Insight into response to mTOR inhibition when PKD1 and TSC2 are mutated

BMC Med Genet. 2015 Jun 17:16:39. doi: 10.1186/s12881-015-0185-y.

Abstract

Background: Mutations in TSC1 or TSC2 cause the tuberous sclerosis complex (TSC), while mutations in PKD1 or PKD2 cause autosomal dominant polycystic kidney disease (ADPKD). PKD1 lays immediately adjacent to TSC2 and deletions involving both genes, the PKD1/TSC2 contiguous gene syndrome (CGS), are characterized by severe ADPKD, plus TSC. mTOR inhibitors have proven effective in reducing angiomyolipoma (AML) in TSC and total kidney volume in ADPKD but without a positive effect on renal function.

Methods and results: We describe a patient with independent truncating PKD1 and TSC2 mutations who has the expected phenotype for both diseases independently instead of the severe one described in PKD1/TSC2-CGS. Treatment with mTOR inhibitors reduced the AML and kidney volume for 2 years but thereafter they resumed growth; no positive effect on renal function was seen throughout. This is the first case addressing the response to mTOR treatment when independent truncating mutations in PKD1 and TSC2 are present.

Conclusions: This case reveals that although PKD1 and TSC2 are adjacent genes and there is likely cross-talk between the PKD1 and TSC2 signalling pathways regulating mTOR, having independent TSC2 and PKD1 mutations can give rise to a milder kidney phenotype than is typical in PKD1/TSC2-CGS cases. A short-term beneficial effect of mTOR inhibition on AML and total kidney volume was not reflected in improved renal function.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Phenotype
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TRPP Cation Channels / genetics*
  • Treatment Outcome
  • Tuberous Sclerosis / diagnosis
  • Tuberous Sclerosis / drug therapy
  • Tuberous Sclerosis / genetics
  • Tuberous Sclerosis / metabolism
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / genetics*

Substances

  • Protein Kinase Inhibitors
  • TRPP Cation Channels
  • TSC2 protein, human
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • polycystic kidney disease 1 protein
  • TOR Serine-Threonine Kinases