Cystic fibrosis: Leakage of lysosomal enzymes and of alkaline phosphatase into the extracellular space

Abstract

Nine lysosomal enzymes and alkaline phosphatase have been assayed with two different ultramicro techniques in the intra- and extracellular space of fibroblast cultures derived from the skin of cystic fibrosis patients, cystic fibrosis carriers, and normal controls, respectively. Evidence has been obtained for a multiple leakage of lysosomal enzymes and of alkaline phosphatase into the medium of fibroblast cultures from cystic fibrosis patients and carriers. The situation is comparable to a certain extent, to that observed in I-cell-disease (mucolipidosis II). This multiple leakage results in the decrease of intracellular activity of several lysosomal enzymes in cultures from cystic fibrosis patients and carriers and due to the coordinate regulation of the synthesis of the “leaky enzymes” in an overshooting of the intracellular alkaline phosphatase activity in cultures from cystic fibrosis patients. It also explains the retarded catabolism of certain molecules, such as the Tamm-Horsfall glycoprotein, in cystic fibrosis cells. It is speculated that the basic defect in cystic fibrosis leads to abnormal recognition sites on lysosomal enzymes and on alkaline phosphatase, and in consequence to the leakage of these enzymes into the extracellular space. The present findings allow one to develop methods for the pre- and postnatal diagnosis of cystic fibrosis with cell cultures, and for the detection of cystic fibrosis carriers with the peripheral blood.