Autosomal dominant Polycystic kidney disease (ADPKD) is one of the most common human genetic disorders and an imponani cause of end stage renal disease. We have used a positional cloning approach to identify the major ADPKD gene, PKD1, on human chromosome 16. Characterisation of this gene has been complicated because it lies in a region of DNA which is reiterated several times in the genome. Nevertheless, the entire PKD1 gene has now been sequenced, revealing an mRNA of over 14 kb which is predicted to encode a protein, polycystin, of about 460 kD. Comparison with other proteins indicates that the N-terminal two thirds of polycystin are probably extracellular, containing various domains involved in protein-protein or protein-carbohydrate interactions. The C-terminal one third is thought to be associated with the cell membrane with multiple transmembrane regions predicted. This molecule may be involved in cell-cell or cell-matrix interactions with the primary defect in PKD1 possibly being a disruption in cell-matrix communication, which is vital for maintaining epithelial cell differentiation and for basement membrane formation. Recent immunohistochemical studies are consistent with this theory showing the PKD1 protAein, expressed in tubular epithelial cells in the fetal, adult and polycystic kidney. Analysis of mutations in the PKD1 gene has shown various nonsense, deletional and splicing changes causing disease. These studies suggest that in all populations a large number of different mutations will be identified, complicating genetic diagnosis and indicating a significant level of new mutation. Identification of the PKD1 gene has, for the first time, allowed us to visualise a protein which plays a primary role in cytogenesis. Further study of the normal role of this protein, and how it is changed in PKD1, will improve our understanding of cyst development and hopefully suggest points for therapeutic intervention.
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