Chloride conductance and genetic background modulate the cystic fibrosis phenotype of ΔF508 homozygous twins and siblings
Inez Bronsveld, Frauke Mekus, Jan Bijman, Manfred Ballmann, Hugo R. de Jonge, Ulrike Laabs, Dicky J. Halley, Helmut Ellemunter, Gianni Mastella, Stephen Thomas, Henk J. Veeze, Burkhard Tümmler
Inez Bronsveld, Frauke Mekus, Jan Bijman, Manfred Ballmann, Hugo R. de Jonge, Ulrike Laabs, Dicky J. Halley, Helmut Ellemunter, Gianni Mastella, Stephen Thomas, Henk J. Veeze, Burkhard Tümmler
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Article

Chloride conductance and genetic background modulate the cystic fibrosis phenotype of ΔF508 homozygous twins and siblings

Abstract

To investigate the impact of chloride (Cl–) permeability, mediated by residual activity of the cystic fibrosis transmembrane conductance regulator (CFTR) or by other Cl– channels, on the manifestations of cystic fibrosis (CF), we determined Cl– transport properties of the respiratory and intestinal tracts in ΔF508 homozygous twins and siblings. In the majority of patients, cAMP and/or Ca2+-regulated Cl– conductance was detected in the airways and intestine. Our finding of cAMP-mediated Cl– conductance suggests that, in vivo, at least some ΔF508 CFTR can reach the plasma membrane and affect Cl– permeability. In respiratory tissue, the expression of basal CFTR-mediated Cl– conductance, demonstrated by 30% of ΔF508 homozygotes, was identified as a positive predictor of milder CF disease. In intestinal tissue, 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid–insensitive (DIDS-insensitive) Cl– secretion, which is indicative of functional CFTR channels, correlated with a milder phenotype, whereas DIDS-sensitive Cl– secretion was observed mainly in more severely affected patients. The more concordant Cl– secretory patterns within monozygous twins compared with dizygous pairs imply that genes other than CFTR significantly influence the manifestation of the basic defect.

Authors

Inez Bronsveld, Frauke Mekus, Jan Bijman, Manfred Ballmann, Hugo R. de Jonge, Ulrike Laabs, Dicky J. Halley, Helmut Ellemunter, Gianni Mastella, Stephen Thomas, Henk J. Veeze, Burkhard Tümmler

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Figure 7

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Wfh% plotted against the influence of DIDS on the Cl– secretory response...
Wfh% plotted against the influence of DIDS on the Cl– secretory response, calculated as the difference between the carbachol response before the incubation of the tissue with DIDS, and the histamine response in the presence of DIDS. Values are plotted for siblings of CONmild (filled circles) pairs, CONsevere (open circles) pairs, and the mildly affected and severely affected siblings of DISC pairs (DISCmild, filled triangles; and DISCsevere, open triangles). All CONmild and DISCmild siblings except one exhibited either a small negative or even a positive influence of DIDS, meaning that DIDS did not inhibit Cl– secretion in these individuals. In contrast, DIDS inhibited the majority of Cl– secretory responses of the CONsevere and DISCsevere siblings. This negative DIDS influence correlated significantly with the CONsevere and DISCsevere patients (P = 0.03, Fisher’s exact test). Moreover, the magnitude of wfh% correlated with the magnitude of the DIDS influence (P < 0.025, Spearman’s test).