A number sign (#) is used with this entry because of evidence that autosomal dominant polycystic kidney disease-6 with or without polycystic liver disease (PKD6) is caused by heterozygous mutation in the DNAJB11 gene (611341) on chromosome 3q27.

Polycystic kidney disease-6 is an autosomal dominant renal disease characterized by the development of multiple small renal cysts and progression to renal insufficiency or end-stage renal disease (ESRD) most often after the sixth decade. The cysts are generally small (less than 1 to 3 cm) and the kidneys are not massively enlarged. Some patients may have evidence of chronic interstitial fibrosis and about half develop liver cysts (summary by Cornec-Le Gall et al., 2018). The renal interstitial fibrosis suggests overlap with autosomal dominant tubulointerstitial kidney disease (ADTKD; see 162000) (summary by Devuyst et al., 2019).

For a discussion of genetic heterogeneity of polycystic kidney disease, see PKD1 (173900).

Cornec-Le Gall et al. (2018) reported 7 unrelated multigenerational families with adult-onset polycystic kidney disease. In total, there were at least 20 genetically confirmed affected individuals in addition to several affected deceased individuals and several affected individuals from whom DNA was not available. Most affected individuals were diagnosed in middle age, mainly in their thirties to sixties, either as incidental findings or through family studies when a proband presented with renal insufficiency. The disorder was progressive and most patients showed a variably decreased glomerular filtration rate. Seven patients developed end-stage renal disease between 70 and 89 years of age; 1 patient developed ESRD at age 59 and underwent renal transplant. Renal imaging of the patients showed multiple bilateral small renal cysts (0.3 to 3 cm), although the kidneys did not tend to be significantly enlarged. Histologic examination of the patient who underwent nephrectomy showed significant and widespread interstitial fibrosis. About half of the patients had high blood pressure and half had liver cysts. Three patients in 1 family (family 5) had gout. Several younger asymptomatic mutation carriers were identified through genetic family studies.

The transmission pattern of PKD6 in the families reported by Cornec-Le Gall et al. (2018) was consistent with autosomal dominant inheritance.

In affected members of 7 unrelated multigenerational families with PKD6, Cornec-Le Gall et al. (2018) identified 5 different heterozygous mutations in the DNAJB11 gene (611341.0001-611341.0005). Mutations in the first 2 families were found by whole-exome sequencing through large screening studies, whereas the remaining mutations were found by targeted next-generation sequencing of candidate genes among 591 families. All mutations were confirmed by Sanger sequencing and segregated with the disorder in the families. The mutations included 2 missense, 2 frameshift, and 1 nonsense, all of which occurred in the J domain, through which DNAJB11 interacts with BIP (HSPA5; 138120), or in the substrate-binding domain. Functional studies of the variants were not performed. Analysis of DNAJB11-null human renal cortical tubular epithelial cells showed decreased levels of mature cleaved polycystin-1 (PKD1; 601313) and increased levels of full-length immature PKD1, indicating a defect in the maturation process. Membrane expression of PKD1 was also significantly decreased in DNAJB11-null cells, consistent with a trafficking defect. There was no evidence of activation of the unfolded protein response in these cells. Kidney tissue samples from 2 unrelated patients showed some abnormal intracellular retention of uromodulin (UMOD; 191845) and MUC1 (158340) in epithelial cells in the thick ascending loop of Henle, suggesting that tubulointerstitial disease may be a component of the disorder.