Autosomal dominant polycystic kidney disease: A genetic perspective

Important advances in understanding the common genetic disease, autosomal dominant polycystic kidney disease (ADPKD), have been made in last 3 years through the identification and characterization of the major genes, PKD1 and PKD2. The PKD1 and PDK2 genes map to the chromosomal regions, 16p13.3 (within a complex reiterated areal and 4q21-23, respectively, and encode transcripts of over 14 kb (PKD1) and 5 kb (PKD2). The predicted PKD1 protein, polycystin, is 4302/3 aa with a calculated molecular mass of approximately 460 kDa. Polycystin has a large extracellular region containing motifs involved in protein-protein and protein-carbohydrate interactions, and is attached to the membrane with multiple transmembrane regions. PKD2 is a small integral membrane protein (110 kD) with cytoplasmic N and C termini, 6 transmembrane domains and a region of homology with polycystin. Similarity of PKD2 to voltage-gated ion channels and an area of homology between polycystin and a receptor for egg jelly protein, which is thought to regulate ion channels, suggests a role for the ADPKD proteins in ion transport. The PKD1 and PKD2 genes are expressed in most tissues and polycystin has been localised to tubular epithelial structures in the fetal and adult kidney. A Western product of approximately 400 kDa has been detected in membrane fractions of renal tissue and strong polycystin expression has been noted in PKD1 cystic epithelia. The mutations detected at PKD1 and PKD2 suggest that these germline changes are inactivating. A specific syndrome due to a deletion of PKD1 and the adjacent TSC2 gene is associated with early onset polycystic kidney disease and tuberous sclerosis. Recent evidence of somatic mutation in cystic epithelia suggests that PKD1 is recessive at the cellular level, although this appears at odds with the continued polycystin expression noted in these cells. Further studies to determine the precise mutational mechanism and the normal role of the ADPKD proteins is required.