Location of mutations within the PKD2 gene influences clinical outcome

Background. Since the cloning of the gene for autosomal dominant polwycysti c kidney disease type 2 (PKD2), approximately 40 different mutations of tha t gene have been reported to he associated with the disease. The relationsh ip between the PKD2 genotype and phenotype. however, remains unclear. Methods. Detailed clinical information was collected for PKD2 families in w hich the underlying mutation had been identified. Logistic regression analy sis was employed to assess the influence of age and sex on hypertension. he maturia. renal calculi. and urinary tract infections, and a clinical phenot ype score was computed. Patients were then grouped according to the relativ e location of their mutation within the cDNA sequence, and differences in t he mean phenotypic score between groups were tested for statistical signifi cance by means of a multiple pairwise t-test. Results. While phenotypic scores for each mutational group revealed a consi derable degree of intragroup variability, the variability in phenotypic sco res was significantly higher between mutational groups than within groups. A group-wise comparison of the mean phenotypic scores confirmed the observa tion of significant nonlinear variation in disease severity, with high- and low-scoring mutational groups interspersed along the gene sequence. Conclusion. The identification of groups of mutations in the PKD2 gene, whi ch differ significantly with respect to clinical outcome, is to our knowled ge the first description of a genotype/phenotype correlation in autosomal d ominant polycystic kidney disease. It also provides evidence against comple te loss of f'unction of the mutant PKD2 gene product.