Mutational screening of phospholamban gene in hypertrophic and idiopathic dilated cardiomyopathy and functional study of the PLN –42 C&gt;G mutation

Medin, Maria; Hermida-Prieto, Manuel; Monserrat, Lorenzo; Laredo, Rafael; Rodríguez‐Rey, José C.; Fernandez, Xustox; Castro‐Beiras, Alfonso

doi:10.1016/j.ejheart.2006.04.007

Cited by 46 publications

(36 citation statements)

References 33 publications

(47 reference statements)

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“…Mutations in genes encoding calciumhandling or calcium-sensitive proteins are a newly established pathogenic mechanism for HCM. Indeed, mutations in the promoter and coding regions of phospholamban, a regulator of the sarcoplasmic reticulum calcium ATPase (SERCA2a) and a modulator of calcium flux within the cell, have been identified in HCM and dilated cardiomyopathy (DCM) respectively [43][44][45]. Recently, mutations in junctophilin-2 (JPH2), a putative structural cardiac protein, confer susceptibility for HCM through disruption of the cardiac dyad and perturbed calciuminduced calcium release of the contracting cardiocyte [46].…”

Section: Discussionmentioning

confidence: 99%

Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C

Landstrom

Parvatiyar

Pinto

et al. 2008

Journal of Molecular and Cellular Cardiology

110

163

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Hypertrophic Cardiomyopathy (HCM) is a common primary cardiac disorder defined by a hypertrophied left ventricle, is one of the main causes of sudden death in young athletes and has been associated with mutations in most sarcomeric proteins (tropomyosin, Troponin T and I, and actin, etc.). Many of these mutations appear to affect the functional properties of cardiac troponin C (cTnC), i.e., by increasing the Ca 2+ -sensitivity of contraction, a hallmark of HCM, and surprisingly, prior to this report, cTnC had not been classified as a HCM susceptibility gene. In this study, we show that mutations occurring in the human cTnC (HcTnC) gene (TNNC1) have the same prevalence (~0.4%) as well established HCM-susceptibility genes that encode other sarcomeric proteins. Comprehensive open reading frame/splice site mutation analysis of TNNC1 performed on 1025 unrelated HCM patients over the last 10 years revealed novel missense mutations in TNNC1: A8V, C84Y, E134D, and D145E. Functional studies with these recombinant HcTnC HCM mutations showed increased Ca 2+ sensitivity of force development (A8V, C84Y and D145E) and force recovery (A8V and D145E). These results are consistent with the HCM functional phenotypes seen with other sarcomeric HCM mutations (E134D showed no changes in these parameters). This is the largest cohort analysis of TNNC1 in HCM that details the discovery of at least three novel HCM-associated mutations and more strongly links TNNC1 to HCM along with functional evidence that supports a central role for its involvement in the disease. These types of studies may help to further define TNNC1 as an HCMsusceptibility gene that has already been established for the other members of the Troponin complex.

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Section: Discussionmentioning

confidence: 99%

Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C

Landstrom

Parvatiyar

Pinto

et al. 2008

Journal of Molecular and Cellular Cardiology

110

163

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“…Functional analysis of the effect of these changes in cultured cells determined alterations in the transcriptional activity of the PLN promoter, suggesting that they may lead to alterations in SR Ca 2+ homeostasis and disease pathogenesis [77][78][79].…”

Section: Pln Mutations Lead To Cardiomyopathy and Heart Failurementioning

confidence: 99%

“…To date, six different PLN genetic variations have been reported [74][75][76][77][78][79]. Two of these mutations (R9C and R14Del) are characterized by gain-of-function, causing chronic inhibition of SERCA2a activity.…”

Section: Pln Mutations Lead To Cardiomyopathy and Heart Failurementioning

confidence: 99%

The role of SERCA2a/PLN complex, Ca2+ homeostasis, and anti-apoptotic proteins in determining cell fate

Vafiadaki

Papalouka

Arvanitis

et al. 2008

Pflugers Arch - Eur J Physiol

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Intracellular calcium is a major coordinator of numerous aspects of cellular physiology, including muscle contractility and cell survival. In cardiac muscle, aberrant Ca(2+) cycling has been implicated in a range of pathological conditions including cardiomyopathies and heart failure. The sarco(endo)plasmic reticulum Ca(2+) transport adenosine triphosphatase (SERCA2a) and its regulator phospholamban (PLN) have a central role in modulating Ca(2+) homeostasis and, therefore, cardiac function. Herein, we discuss the mechanisms through which SERCA2a and PLN control cardiomyocyte function in health and disease. Emphasis is placed on our newly identified PLN-binding partner HS-1-associated protein X-1 (HAX-1), which has an anti-apoptotic function and presents with numerous similarities to Bcl-2. Recent evidence indicates that proteins of the Bcl-2 family can influence ER Ca(2+) content, a critical determinant of cellular sensitivity to apoptosis. The discovery of the PLN/HAX-1 interaction therefore unveils an important new link between Ca(2+) homeostasis and cell survival, with significant therapeutic potential.

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“…Moreover, promoter mutations of PLN, which increased transcription, were recently reported in HCM. 103,104 As transgenic mice over-expressing PLN did not show cardiac hypertrophy, rather they showed systolic dysfunction, 105 pathological significance of PLN promoter mutations in HCM remains to be clarified.…”

Section: Other Mutations In Dcmmentioning

confidence: 99%

Molecular basis of hereditary cardiomyopathy: abnormalities in calcium sensitivity, stretch response, stress response and beyond

Kimura

2010

J Hum Genet

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Cardiomyopathy is caused by functional abnormality of cardiac muscle. The functional abnormality involved in its etiology includes both extrinsic and intrinsic factors, and cardiomyopathy caused by the intrinsic factors is called as idiopathic or primary cardiomyopathy. There are several clinical types of primary cardiomyopathy including hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Linkage studies and candidate gene approaches have explored the disease genes for hereditary primary cardiomyopathy. The most notable finding was that mutations in the same disease gene can be found in different clinical types of cardiomyopathy. Functional analyses of disease-related mutations have revealed that characteristic functional alterations are associated with the clinical types, such that increased and decreased Ca 2+ sensitivity due to sarcomere mutations are associated with HCM and DCM, respectively. In addition, our recent studies have suggested that mutations in the Z-disc components found in HCM and DCM may result in increased and decreased stiffness of sarcomere; that is, stiff sarcomere and loose sarcomere, respectively, and hence altered stretch response. More recently, mutations in the components of I region were found in hereditary cardiomyopathy and the functional analyses of the mutations suggested that the altered stress response was associated with cardiomyopathy, further complicating the etiology and pathogenesis. However, elucidation of genetic etiology and functional alterations caused by the mutations shed lights on the new therapeutic approaches to hereditary cardiomyopathy, such that treatment of DCM with a Ca 2+ sensitizer prevented the disease in a mouse model.

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Mutational screening of phospholamban gene in hypertrophic and idiopathic dilated cardiomyopathy and functional study of the PLN –42 C>G mutation

Cited by 46 publications

References 33 publications

Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C

Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C

The role of SERCA2a/PLN complex, Ca2+ homeostasis, and anti-apoptotic proteins in determining cell fate

Molecular basis of hereditary cardiomyopathy: abnormalities in calcium sensitivity, stretch response, stress response and beyond

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