Novel mutations identified within the 3′ region of the PKD1 gene in South African polycystic kidney disease patients
Autosomal dominant polycystic kidney disease (ADPKD), a common, potentially lethal, inherited disorder, can arise from mutations in the polycystln-1 and polycystin-2 encoding genes (PKD1 and PKD2, respectively). To date, more than 260 PKD1 mutations have been reported in American, European and Asian populations. No information, however, is available on the molecular aetiology of ADPKD in South Africa. Since polycystic kidney disease (PKD) occurs in this country, the aim of this study was to investigate whether disease-causing mutations in PKD1 exist in a South African cohort of PKD patients. Thirty-two PKD-affected index cases (probands) were recruited from Tygerberg Hospital, Western Cape, for mutation screening of PKD1 exons 34 to 46. We identified three novel, putative disease-causing substitutions (V3682L, R3832P, and R4149L) and one previously reported substitution (R4227P) in four of the probands. Additionally, using genetic linkage analysis, the disease phenotype was strongly linked to the PKD1 locus in two multi-generation ADPKD pedigrees and, less clearly, in a third. The identification of novel, disease-causing mutations in PKD1 will help to identify functionally important domains, thereby furthering an understanding of the role of this membrane-bound protein in the healthy and the polycystic kidney.