Molecular genetics and pathogenesis of autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is a common and system ic disease characterized by formation of focal cysts. Of the three potentia l causes of cysts, downstream obstruction, compositional changes in extrace llular matrix, and proliferation of partially dedifferentiated cells, evide nce strongly supports the latter as the primary abnormality. In the vast ma jority of cases, the disease is caused by mutations in PKD1 or PKD2, and ap pears to be recessive at the cellular level. Somatic second hits in the nor mal allele of cells containing the germ line mutation initiate or accelerat e formation of cysts. The intrinsically high frequency of somatic second hi ts in epithelia appears to be sufficient to explain the frequent occurrence of somatic second hits in the disease-causing genes. PKD1 and PKD2 encode a putative adhesive/ion channel regulatory protein and an ion channel, resp ectively. The two proteins interact directly in vitro. Their cellular and s ubcellular localization suggest that they may also function independently i n a common signaling pathway that may involve the membrane skeleton and tha t links cell-cell acid cell-matrix adhesion to the development of cell pola rity.