Dnajb11-Kidney Disease Develops from Reduced Polycystin-1 Dosage but not Unfolded Protein Response in Mice

Background Patients with heterozygous inactivating mutations in DNAJB11 manifest with cystic but not enlarged kidneys and renal failure in adulthood. Pathogenesis is proposed to resemble an overlap of autosomal-dominant polycystic kidney disease (ADPKD) and autosomal-dominant tubulointerstitial kidney disease (ADTKD), but this phenotype has never been modeled in vivo. DNAJB11 encodes an Hsp40 cochaperone in the endoplasmic reticulum: the site of maturation of the ADPKD polycystin-1 (PC1) protein and of unfolded protein response (UPR) activation in ADTKD. We hypothesized that investigation of DNAJB11 would shed light on mechanisms for both diseases.Methods We used germline and conditional alleles to model Dnajb11-kidney disease in mice. In complementary experiments, we generated two novel Dnajb11(-/-) cell lines that allow assessment of PC1 C-terminal fragment and its ratio to the immature full-length protein.Results Dnajb11 loss results in a profound defect in PC1 cleavage but with no effect on other cystoproteins assayed. Dnajb11(-/-)mice are live-born at below the expected Mendelian ratio and die at a weaning age with cystic kidneys.Conditional loss of Dnajb11 in renal tubular epithelium results in PC1 dosage-dependent kidney cysts, thus defining a shared mechanism with ADPKD. Dnajb11 mouse models show no evidence of UPR activation or cyst-independent fibrosis, which is a fundamental distinction from typical ADTKD pathogenesis. Conclusions DNAJB11-kidney disease is on the spectrum of ADPKD phenotypes with a PC1-dependent pathomechanism. The absence of UPR across multiple models suggests that alternative mechanisms, which may be cyst-dependent, explain the renal failure in the absence of kidney enlargement.

Automated summary

DNAJB11-kidney disease is a phenotype on the spectrum of ADPKD, with a PC1-dependent pathomechanism. The absence of UPR in multiple models suggests that alternative mechanisms, which may be cyst-dependent, explain renal failure in the absence of kidney enlargement.