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Extensive DNA Repeats Residing in Orthologs of PKD1 Correspond With Inactivating Mutagenesis and Polycystic Kidney Disease
Author(s) -
Larson Erik,
Zebolsky Aaron,
Dewey John,
Swayze Emma,
Alvarado Gloria,
Ellis Monica,
Heuvel Gregory Vanden
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.619.5
Subject(s) - pkd1 , genetics , autosomal dominant polycystic kidney disease , biology , gene , polycystic kidney disease , mutagenesis , mutation , microbiology and biotechnology , kidney
Bi‐allelic inactivation of the PKD1 gene results in Autosomal Dominant Polycystic Kidney Disease (ADPKD), a common and lethal disorder. ADPKD is thought to follow a two‐hit pathway, where one inherited mutation in PKD1 is followed later by somatic inactivation of the other allele. Loss of PKD1 expression results in cysts, which are clonal in nature and can number in the thousands. The mechanisms are unclear, but human PKD1 appears prone to mutagenesis and inactivation. Interestingly, naturally occurring ADPKD is observed in humans, cats, and pigs, but not mice. We have therefore compared PKD1 gene sequences across species to determine if there are shared sequence or structural characteristics that could explain PKD1 instability. Despite conservation of PKD1 organization and coding across species, we find an over‐representation of G/C content and tandem repeats in PKD1 from species that are naturally prone to ADPKD. It is already established that guanine‐rich DNA triggers site‐specific genetic instability via the formation of G‐quadruplex (G4) DNA structures. Cytosine repeats also support structures called, i‐motifs, which have the potential to induce site‐specific genetic instability. We find that the human, feline, and porcine PKD1 genes are rich in G and C tandem repeats and G4 sequences, while murine Pkd1 is not. Circular dichroism spectroscopy demonstrates that structure formation occurs under physiological conditions. The possibility that G4 DNA contributes to PKD1 instability is further supported by the fact that cataloged somatic mutations are clustered near predicted G4 forming motifs. Our results identify G4 DNA and i‐motifs as structures that may form on both strands of the PKD1 gene, uncovering a molecular rationale to explain the instability of the gene and the emergence of cysts in ADPKD carriers. Support or Funding Information WMed Pilot Grant Program This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .