Mutation detection in the duplicated region of the polycystic kidney disease 1 (PKD1) gene in PKD1-linked Australian families

Abstract

Screening for disease-causing mutations in the duplicated region of the PKD1 gene was performed in 17 unrelated Australian individuals with PKD1-linked autosomal dominant polycystic kidney disease. Exons 2-21 and 23-34 were assayed using PKD1-specific PCR amplification and direct sequencing. We have identified 12 novel probably pathogenic DNA variants, including five truncating mutations (Q563X, c.5105delAT, c.5159delG, S2269X, c.9847delC), two in-frame deletions (c.7472del3, c.9292del39), and two splice-site mutations (IVS14+1G>C, IVS16+1G>T). Three of the mutations (G381C, Y2185D, G2785D) were predicted to lead to the replacement of conserved amino acid residues, with ensuing changes in protein conformation. Defects in the duplicated region of PKD1 thus account for 63% of our patients. Together with the previously detected mutations (Q4041X, R4227P) in the 3 region of the gene, the study has achieved an overall mutation detection rate of 74%. In addition, we have detected 31 variants (nine novel and 22 previously published) that did not segregate with the disease and were considered to be neutral polymorphisms. Three of the nine novel polymorphisms were missense mutations with a predicted effect on protein conformation, emphasizing the problems of interpretation in PKD1 mutation screening.

Autosomal Dominant Polycystic Kidney Disease – Clinical and Genetic Aspects

“…Multiple clustered sequence alterations producing several amino acid changes have been detected in exon 23 in 2 individuals, most probably a result of a gene conversion event between PKD1 and its homologues [12]. Two recent reports [124,125] show successful use of specific differences between PKD1 and two of its homologues as shown in a 12-Mb sequencing work of human chromosome 16 [68]. The specific long-range amplification of the exon 1-15 region combined with direct sequencing has allowed nine mutations to be detected, four missense and five translation terminating alterations, in a total of 65 ADPKD patients.…”