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Am J Physiol Cell Physiol 277: C833-C839, 1999;
0363-6143/99 $5.00
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Vol. 277, Issue 4, C833-C839, October 1999

RAPID COMMUNICATION
Defective function of the cystic fibrosis-causing missense mutation G551D is recovered by genistein

Beate Illek1, Lei Zhang2, Nancy C. Lewis1, Richard B. Moss3, Jian-Yun Dong2, and Horst Fischer1

1 Research Institute and Pulmonary Center, Children's Hospital Oakland, Oakland 94609; 2 Laboratory Medicine, University of California at San Francisco, San Francisco 94143; and 3 Pediatric Pulmonary Medicine, Stanford University Medical Center, Stanford, California 94305

The patch-clamp technique was used to investigate the effects of the isoflavone genistein on disease-causing mutations (G551D and Delta F508) of the cystic fibrosis transmembrane conductance regulator (CFTR). In HeLa cells recombinantly expressing the trafficking-competent G551D-CFTR, the forskolin-stimulated Cl currents were small, and average open probability of G551D-CFTR was Po = 0.047 ± 0.019. Addition of genistein activated Cl currents ~10-fold, and the Po of G551D-CFTR increased to 0.49 ± 0.12, which is a Po similar to wild-type CFTR. In cystic fibrosis (CF) epithelial cells homozygous for the trafficking-impaired Delta F508 mutation, forskolin and genistein activated Cl currents only after 4-phenylbutyrate treatment. These data suggested that genistein activated CFTR mutants that were present in the cell membrane. Therefore, we tested the effects of genistein in CF patients with the G551D mutation in nasal potential difference (PD) measurements in vivo. The perfusion of the nasal mucosa of G551D CF patients with isoproterenol had no effect; however, genistein stimulated Cl-dependent nasal PD by, on average, -2.4 ± 0.6 mV, which corresponds to 16.9% of the responses (to beta -adrenergic stimulation) found in healthy subjects.

cystic fibrosis transmembrane conductance regulator mutations; patch clamp; nasal potential difference; flavonoids


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