Fig. 1 In normal wild-type (WT) cells, both Cl–and HC03–are transported at high rates through the plasma membrane of epithelial cells expressing the CFTR Cl–channel protein (top). In mild forms of cystic fibrosis (CF), HC03–transport is significantly diminished, but present (middle). Some CFTR mutations (E193K) may support apparently normal, or even much larger than normal (A800G), Cl–transport whereas others (R117H) do not. However, mutations in CFTR that result in pancreatic insufficiency and more severe forms of the disease (bottom) do not support HC03–transport but, surprisingly, may support normal Cl–transport (I148T). These data indicate that the severity of CF disease may better correlate with defects in HC03–transport than with defects in Cl–transport. Exactly how mutations in CFTR affect HC03–transport, or even how it is transported normally, is not yet understood.