Mutations in multiple PKD genes may explain early and severe polycystic kidney disease

J Am Soc Nephrol. 2011 Nov;22(11):2047-56. doi: 10.1681/ASN.2010101080. Epub 2011 Oct 27.


Autosomal dominant polycystic kidney disease (ADPKD) is typically a late-onset disease caused by mutations in PKD1 or PKD2, but about 2% of patients with ADPKD show an early and severe phenotype that can be clinically indistinguishable from autosomal recessive polycystic kidney disease (ARPKD). The high recurrence risk in pedigrees with early and severe PKD strongly suggests a common familial modifying background, but the mechanisms underlying the extensive phenotypic variability observed among affected family members remain unknown. Here, we describe severely affected patients with PKD who carry, in addition to their expected familial germ-line defect, additional mutations in PKD genes, including HNF-1β, which likely aggravate the phenotype. Our findings are consistent with a common pathogenesis and dosage theory for PKD and may propose a general concept for the modification of disease expression in other so-called monogenic disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Aged
  • Amino Acid Sequence
  • Aryl Hydrocarbon Receptor Nuclear Translocator / genetics*
  • Family Health
  • Female
  • Genotype
  • Humans
  • Male
  • Molecular Sequence Data
  • Pedigree
  • Phenotype
  • Polycystic Kidney, Autosomal Dominant / epidemiology
  • Polycystic Kidney, Autosomal Dominant / genetics*
  • Polycystic Kidney, Autosomal Dominant / pathology
  • Pregnancy
  • Risk Factors
  • Severity of Illness Index*
  • TRPP Cation Channels / genetics*


  • ARNT protein, human
  • TRPP Cation Channels
  • polycystic kidney disease 1 protein
  • polycystic kidney disease 2 protein
  • Aryl Hydrocarbon Receptor Nuclear Translocator