Human Autosomal Dominant Polycystic Disease Research Articles

Linkage confirms canine pkd1 orthologue as a candidate for bull terrier polycystic kidney disease

Bull terrier polycystic kidney disease (BTPKD) is a Mendelian disorder with many features reminiscent of human autosomal dominant polycystic disease, the latter disease being due to mutations at PKD1 and PKD2 loci. We investigated the role of the canine pkd1 orthologue in BTPKD via linkage analysis of a large kindred in which the disorder is segregating. Twelve microsatellite markers around the canine pkd1 locus (CFA6) were amplified from the genomic DNA of 20 affected and 16 unaffected bull terriers. An additional 28 affected dogs were genotyped at five key microsatellites. A highly significant multi-point LOD score that peaked over the canine pkd1 locus was observed (LOD = 6.59, best two-point LOD score LOD = 6.02), implicating this as the BTPKD locus.

Rational proteomics of PKD1. I. Modeling the three dimensional structure and ligand specificity of the C_lectin binding domain of Polycystin-1.

Polycystin-1 (Pc-1) is the 4303 amino acid multi-domain glycoprotein product of the polycystic kidney disease-1 (PKD1) gene. Mutations in this gene are implicated in 85% of cases of human autosomal dominant polycystic disease. Although the biochemistry of Pc-1 has been extensively studied its three dimensional structure has yet to be determined. We are combining bioinformatics, computational and biochemical data to model the 3D structure and function of individual domains of Pc-1. A three dimensional model of the C-type lectin domain (CLD) of Pc-1 (sequence region 405-534) complexed with galactose (Gal) and a calcium ion (Ca(+2)) has been developed (the coordinates are available on request, e-mail: pletnev@hwi.buffalo.edu). The model has alpha/beta structural organization. It is composed of eight beta strands and three alpha helices, and includes three disulfide bridges. It is consistent with the observed Ca(+2) dependence of sugar binding to CLD and identifies the amino acid side chains (E499, H501, E506, N518, T519 and D520) that are likely to bind the ligand. The model provides a reliable basis upon which to map functionally important residues using mutagenic experiments and to refine our knowledge about a preferred sugar ligand and the functional role of the CLD in polycystin-1.