Characterization of the role of DZIP1L at the ciliary transition zone and its interdependencies with other polycystic kidney disease proteins

• Applicant: Professor Dr. Carsten Bergmann
• Subject Area: Nephrology ; Human Genetics
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 433643139

Autosomal recessive polycystic kidney disease (ARPKD) is a cilia-related disorder and an important cause of childhood renal- and liver-related morbidity and mortality with variable expressivity. Most patients are diagnosed in late pregnancy or at birth, but milder courses in adults are also observed. PKHD1 was long thought to be the only gene causing the disease. We recently demonstrated locus heterogeneity and described mutations in DZIP1L in patients with ARPKD. We found that DZIP1L, a zinc-finger and coiled-coil containing protein, interacts with SEPTIN2, a protein implicated in the maintenance of the periciliary diffusion barrier, which localizes to centrioles and to the distal ends of basal bodies at the ciliary transition zone. Consistent with a defect in the diffusion barrier, we demonstrated that trafficking of the autosomal dominant polycystic kidney disease (ADPKD) proteins Polycystin-1 (PC1) and Polycystin-2/TRPP2 (PC2) to the ciliary axoneme was considerably disrupted in DZIP1L mutant patient cells. Instead, PC1 and TRPP2 remained at the ciliary base in mutant cells. These data provide conclusive evidence that the ciliary transition zone represents a functional domain that is central to the pathogenesis of PKD. Based on a large cohort of clinically well-characterized patients, we propose to use a multi-disciplinary approach to better understand the role of DZIP1L in PKD, and aim to 1) identify and characterize novel DZIP1L binding partners, 2) investigate the role of DZIP1L at the ciliary transition zone, and 3) characterize interdependencies between DZIP1L and other PKD proteins to determine the dosage-sensitive pattern in patients with early and severe disease manifestations who carry trans-heterozygous germline mutations in DZIP1L and one of the other main PKD genes (PKD1, PKD2, PKHD1).

• DFG Programme: Research Grants