BICC1 interacts with PKD1 and PKD2 to drive cystogenesis in ADPKD.

Abstract

Autosomal-dominant polycystic kidney disease (ADPKD) is primarily of adult-onset and caused by pathogenic variants in <i>PKD1</i> or <i>PKD2</i>. Yet, disease expression is highly variable and includes very early-onset PKD presentations in utero or infancy. In animal models, the RNA-binding molecule Bicc1 has been shown to play a crucial role in the pathogenesis of PKD. To study the interaction between BICC1, PKD1, and PKD2, we combined biochemical approaches, knockout studies in mice and <i>Xenopus,</i> genetic engineered human kidney cells carrying <i>BICC1</i> variants, as well as genetic studies in a large ADPKD cohort. We first demonstrated that BICC1 physically binds to the proteins Polycystin-1 and -2 encoded by <i>PKD1</i> and <i>PKD2</i> via distinct protein domains. Furthermore, PKD was aggravated in loss-of-function studies in <i>Xenopus</i> and mouse models, resulting in more severe disease when <i>Bicc1</i> was depleted in conjunction with <i>Pkd1 or Pkd2</i>. Finally, in a large human patient cohort, we identified a sibling pair with a homozygous <i>BICC1</i> variant and patients with very early onset PKD (VEO-PKD) that exhibited compound heterozygosity of <i>BICC1</i> in conjunction with <i>PKD1 and PKD2</i> variants. Genome editing demonstrated that these <i>BICC1</i> variants were hypomorphic in nature and impacted disease-relevant signaling pathways. These findings support the hypothesis that BICC1 cooperates functionally with PKD1 and PKD2, and that <i>BICC1</i> variants may aggravate PKD severity, highlighting RNA metabolism as an important new concept for disease modification in ADPKD.