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Abstract:
We report a kindred in which members in four successive generations suffered from paroxysmal ventricular tachycardia associated with polycystic kidney disease. First, we followed a candidate gene approach by microsatellite marker analysis. We could clearly exclude a linkage in our kindred for the majority of the known loci of polycystic kidney disease and long QT syndrome. The LQTS is electrocardiographically
characterized by a prolonged QT interval and polymorphic ventricular arrhythmias. For the LQTS six loci on 11p15 (KCNQ1), 7q35-36 (HERG), 3p21-24 (SCN5A), 21q22 (KCNE1 and KCNE2) 4q25-27 (ANK2) are known. Autosomal dominant polycystic kidney disease (ADPKD) is an inherited nephropathy, primarily characterized by the formation of fluid-filled cysts in kidney, liver or pancreas. Moreover, clinical features are the occurrence of hypertension, symptomatic extrarenal cysts, and subarachnoid haemorrhage from intracranial 'berry' aneurysm. Isolated ADPKD is one of the most frequent genetic disorders with an incidence of 1 in 1000 individuals. The linkage of SCN5A and PKD1 locus appeared unlikely. Moreover, comparative sequencing of these genes revealed no coding mutations.
Second, a genome-wide linkage analysis was performed using 404 microsatellite markers at an average distance of 10 cM. Two possible candidate regions were identified on chromosomes 16p13 and 7q22. For further fine mapping we genotyped each localisation with nine additional markers. This analysis excluded the locus on chromosome 16 and
proved a linkage to the smallest critical interval on 7q22.1-q22.3.We performed an expression study by RT-PCR on 25 genes localised in the candidate interval using adult
normal heart and kidney tissues. The possible candidate genes Claudin-15 (CLDN15) and hypothetical protein FLJ23834 (FLJ23834) were screened for coding mutations by sequencing. They showed a detectable expression in both observed tissues. We could detect a kwon disease-associated SNP (dbSNP: 6967330 [50]), which occurs only in all patients.
