Elsevier

The Journal of Pediatrics

Volume 127, Issue 5, November 1995, Pages 705-710
The Journal of Pediatrics

Correlation of sweat chloride concentration with classes of the cystic fibrosis transmembrane conductance regulator gene mutations,☆☆,,★★

https://doi.org/10.1016/S0022-3476(95)70157-5Get rights and content

Abstract

Objective: To compare differences in epithelial chloride conductance according to class of mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Methods: We evaluated the relationship between the functional classes of CFTR mutations and chloride conductance using the first diagnostic sweat chloride concentration in a large cystic fibrosis (CF) population. Results: There was no difference in sweat chloride value between classes of CFTR mutations that produce no protein (class I), fail to reach the apical membrane because of defective processing (class II), or produce protein that fails to respond to cyclic adenosine monophosphate (class III). Those mutations that produce a cyclic adenosine monophosphate-responsive channel with reduced conductance (class IV) were associated with a significantly lower, intermediate sweat chloride value. However, patients with the mutations that cause reduced synthesis or partially defective processing of normal CFTR (class V) had sweat chloride concentrations similar to those in classes I to III. Conclusion: Studies of differences in chloride conductance between functional classes of CFTR mutations provide insight into phenotypic expression of the disease. (J PEDIATR 1995;127:705-10)

Section snippets

METHODS

The study group was assembled by a retrospective review of the 455 patients who attended the CF clinic at the Hospital for Sick Children in Toronto and who had two identified CF mutations, at least one of which was ΔF508. The patients were first grouped on the basis of the CFTR genotypes. Except for ΔF508 homozygous patients and heterozygous patients with a few common mutations, most of the genotype groups were small. To increase the sample size for analysis, we further grouped the patients

RESULTS

There were no statistically significant differences in sweat chloride concentrations between those patients homozygous for ΔF508 (class II) and the class I group, including those with ΔF508/stop or ΔF508/frameshift mutations (Table). However, those patients with the class I mutations of ΔF508/splice junction had significantly lower sweat chloride values. Only two patients in class I had a PS phenotype-two siblings with 875+1G(r)C. One patient in class II had a PS phenotype.

There were no

DISCUSSION

The results of this analysis show that there is no difference in chloride conductance between patients with mutations that fail to produce a complete CFTR protein and those patients in whom the CFTR protein fails to traffic to the epithelial membrane. This observation is not surprising because in both situations there is no anatomic channel in situ. However, in the case of ΔF508, the most common class II mutation, experimental studies demonstrate chloride channel responsiveness to appropriate

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  • Cited by (195)

    • Modulators of CFTR. Updates on clinical development and future directions

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      Citation Excerpt :

      The sweat test remains one of the most sensitive biomarkers, widely used during clinical trials for its dynamic range and its capacity to adjust quickly. Sweat Cl− concentration was previously shown to differ at the basal state depending on the mutation class, with notably lower concentrations for class IV mutations [92]. More recently, changes in sweat Cl− concentration were related to variations in other interesting biomarkers, such as nasal potential difference (NPD) and intestinal current measurements (ICM) in patients initiating Orkambi® treatment [93,94].

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    From the Department of Genetics and the Division of Gastroenterology, Chest and Cystic Fibrosis Research, Research Institute, Hospital for Sick Children, and the Departments of Pediatrics and Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada

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    Supported by research grants from the Canadian Cystic Fibrosis Foundation and from the National Institutes of Health (DDK-P50-DK41980). Dr. Wilschanski is supported by a research fellowship from the Canadian Cystic Fibrosis Foundation, Janssen Pharmaceutica, and American Physicians Fellowship.

    Reprint requests: P. R. Durie, MD, FRCP(C), Head, Division of Gastroenterology and Nutrition, Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada.

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    0022-3476/95/$5.00 + 0 9/20/67454

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