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CORRELATION OF CFTR CL^- CHANNEL FUNCTION IN HUMAN COLON, GENOTYPE AND PHENOTYPE IN CYSTIC FIBROSIS

T Gonska, S Hirtz, HH Seydewitz, J Thomas, P Greiner, J Kuehr, M Brandis, I Eichler, H Rocha, A-I Lopes, C Barreto, MD Amaral, K Kunzelmann, M Mall

BACKGROUND: Cystic fibrosis is caused by defect in the CFTR Cl. channel. Over 1300 known CFTR mutations and a wide spectrum of CF phenotypes challenge genotype-phenotype studies. While mild CFTR mutations have been described in patients presenting with pancreatic sufficiency, severe mutations are associated with pancreatic insufficiency. Some mutations have been studied and categorized in a classification system according to the predicted mechanism of the molecular defect. However, most of the mutations have not been functionally characterized.

METHOD: We investigated the correlation of CFTR function, genotype and phenotype of 45 non-DF508 homozygous patients carrying a wide spectrum of CFTR mutations. Clinical symptoms were recorded and the genotype was determined. CFTR function was assessed by measuring the short circuit current of rectal tissue biopsies using a perfused Ussing-chamber. Genotype and clinical symptoms were compared between CF patients who expressed residual CFTR mediated Cl^- secretion and CF patients in whom no Cl^- secretion was detected.
RESULTS: A subgroup of CF patients who carried at least one missense or splice mutation showed residual CFTR function in the range of 12% to 50% of control subjects. These patients also exhibited milder disease symptoms with a higher frequency of pancreatic sufficiency. The clinical outcome correlated with the magnitude of residual CFTR activity.
CONCLUSION: Specific CFTR mutations exhibit residual CFTR function in rectal epithelial tissues which correlates strongly with a milder CF phenotype. Functional assessment of rectal tissue biopsies in a perfused Ussing-chamber may therefore be useful to predict prognosis in CF disease, and serve as a valuable tool to identify CF patients who may profit from therapeutic strategies aiming to increase CFTR activity.
Supported by the Mukoviszidose eV and the Deutsche Forschungsgemeinschaft (DFG MA 2081/2-1 and KU 1228/1-1)

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