Genetic Heterogeneity of PKD1 and PKD2 Genes in Iran and Determination of the Genotype/Phenotype Correlations in Several Families with Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic nephropathy, which is characterized by replacement of renal parenchyma with multiple cysts. In Iran, the disease prevalence within the chronic hemodialysis patient population is approximately 8-10%. So far, three genetic loci have been identified to be responsible for ADPKD. Little information is available concerning the pattern of linkage in Iranian population. In the present study, the linkage analysis was performed using three pairs of polymorphic microsatellite markers including 16AC2.5-CA (D16S291), SM7-CA (D16S283) and KG8-CA (intragenic marker at the 3' end of the gene). These markers are closely linked to the ADPKD1 locus and three pairs of the selected polymorphic microsatellite markers including YUNCA9 (D4S231), AFM155xe11 (D4S1534) and AFM224x6 (D4S423), which were closely linked to the ADPKD2 locus. In parallel, the genomic DNA of 150 unrelated healthy individuals was used to determine frequency, heterozygosity rate and polymorphic information content (PIC) for each marker. In our study, haplotypes were constructed in a number of ADPKD families using respective markers. Assignment of the disease gene loci was performed following phasing and haplotype construction, genotype/phenotype correlations were deduced from the constructed haplotypes. Analysis of clinical data confirms a milder ADPKD phenotype for PKD2 families in Iran. Our results showed relatively high heterozygosity rates and PIC values for some markers, while the most informative markers were KG8 (PIC: 0.772) and 16AC2.5 (PIC: 0.689) for PKD1 gene and AFM224x6 (PIC: 0.712) for PKD2 gene. We report here the first molecular genetic study of ADPKD and the existence of locus heterogeneity for ADPKD in Iranian population by performing linkage analysis on 15 affected families. Eleven families showed linkage to PKD1 and two families linked to PKD2 gene. In 2 families, PKD1 markers were common in all affected members but PKD2 markers were not informative.