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The identification of the primary defect in autosomal dominant polycystic kidney disease (ADPKD) by biochemical methods has proved difficult because of the complexity of the cystic kidney. However, by the use of the genetic method of positional cloning, a gene accounting for approximately 85% of ADPKD, PKD1, has now been identified in the chromosome region 16p13.3. Its exact location was pinpointed because it was bisected by a chromosome translocation; members with the balanced exchange had PKD1. The PKD1 gene encodes an approximately 14-kb transcript, but full characterization was complicated, because most of the gene lies in a genomic region that is duplicated elsewhere on chromosome 16; the duplicate area encodes three genes with substantial homology to PKD1. At present, only seven mutations of PKD1 have been characterized and these are clustered in the nonduplicated, 3' end of the gene. However, a number of patients with large deletions of the PKD1 and adjacent tuberous sclerosis 2 (TSC2) genes, who have tuberous sclerosis and severe childhood-onset polycystic kidney disease, have also been described. Recently, the entire sequence of the PKD1 transcript and the genomic region containing the gene have been determined. The PKD1 gene covers approximately 52 kb of genomic DNA and is divided into 46 exons. The transcript is approximately 14.15 kb, and the predicted protein polycystin is 4302/3 amino acids with a calculated mass of approximately 460 kd. Polycystin contains several distinctive extracellular domains, including a flank-leucine rich repeat-flank domain, a C-type lectin, 16 approximately 85-amino-acid units that are similar to immunoglobulin repeats, four fibronectin Type III-related domains, and a low-density lipoprotein A domain. The C-terminal third of the protein has multiple hydrophobic regions, and modeling of this region suggests the presence of many transmembrane domains and a cytoplasmic C terminus. Hence, polycystin is probably an integral membrane protein with multiple extracellular domains that are involved in cell-cell and/or cell-matrix interactions. The ADPKD phenotype suggests that polycystin may play a role in cell-matrix communication, which is important for normal basement membrane production and for controlling cellular differentiation.


Journal article


J Am Soc Nephrol

Publication Date





1125 - 1133


Chromosome Mapping, Cloning, Molecular, Genes, Humans, Mutation, Polycystic Kidney, Autosomal Dominant, Proteins, Sequence Homology, Amino Acid, TRPP Cation Channels, Transcription, Genetic, Translocation, Genetic