Data from: 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 in PKD1 or PKD2. 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 Xenopus,
genetically engineered human kidney cells carrying BICC1 variants, 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 by PKD1 and PKD2 via distinct protein domains. Furthermore, PKD
was aggravated in loss-of-function studies in Xenopus and mouse models,
resulting in more severe disease when Bicc1 was depleted in conjunction
with Pkd1 or Pkd2. Finally, in a large human patient cohort, we identified
a sibling pair with a homozygous BICC1 variant and patients with very
early onset PKD (VEO-PKD) that exhibited compound heterozygosity of BICC1
in conjunction with PKD1 and PKD2 variants. Genome editing demonstrated
that these BICC1 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 BICC1
variants may aggravate PKD severity, highlighting RNA metabolism as an
important new concept for disease modification in ADPKD.