BICC1 Interacts with PKD1 and PKD2 to Drive Cystogenesis in ADPKD

Autosomal dominant polycystic kidney disease (ADPKD) is primarily of adult-onset and caused by pathogenic variants inPKD1orPKD2. Yet, disease expression is highly variable and includes very early-onset PKD presentationsin uteroor 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 betweenBICC1, PKD1 and PKD2we combined biochemical approaches, knockout studies in mice andXenopus,genetic engineered human kidney cells as well as genetic association studies in a large ADPKD cohort. We first demonstrated that BICC1 physically binds to the proteins Polycystin-1 and −2 encoded byPKD1andPKD2via distinct protein domains. Furthermore, PKD was aggravated in loss-of-function studies inXenopusand mouse models resulting in more severe disease whenBicc1was depleted in conjunction withPkd1 or Pkd2. Finally, in a large human patient cohort, we identified a sibling pair with a homozygousBICC1variant and patients with very early onset PKD (VEO-PKD) that exhibited compound heterozygosity ofBICC1in conjunctionwith PKD1 and PKD2variants. Genome editing demonstrated that theseBICC1variants were hypomorphic in nature and impacted disease-relevant signaling pathways. These findings support the hypothesis thatBICC1cooperates functionally withPKD1 and PKD2, and thatBICC1variants may aggravate PKD severity highlighting RNA metabolism as an important new concept for disease modification in ADPKD.