordonae, Mycobacterium xenopi, and Mycobacterium abcessus.

 

Other infections include Pseudomonas aeruginosa (PA), Staphylococcus aureus (SA), and Stenotrophomonas maltophilia (S malto).

§ 

Intervening sequence (intron) 8 poly-T tract polymorphism status on each chromosome is reported. The wild type is considered to be 9T/9T.

Table Graphic Jump Location
Table 2. Subjects With Indeterminate Sweat Chloride Concentrations (40 to 60 mEq/dL)*
* 

See Table 1 for expansion of abbreviations.

 

Pulmonary NTM infections include M gordonae (Mgo).

Table Graphic Jump Location
Table 3. Subjects With Normal Sweat Chloride Concentrations (< 40 mEq/dL)*
* 

See Tables 1and 2 for expansion of abbreviations.

 

Pulmonary NTM infections include M abcessus (Mab), M fortuitum (Mfo),M xenopi (Mxe), and Mycobacterium mucogenicus (Mmu).

 

Other infections include Aspergillus fumigatus (Asp) and Nocardia asteroides (Noc).

§ 

Inadequate sweat for testing despite three separate attempts.

Table Graphic Jump Location
Table 4. Relationship of Sweat Chloride Concentration to CFTR Mutation Status and Selected Clinical Parameters*
* 

See Table 1 for expansion of abbreviation.

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Dork, T, Dworniczak, B, Aulehla-Scholz, C, et al Distinct spectrum ofCFTRgene mutations in congenital absence of vas deferens.Hum Genet1997;100,365-377. [CrossRef] [PubMed]
 
Feldmann, D, Rochemaure, J, Plouvier, E, et al Mild course of cystic fibrosis in an adult with the D1152H mutation [letter]. Clin Chem. 1995;;41 ,.:1675
 
Groman, JD, Meyer, ME, Wilmott, RW, et al Variant cystic fibrosis phenotypes in the absence ofCFTRmutations.N Engl J Med2002;347,401-407. [CrossRef] [PubMed]
 
Lebecque, P, Leal, T, De Boeck, C, et al Mutations of the cystic fibrosis gene and intermediate sweat chloride levels in children.Am J Respir Crit Care Med2002;165,757-761. [PubMed]
 
Claustres, M, Guittard, C, Bozon, D, et al Spectrum ofCFTRmutations in cystic fibrosis and in congenital absence of the vas deferens in France.Hum Mutat2000;16,143-156. [CrossRef] [PubMed]
 
Wang, X, Moylan, B, Leopold, DA, et al Mutation in the gene responsible for cystic fibrosis and predisposition to chronic rhinosinusitis in the general population.JAMA2000;284,1814-1819. [CrossRef] [PubMed]
 
Chu, CS, Trapnell, BC, Murtagh, JJ, Jr, et al Variable deletion of exon 9 coding sequences in cystic fibrosis transmembrane conductance regulator gene mRNA transcripts in normal bronchial epithelium.EMBO J1991;10,1355-1363. [PubMed]
 
Chu, CS, Trapnell, BC, Curristin, SM, et al Extensive posttranscriptional deletion of the coding sequences for part of nucleotide-binding fold 1 in respiratory epithelial mRNA transcripts of the cystic fibrosis transmembrane conductance regulator gene is not associated with the clinical manifestations of cystic fibrosis.J Clin Invest1992;90,785-790. [CrossRef] [PubMed]
 
Strong, TV, Wilkinson, DJ, Mansoura, MK, et al 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 Genet1993;2,225-230. [CrossRef] [PubMed]
 
de Meeus, A, Guittard, C, Desgeorges, M, et al Linkage disequilibrium between the M470V variant and the IVS8 polyT alleles of theCFTRgene in CBAVD.J Med Genet1998;35,594-596. [CrossRef] [PubMed]
 
Cuppens, H, Lin, W, Jaspers, M, et al 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 Invest1998;101,487-496. [CrossRef] [PubMed]
 
Pagani, F, Buratti, E, Stuani, C, et al Splicing factors induce cystic fibrosis transmembrane regulator exon 9 skipping through a nonevolutionary conserved intronic element.J Biol Chem2000;275,21041-21047. [CrossRef] [PubMed]
 
Nissim-Rafinia, M, Chiba-Falek, O, Sharon, G, et al Cellular and viral splicing factors can modify the splicing pattern of CFTR transcripts carrying splicing mutations.Hum Mol Genet2000;9,1771-1778. [CrossRef] [PubMed]
 
Wilschanski, M, Famini, H, Strauss-Liviatan, N, et al Nasal potential difference measurements in patients with atypical cystic fibrosis.Eur Respir J2001;17,1208-1215. [CrossRef] [PubMed]
 
Reddy, MM, Quinton, PM Functional interaction of CFTR and ENaC in sweat glands.Pflugers Arch2003;445,499-503. [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1. Subjects With Diagnosis of CF*
* 

Bronch = bronchiectasis (Bronch); F = female; M = male; Y = yes; N = no.

 

NTM infection includes M avium complex (MAC), Mycobacterium chelonae (MCh), Mycobacterium fortuitum, Mycobacterium simiae (Msi), Mycobacterium kansasii (Mka), Mycobacterium gordonae, Mycobacterium xenopi, and Mycobacterium abcessus.

