Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic form of kidney disease. Most cases result from mutations in PKD1 and PKD2, which encode the cilia membrane glycoproteins PC1 and PC2, respectively. A third ADPKD gene, GANAB, was described 2 years ago; however, the cause of ADPKD remains unresolved for ~7% of families. Now, use of whole-exome sequencing (WES) and next-generation sequencing (NGS) has identified an additional ADPKD gene, DNAJB11, which encodes a co-chaperone protein involved in endoplasmic reticulum (ER) protein processing. “This study demonstrates that ADPKD is more complex than previously thought, with a number of rare genes that phenocopy ADPKD,” explains Peter Harris. “It also suggests that chaperone treatment might be valuable in some patients with PKD1 and PKD2 mutations that cause problems with protein folding and transport.”

To identify ADPKD candidate genes, Harris and colleagues performed WES in two ADPKD-affected families, identifying DNAJB11. They then performed targeted NGS of 65 candidate genes in a further 591 genetically unresolved families, leading to the identification of DNAJB11 mutants in five additional families. The affected patients were phenotypically similar, with small renal cysts and non-enlarged kidneys and liver cysts in some individuals. Chronic interstitial fibrosis, characteristic of autosomal dominant tubulointerstitial disease (ADTKD), was also evident. “The phenotypic overlap between ADPKD and ADTKD indicates the related pathogenic mechanisms,” notes Harris. Characterization of the DNAJB11 variants suggested a role in the appropriate trafficking of PC1 and uromodulin, proteins involved in ADPKD and ADTKD, respectively. “These findings emphasize the involvement of ER quality control proteins in ADPKD and polycystic liver disease, due to the susceptibility of PC1 and ADTKD proteins such as uromodulin to trafficking deficiencies,” says Harris.