POLYCYSTIC KIDNEY-DISEASE .1. IDENTIFICATION AND ANALYSIS OF THE PRIMARY DEFECT

The identification of the primary defect in autosomal dominant polycys tic kidney disease (ADPKD) by bio-chemical methods has proved difficul t because of the complexity of the cystic kidney. However, by the use of the genetic method of positional cloning, a gene accounting for sim ilar to 85% of ADPKD, PKD1, has now been identified in the chromosome region 16p13.3. Its exact location was pinpointed because it was bisec ted by a chromosome translocation; members with the balanced exchange had PKD1. The PKD1 gene encodes a similar to 14-kb transcript, but ful l characterization was complicated, because most of the gene lies in a genomic region that is duplicated elsewhere on chromosome 16; the dup licate area encodes three genes with substantial homology to PKD1. At present, only seven mutations of PKD1 have been characterized and thes e are clustered in the nonduplicated, 3' end of the gene. However, a n umber of patients with large deletions of the PKD1 and adjacent tubero us sclerosis 2 (TSC2) genes, who have tuberous sclerosis and severe ch ildhood-onset polycystic kidney disease, have also been described. Rec ently, the entire sequence of the PKD1 transcript and the genomic regi on containing the gene have been determined. The PKD1 gene covers simi lar to 52 kb of genomic DNA and is divided into 46 exons. The transcri pt is similar to 14.15 kb, and the predicted protein polycystin is 430 2/3 amino acids with a calculated mass of similar to 460 kd. Polycysti n contains several distinctive extracellular domains, including a flan k-leucine rich repeat-flank domain, a C-type lectin, 16 similar to 85 aminoc-acid units that are similar to immunoglobulin repeats, four fib ronectin Type Ill-related domains, and a low-density lipoprotein A dom ain. The C-terminal third of the protein has multiple hydrophobic regi ons, and modeling of this region suggests the presence of many transme mbrane domains and a cytoplasmic C terminus. Hence, polycystin is prob ably an integral membrane protein with multiple extracellular domains that are involved in cell-cell and/or cell-matrix interactions. The AD PKD phenotype suggests that polycystin may play a role in cell-matrix communication, which is important for normal basement membrane product ion and for controlling cellular differentiation.