A SPECTRUM OF MUTATIONS IN THE 2ND GENE FOR AUTOSOMAL-DOMINANT POLYCYSTIC KIDNEY-DISEASE (PKD2)

Recently the second gene for autosomal dominant poly-cystic kidney dis ease (ADPKD), located on chromosome 4q21-q22, has been cloned and char acterized. The gene encodes an integral membrane protein, polycystin-2 , that shows amino acid similarity to the PKD1 gene product and to the family of voltage-activated calcium (and sodium) channels. We have sy stematically screened the gene for mutations by single-strand conforma tion-poly-morphism analysis in 35 families with the second type of ADP KD and have identified 20 mutations. So far, most mutations found seem to be unique and occur throughout the gene, without any evidence of c lustering. In addition to small deletions, insertions, and substitutio ns leading to premature translation stops, one amino acid substitution and five possible splice-site mutations have been found. These findin gs suggest that the first step toward cyst formation in PKD2 patients is the loss of one functional copy of polycystin-2.