Snarey, Angela Bridgit Maria; (1994) Genetic analysis of the region containing the autosomal dominant polycystic kidney disease gene (PKD1). Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The gene for autosomal dominant polycystic kidney disease (PKD1) is located on chromosome 16p, between the flanking markers D16S84 (GGG1) and D16S125 (26.6PROX). This region is 750 kb long and has been cloned into cosmids and phages. The region is thought to contain approximately 15 genes. Since no chromosomal aberrations have been identified that are correlated with the presence of the disease phenotype, all candidate genes are being extensively analysed by sequence analysis and mutational analysis. This approach to identify the PKD1 gene involves much work and therefore other complementary strategies have been employed to optimise efforts in candidate gene analysis. In this project, studies of recombinant families and linkage disequilibrium studies have both been applied to the genetic analysis of the PKD1 region. To this end, ten new polymorphic markers were identified, several of which were obtained through collaborations with S. Reeders and P. Harris. Except where indicated, all characterisation and typing of markers was carried out as part of this project. To further narrow down the location of recombination events close to the gene, family linkage studies, using the newly isolated markers, were carried out on seventeen PKD1 families containing recombinant individuals. Four of these families were previously published, and in thirteen families there was ambiguity about recombination events. The new data suggests that the PKD1 gene lies in a region of approximately 350 kb, flanked by KG8 on the distal side, and W5.2 on the proximal side. The association of the same ten polymorphic markers, with the disease and with each other, has also been investigated. This was done in a set of 76 families from four populations, including 33 Scottish families that had previously shown association with D16S94 (VK5), a marker proximal to the PKD1 region. Significant association is reported between two CA repeat markers and the disease in the Scottish population, but no evidence for a single founder haplotype in these families has been found. This indicates the presence of several mutations in the Scottish population. The results presented in this thesis, from both the family linkage studies and the linkage disequilibrium studies, are compatible and favour a location of the PKD1 gene in the proximal part of the candidate region.

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