A total of 33 polymorphic markers were analyzed to generate a high- resolution genetic linkage map of the locus PKHD1 (polycystic kidney and hepatic disease 1) for the autosomal recessive polycystic kidney disease (ARPKD), using a combination of recombination mapping and linkage analysis in 164 families. Recombinants narrowed the PKHD1 region from 3.8 cM to a 1-cM interval flanked by the markers D6S1024 and D6S1714. Linkage disequilibrium analysis in 13 Finnish ARPKD families identified two different highly conserved haplotypes with four distal flanking markers, suggesting the existence of at least two major mutations of Finnish origin. The genes MUT (methylmalonyl coenzyme A-mutase), RDS (retinal degeneration, slow), CSNK2β (casein kinase II, β subunit), and GSTA1 (glutathione S-transferase α, type 1) were excluded as PKHD1 genes using both established and novel intragenic polymorphisms in families with key recombinants. These genetic data, combined with our YAC-based physical map of the 6p21-p12region, will facilitate efforts to positionally clone the PKHD1 gene.
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