Putative mutation of PKD1 gene responsible for autosomal dominant polycystic kidney disease in a Chinese family

Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
International Journal of Urology (Impact Factor: 2.41). 03/2011; 18(3):240-2. DOI: 10.1111/j.1442-2042.2010.02709.x
Source: PubMed


Autosomal dominant polycystic kidney disease (ADPKD) is a common and severe renal disease. Mutations of PKD1 and PKD2 genes are responsible for approximately 85% and 15% of ADPKD cases, respectively. In the present study, PKD1 and PKD2 genes were analyzed in a large Chinese family with ADPKD using denaturing high-performance liquid chromatography and DNA sequencing. A novel mutation, c.3623-3624insGTGT in exon 15 of the PKD1 gene, was identified in all nine affected family members, but not in any unaffected consanguineous relatives or 100 unrelated controls. These findings suggest that the unique 4 bp insertion, c.3623-3624insGTGT, in the PKD1 gene might be the pathogenic mutation responsible for the disease in this family.

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Available from: Zhangxue Hu, May 24, 2015
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    ABSTRACT: Abstract Genetic heterogeneity is the main factor for significant variation in the course of autosomal dominant polycystic kidney disease (ADPKD). PKD1 patients have more severe renal outcomes compared with PKD2 patients. Co-inheritance of a mutation in both genes is associated with more severe phenotypes than that found with either mutation alone. However, the genotype-phenotype relationship is far from clear in ADPKD. Here, we observed two novel mutations, PKD1:c.12444G > A and PKD1:c.12444 + 1G > A, which alter the same splice donor site of intron 45, correlate with different renal outcomes. To explain the phenomenon, we analyzed the genic and allelic background of the patients, as well as the genetic modifiers, DKK3 and HNF-1β as suggested. Only PKD1 variants were found, which highlights the allelic influence of PKD1 gene to be the last candidate factor. Segregation analysis, online mutation prediction, and recurrence mutation searching were applied to sort the variants. However, none of variants was found to be damaging or associated with the disease except PKD1:c.12444G > A and PKD1:c.12444 + 1G > A. Cloning and sequencing of the mutated cDNA sequences had shown unexpected different splicing effects caused by the mutations. PKD1:c.12444 + 1G > A definitely destroyed the native splice site and created a novel donor site with truncating effect on PC1. In contrast, PKD1:c.12444G > A mainly weakened the site and decreased the expression of normal PC1. Since PC1 negatively regulates cell proliferation in the process of cyst formation and enlargement, our observation may explain this new genotype-phenotype correlation and help to improve genetic counseling and diagnosis of the disease.
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