COMPARATIVE-ANALYSIS OF THE POLYCYSTIC KIDNEY-DISEASE-1 (PKD1) GENE REVEALS AN INTEGRAL MEMBRANE GLYCOPROTEIN WITH MULTIPLE EVOLUTIONARY CONSERVED DOMAINS

PKD1 is the major locus of the common genetic disorder autosomal domin ant polycystic kidney disease (ADPKD). Analysis of the predicted prote in sequence of the human PKD1 gene, polycystin, shows a large molecule with a unique arrangement of extracellular domains and multiple putat ive transmembrane regions, The precise function of polycystin remains unclear with a paucity of mutations to define key structural and funct ional domains. To refine the structure of this protein we have cloned the genomic region encoding the Fugu PKD1 gene. Fugu PKD1 spans 36 kb of genomic DNA and has greater complexity with 54 exons compared with 46 in man. Comparative analysis of the predicted protein sequences sho ws a lower level of homology than in similar studies with identity of 40 and 59% similarity, However key structural motifs including leucine rich repeats (LRR), a C-type lectin and LDL-A like domains and 16 PKD repeats are maintained, A region of homology with the sea urchin REJ protein was also confirmed in Fugu but found to extend over 1000 amino acids. Several highly conserved intra-and extra-cellular regions, wit h no known sequence homologies, that are likely to be of functional im portance were detected, The likely structure of the membrane associate d region has been refined with similarity to the PKD2 protein and volt age gated Ca2+ and Na+ channels highlighted over part of this area, Th e overall protein structure has therefore been clarified and this comp arative analysis derived structure will form the basis for the functio nal study of polycystin and its individual domains.