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 inor. 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 andgenetic engineered human kidney cells carryingvariants, 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 byandvia distinct protein domains. Furthermore, PKD was aggravated in loss-of-function studies inand mouse models, resulting in more severe disease whenwas depleted in conjunction with. Finally, in a large human patient cohort, we identified a sibling pair with a homozygousvariant and patients with very early onset PKD (VEO-PKD) that exhibited compound heterozygosity ofin conjunction withvariants. Genome editing demonstrated that thesevariants were hypomorphic in nature and impacted disease-relevant signaling pathways. These findings support the hypothesis that BICC1 cooperates functionally with PKD1 and PKD2, and thatvariants may aggravate PKD severity, highlighting RNA metabolism as an important new concept for disease modification in ADPKD.