Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease

Am J Hum Genet. 2018 May 3;102(5):832-844. doi: 10.1016/j.ajhg.2018.03.013. Epub 2018 Apr 26.


Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney cysts, often resulting in end-stage renal disease (ESRD). This disorder is genetically heterogeneous with ∼7% of families genetically unresolved. We performed whole-exome sequencing (WES) in two multiplex ADPKD-like pedigrees, and we analyzed a further 591 genetically unresolved, phenotypically similar families by targeted next-generation sequencing of 65 candidate genes. WES identified a DNAJB11 missense variant (p.Pro54Arg) in two family members presenting with non-enlarged polycystic kidneys and a frameshifting change (c.166_167insTT) in a second family with small renal and liver cysts. DNAJB11 is a co-factor of BiP, a key chaperone in the endoplasmic reticulum controlling folding, trafficking, and degradation of secreted and membrane proteins. Five additional multigenerational families carrying DNAJB11 mutations were identified by the targeted analysis. The clinical phenotype was consistent in the 23 affected members, with non-enlarged cystic kidneys that often evolved to kidney atrophy; 7 subjects reached ESRD from 59 to 89 years. The lack of kidney enlargement, histologically evident interstitial fibrosis in non-cystic parenchyma, and recurring episodes of gout (one family) suggested partial phenotypic overlap with autosomal-dominant tubulointerstitial diseases (ADTKD). Characterization of DNAJB11-null cells and kidney samples from affected individuals revealed a pathogenesis associated with maturation and trafficking defects involving the ADPKD protein, PC1, and ADTKD proteins, such as UMOD. DNAJB11-associated disease is a phenotypic hybrid of ADPKD and ADTKD, characterized by normal-sized cystic kidneys and progressive interstitial fibrosis resulting in late-onset ESRD.

Keywords: ADPKD; ADPLD; ADTKD; DNAJB11; pathogenic variants; renal cystic disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles*
  • Amino Acid Sequence
  • Base Sequence
  • Epithelial Cells / metabolism
  • Family
  • Female
  • HSP40 Heat-Shock Proteins / chemistry
  • HSP40 Heat-Shock Proteins / genetics*
  • Humans
  • Loop of Henle / pathology
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Pedigree
  • Polycystic Kidney, Autosomal Dominant / diagnostic imaging
  • Polycystic Kidney, Autosomal Dominant / genetics*
  • Polycystic Kidney, Autosomal Dominant / pathology
  • TRPP Cation Channels / genetics
  • Uromodulin / metabolism
  • Whole Exome Sequencing
  • Young Adult


  • DNAJB11 protein, human
  • HSP40 Heat-Shock Proteins
  • TRPP Cation Channels
  • Uromodulin