A human phospholamban promoter polymorphism in dilated cardiomyopathy alters transcriptional regulation by glucocorticoids

Kobra Haghighi, Guoli Chen, Yoji Sato, Guo Chang Fan, Suiwen He, Fotis Kolokathis, Luke Pater, Ioannis Paraskevaidis, W. Keith Jones, Gerald W. Dorn, Dimitrios Th Kremastinos, Evangelia G. Kranias

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


Depressed calcium handling by the sarcoplasmic reticulum (SR) Ca-ATPase and its regulator phospholamban (PLN) is a key characteristic of human and experimental heart failure. Accumulating evidence indicates that increases in the relative levels of PLN to Ca-ATPase in failing hearts and resulting inhibition of Ca sequestration during diastole, impairs contractility. Here, we identified a genetic variant in the PLN promoter region, which increases its expression and may serve as a genetic modifier in dilated cardiomyopathy (DCM). The variant AF177763.1:g.203A>C (at position -36bp relative to the PLN transcriptional start site) was found only in the heterozygous form in 1 out of 296 normal subjects and in 22 out of 381 cardiomyopathy patients (heart failure at age of 18-44 years, ejection fraction = 22 + 9%). In vitro analysis, using luciferase as a reporter gene in rat neonatal cardiomyocytes, indicated that the PLN-variant increased activity by 24% compared to the wild type. Furthermore, the g.203A>C substitution altered the specific sequence of the steroid receptor for the glucocorticoid nuclear receptor (GR)/transcription factor in the PLN promoter, resulting in enhanced binding to the mutated DNA site. These findings suggest that the g.203A>C genetic variant in the human PLN promoter may contribute to depressed contractility and accelerate functional deterioration in heart failure.

Original languageEnglish
Pages (from-to)640-647
Number of pages8
JournalHuman mutation
Issue number5
StatePublished - May 2008


  • Cardiomyopathy
  • GR
  • GRE
  • PLN
  • Polymorphism
  • Promoter
  • SR Ca-ATPase
  • Transcriptional factor


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