A new conceptual framework for PKD1 in ADPKD; integrating DNA structures and inflammation.

Abstract

In ADPKD renal function is corrupted by the accumulation and growth of fluid-filled cysts. Disruption of the PKD1 gene product, polycystin-1, is the most frequent cause of ADPKD, but the mechanisms that predispose PKD1 to recurrent somatic mutation remain poorly understood. Because current evidence for sequence- and structure-dependent mutational susceptibility is strongest at the human PKD1 locus, we will focus here on mechanisms that may promote somatic PKD1 inactivation. Experimental evidence for polycistin-1 inactivation supports a two-hit pathway, with the first hit being an inherited germline pathogenic mutation in PKD1 and the second hit mutation arising later in a somatic cell to inactivate the gene or lower the gene's dosage to lift a barrier to cyst initiation. An affected kidney can have thousands of cysts, each of which is a clonal lineage arising from an independent mutational second-hit event. Why human PKD1 is prone to inactivation and why the rodent orthologs escape similar mutagenesis is a mystery that, once solved, promises to provide important insights into the molecular mechanisms governing cyst initiation. A step toward that goal came from the characterization of the guanine-rich sequence architecture of human PKD1 that distinguishes it from rodent Pkd1. These guanine-rich tracts are intrinsically susceptible to oxidative damage and can adopt non-duplex secondary structures such as guanine-quadruplex DNA. Although guanine quadruplexes serve important regulatory functions, both oxidized guanine lesions and guanine quadruplex structures can interfere with faithful DNA replication and repair, thereby increasing mutation risk. Here, we discuss PKD1 mutagenesis in the context of the renal inflammatory microenvironment, integrating established principles of sequence-dependent mutagenesis and guanine-rich DNA structure biology with mechanisms of cyst initiation in ADPKD. This synthesis supports a conceptual model in which intrinsic sequence-dependent mutational susceptibility at the human PKD1 locus may interact with localized inflammatory microenvironments characterized by oxidative stress and epithelial proliferation to contribute to recurrent somatic second-hit formation.