Research Day

The Potential Mutagenic Influence of Structural Element Variants Within the PKD1 Gene

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In the autosomal dominant form of polycystic kidney disease (PKD), inheritance of a single mutation in the PKD1 gene is followed by somatic inactivation of the second allele, leading to cyst formation. Cysts can number in the thousands in affected kidneys, with each potentially having a different mutation. This reveals a high level of PKD1 mutagenesis, but the mechanisms are undefined. We have analyzed human PKD1 for sequence elements that may explain the higher level of somatic inactivation. Guanine repeats are of particular interest because they support four-stranded structures known as G-quadruplex (G4) DNA. G4 is a structure that leads to genetic instability, and is often found within oncogenic translocation hot spots, cancer genes, and at recombination sites. Inter-species comparisons show that species subject to autosomal dominant PKD, including humans, share a similar sequence bias. Guanine repeats are over-represented in human PKD1 and are found in tandem arrays within at least three introns. On the other strand, cytosine repeats argue for a potential to form i-Motif structures during transcription, which may contribute to gene regulation. G4 formation may directly contribute to PKD1 inactivation, as cataloged somatic mutations are clustered near predicted G4-forming motifs. G4 formation blocks polymerase activities, leading to DNA breaks and recombination, elevating inactivating mutagenesis risk. Our results not only provide a molecular rationale for ADPKD, but also identify a DNA structure within PKD1 that could be targeted for diagnosis or disease prevention

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