BICC1 is a genetic modifier for Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is primarily of adult-onset and caused by pathogenic variants in PKD1 or PKD2. Variable disease expression is incompletely understood with rare very early-onset PKD (VEO-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 further investigate this, we first demonstrated that BICC1 physically binds to the proteins Polycystin-1 and -2 encoded by PKD1 and PKD2 via distinct protein domains. Furthermore, PKD was aggravated in loss-of-function studies in Xenopus and mice. These resulted in more severe disease when Bicc1 was depleted in conjunction with Pkd1, Pkd2 or Pkhd1., Finally, in a large human patient cohort, we identified several VEO-PKD patients that exhibited compound situations of PKD1, PKD2 and PKHD1 in conjunction with BICC1 as well as a sibling pair with a homozygous BICC1 mutation. Together these findings support the hypothesis that BICC1 cooperates with PKD1 and PKD2, and that BICC1 variants may aggravate disease severity highlighting RNA metabolism as an important new concept for disease modification in ADPKD.