BICC1 interacts with PKD1 and PKD2 to drive cystogenesis in ADPKD

Area of Science:

• Genetics
• Molecular Biology
• Nephrology

Background:

• Autosomal-dominant polycystic kidney disease (ADPKD) typically presents in adulthood, caused by mutations in PKD1 or PKD2.
• However, variable disease expression includes very early-onset presentations, indicating other genetic factors may influence severity.
• The RNA-binding molecule Bicc1 is implicated in polycystic kidney disease (PKD) pathogenesis in animal models.

Purpose of the Study:

• To investigate the functional interaction between BICC1, PKD1, and PKD2 in ADPKD.
• To determine if BICC1 variants contribute to disease severity, particularly in very early-onset PKD (VEO-PKD).

Main Methods:

• Biochemical assays to confirm BICC1 binding to Polycystin-1 and -2.
• Loss-of-function studies in Xenopus and mouse models with Bicc1 depletion.
• Genetic analysis of a large ADPKD cohort, including patients with VEO-PKD.
• Genome editing to assess the impact of BICC1 variants.

Main Results:

• BICC1 physically interacts with Polycystin-1 and Polycystin-2 via distinct protein domains.
• Depletion of Bicc1 exacerbates PKD in mouse and Xenopus models, especially when combined with Pkd1 or Pkd2 loss.
• A homozygous BICC1 variant was identified in a sibling pair, and compound heterozygous BICC1 variants were found in patients with VEO-PKD.
• BICC1 variants were shown to be hypomorphic and affect disease-relevant signaling pathways.

Conclusions:

• BICC1 functionally cooperates with PKD1 and PKD2 in kidney development and function.
• BICC1 variants can aggravate ADPKD severity, contributing to early-onset disease.
• RNA metabolism represents a novel therapeutic target for modifying ADPKD progression.