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A human phospholamban promoter polymorphism in dilated cardiomyopathy alters transcriptional regulation by glucocorticoids
Author(s) -
Haghighi Kobra,
Chen Guoli,
Sato Yoji,
Fan GuoChang,
He Suiwen,
Kolokathis Fotis,
Pater Luke,
Paraskevaidis Ioannis,
Jones W. Keith.,
Dorn II Gerald W.,
Th. Kremastinos Dimitrios,
Kranias Evangelia G.
Publication year - 2008
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20692
Subject(s) - phospholamban , biology , contractility , medicine , dilated cardiomyopathy , endocrinology , promoter , heart failure , transcriptional regulation , serca , transcription factor , microbiology and biotechnology , gene expression , endoplasmic reticulum , gene , atpase , genetics , biochemistry , enzyme
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 –36 bp 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. Hum Mutat 29(5), 640–647, 2008. © 2008 Wiley‐Liss, Inc.