The ANKS3/BICC1 protein complex is a master post-transcriptional regulator of NPHP1 ciliopathy-gene transcripts

Ciliopathies are a class of multi-systemic genetic diseases characterized by ciliary dysfunction. Here, we report a novel ANKS3 variant in patients with a renal ciliopathy known as nephronophthisis (NPH) associated with hepatic defects. ANKS3 is an ankyrin and sterile alpha motif domain-containing protein that interacts with many NPH proteins as well as with BICC1, an RNA-binding protein involved in renal cystic diseases. The pathogenic effect of the ANKS3 mutation was validated in the zebrafish mutant and knock-in rat model, the latter showing urine concentration defect and tubular dilatations similar to NPH patients. In addition, cilia morphology and function as well as epithelialization of kidney tubular cells was affected by loss or mutation of ANKS3 . Finally, our results evidenced that these classically renal ciliopathy-associated phenotypes were linked to the negative regulation of BICC1 by ANKS3 which binds to transcripts of the major NPH gene NPHP1 and mediates their decay through the AGO2-RISC complex and recruitment into P-bodies. Altogether, our findings suggest that the ANKS3/BICC1 complex is a key post-transcriptional regulator of NPHP1 transcript stability, providing another level of regulation of cilium biogenesis and kidney homeostasis, as well as an unusual mechanism leading to NPH-related ciliopathies.