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

作者：Haghighi Kobra; Chen Guoli; Sato Yoji; Fan Guo Chang; He Suiwen; Kolokathis Fotis; Pater Luke; Paraskevaidis Ioannis; Jones W Keith; Dorn Gerald W II; Kremastinos Dimitrios Th; Kranias Evangelia G^*

来源：Human Mutation, 2008, 29(5): 640-647.

DOI：10.1002/humu.20692

• promoter
• polymorphism
• transcriptional factor
• GR
• GRE
• cardiomyopathy
• PLN
• SR Ca-ATPase

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.

• 出版日期2008-5