 

Other infections include Pseudomonas aeruginosa (PA), Staphylococcus aureus (SA), and Stenotrophomonas maltophilia (S malto).

§ 

Intervening sequence (intron) 8 poly-T tract polymorphism status on each chromosome is reported. The wild type is considered to be 9T/9T.

Table Graphic Jump Location
Table 2. Subjects With Indeterminate Sweat Chloride Concentrations (40 to 60 mEq/dL)*
* 

See Table 1 for expansion of abbreviations.

 

Pulmonary NTM infections include M gordonae (Mgo).

Table Graphic Jump Location
Table 3. Subjects With Normal Sweat Chloride Concentrations (< 40 mEq/dL)*
* 

See Tables 1and 2 for expansion of abbreviations.

 

Pulmonary NTM infections include M abcessus (Mab), M fortuitum (Mfo),M xenopi (Mxe), and Mycobacterium mucogenicus (Mmu).

 

Other infections include Aspergillus fumigatus (Asp) and Nocardia asteroides (Noc).

§ 

Inadequate sweat for testing despite three separate attempts.

Table Graphic Jump Location
Table 4. Relationship of Sweat Chloride Concentration to CFTR Mutation Status and Selected Clinical Parameters*
* 

See Table 1 for expansion of abbreviation.

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Hughes, D, Dork, T, Stuhrmann, M, et al Mutation and haplotype analysis of theCFTRgene in atypically mild cystic fibrosis patients from Northern Ireland.J Med Genet2001;38,136-139. [CrossRef] [PubMed]
 
Chillon, M, Casals, T, Mercier, B, et al Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens.N Engl J Med1995;332,1475-1480. [CrossRef] [PubMed]
 
Dork, T, Dworniczak, B, Aulehla-Scholz, C, et al Distinct spectrum ofCFTRgene mutations in congenital absence of vas deferens.Hum Genet1997;100,365-377. [CrossRef] [PubMed]
 
Feldmann, D, Rochemaure, J, Plouvier, E, et al Mild course of cystic fibrosis in an adult with the D1152H mutation [letter]. Clin Chem. 1995;;41 ,.:1675
 
Groman, JD, Meyer, ME, Wilmott, RW, et al Variant cystic fibrosis phenotypes in the absence ofCFTRmutations.N Engl J Med2002;347,401-407. [CrossRef] [PubMed]
 
Lebecque, P, Leal, T, De Boeck, C, et al Mutations of the cystic fibrosis gene and intermediate sweat chloride levels in children.Am J Respir Crit Care Med2002;165,757-761. [PubMed]
 
Claustres, M, Guittard, C, Bozon, D, et al Spectrum ofCFTRmutations in cystic fibrosis and in congenital absence of the vas deferens in France.Hum Mutat2000;16,143-156. [CrossRef] [PubMed]
 
Wang, X, Moylan, B, Leopold, DA, et al Mutation in the gene responsible for cystic fibrosis and predisposition to chronic rhinosinusitis in the general population.JAMA2000;284,1814-1819. [CrossRef] [PubMed]
 
Chu, CS, Trapnell, BC, Murtagh, JJ, Jr, et al Variable deletion of exon 9 coding sequences in cystic fibrosis transmembrane conductance regulator gene mRNA transcripts in normal bronchial epithelium.EMBO J1991;10,1355-1363. [PubMed]
 
Chu, CS, Trapnell, BC, Curristin, SM, et al Extensive posttranscriptional deletion of the coding sequences for part of nucleotide-binding fold 1 in respiratory epithelial mRNA transcripts of the cystic fibrosis transmembrane conductance regulator gene is not associated with the clinical manifestations of cystic fibrosis.J Clin Invest1992;90,785-790. [CrossRef] [PubMed]
 
Strong, TV, Wilkinson, DJ, Mansoura, MK, et al 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 Genet1993;2,225-230. [CrossRef] [PubMed]
 
de Meeus, A, Guittard, C, Desgeorges, M, et al Linkage disequilibrium between the M470V variant and the IVS8 polyT alleles of theCFTRgene in CBAVD.J Med Genet1998;35,594-596. [CrossRef] [PubMed]
 
Cuppens, H, Lin, W, Jaspers, M, et al 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 Invest1998;101,487-496. [CrossRef] [PubMed]
 
Pagani, F, Buratti, E, Stuani, C, et al Splicing factors induce cystic fibrosis transmembrane regulator exon 9 skipping through a nonevolutionary conserved intronic element.J Biol Chem2000;275,21041-21047. [CrossRef] [PubMed]
 
Nissim-Rafinia, M, Chiba-Falek, O, Sharon, G, et al Cellular and viral splicing factors can modify the splicing pattern of CFTR transcripts carrying splicing mutations.Hum Mol Genet2000;9,1771-1778. [CrossRef] [PubMed]
 
Wilschanski, M, Famini, H, Strauss-Liviatan, N, et al Nasal potential difference measurements in patients with atypical cystic fibrosis.Eur Respir J2001;17,1208-1215. [CrossRef] [PubMed]
 
Reddy, MM, Quinton, PM Functional interaction of CFTR and ENaC in sweat glands.Pflugers Arch2003;445,499-503. [PubMed]
 
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