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Mario Delmar - One of the best experts on this subject based on the ideXlab platform.
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transcriptomic coupling of PKP2 with inflammatory and immune pathways endogenous to adult cardiac myocytes
Frontiers in Physiology, 2021Co-Authors: Marta Perezhernandez, Marina Cerrone, Mingliang Zhang, Fengxia Liang, Grecia M Marronlinares, Florencia Schlamp, Adriana Heguy, Chantal J M Van Opbergen, Valeria Mezzano, Mario DelmarAbstract:Plakophilin-2 (PKP2) is classically defined as a component of the desmosome. Besides its role in cell-cell adhesion, PKP2 can modulate transcription through intracellular signals initiated at the site of cell-cell contact. Mutations in PKP2 associate with arrhythmogenic right ventricular cardiomyopathy (ARVC). Recent data demonstrate that inflammation plays a key role in disease progression; other results show an abundance of anti-heart antibodies in patients with confirmed diagnosis of ARVC. Here, we test the hypothesis that, in adult cardiac myocytes, PKP2 transcript abundance is endogenously linked to the abundance of transcripts participating in the inflammatory/immune response. Cardiac-specific, tamoxifen (TAM)-activated PKP2-knockout mice (PKP2cKO) were crossed with a RiboTag line to allow characterization of the ribosome-resident transcriptome of cardiomyocytes after PKP2 knockdown. Data were combined with informatics analysis of human cardiac transcriptome using GTEx. Separately, the presence of non-myocyte cells at the time of analysis was assessed by imaging methods. We identified a large number of transcripts upregulated consequent to PKP2 deficiency in myocytes, inversely correlated with PKP2 abundance in human transcriptomes, and part of functional pathways associated with inflammatory/immune responses. Our data support the concept that PKP2 is transcriptionally linked, in cardiac myocytes, to genes coding for host-response molecules even in the absence of exogenous triggers. Targeted anti-inflammatory therapy may be effective in ARVC.
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plakophilin 2 truncation variants in patients clinically diagnosed with catecholaminergic polymorphic ventricular tachycardia and decedents with exercise associated autopsy negative sudden unexplained death in the young
JACC: Clinical Electrophysiology, 2019Co-Authors: David J Tester, Marina Cerrone, Mario Delmar, Jaeger P Ackerman, John R Giudicessi, Nicholas C Ackerman, Michael J AckermanAbstract:Abstract Objectives This study determined if radical plakophilin-2 (PKP2) variants might underlie some cases of clinically diagnosed catecholaminergic polymorphic ventricular tachycardia (CPVT) and exercise-associated, autopsy-negative sudden unexplained death in the young (SUDY). Background Pathogenic variants in PKP2 cause arrhythmogenic right ventricular cardiomyopathy (ARVC). Recently, a cardiomyocyte-specific PKP2 knockout mouse model revealed that loss of PKP2 markedly reduced expression of genes critical in intracellular calcium handling. The mice with structurally normal hearts exhibited isoproterenol-triggered polymorphic ventricular arrhythmias that mimicked CPVT. Methods A PKP2 gene mutational analysis was performed on DNA from 18 unrelated patients (9 males; average age at diagnosis: 19.6 ± 12.8 years) clinically diagnosed with CPVT but who were RYR2-, CASQ2-, KCNJ2-, and TRDN-negative, and 19 decedents with SUDY during exercise (13 males; average age at death: 14 ± 3 years). Only radical (i.e., frame-shift, canonical splice site, or nonsense) variants with a minor allele frequency of ≤0.00005 in the genome aggregation database (gnomAD) were considered pathogenic. Results Radical PKP2 variants were identified in 5 of 18 (27.7%) CPVT patients and 1 of 19 (5.3%) exercise-related SUDY cases compared with 96 of 138,632 (0.069%) individuals in gnomAD (p = 3.1 × 10−13). Cardiac imaging or autopsy demonstrated a structurally normal heart in all patients at the time of their CPVT diagnosis or sudden death. Conclusions Our data suggested that the progression of the PKP2-dependent electropathy can be independent of structural perturbations and can precipitate exercise-associated sudden cardiac arrest or sudden cardiac death before the presence of overt cardiomyopathy, which clinically mimics CPVT, similar to the PKP2 knockout mouse model. Thus, CPVT and SUDY genetic test panels should now include PKP2.
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Table_1_Blockade of the Adenosine 2A Receptor Mitigates the Cardiomyopathy Induced by Loss of Plakophilin-2 Expression.XLS
2018Co-Authors: Marina Cerrone, Mingliang Zhang, Chantal J M Van Opbergen, Kabir Malkani, Natasha Irrera, Toon A. B. Van Veen, Bruce Cronstein, Mario DelmarAbstract:Background: Mutations in plakophilin-2 (PKP2) are the most common cause of familial Arrhythmogenic Right Ventricular Cardiomyopathy, a disease characterized by ventricular arrhythmias, sudden death, and progressive fibrofatty cardiomyopathy. The relation between loss of PKP2 expression and structural cardiomyopathy remains under study, though paracrine activation of pro-fibrotic intracellular signaling cascades is a likely event. Previous studies have indicated that ATP release into the intracellular space, and activation of adenosine receptors, can regulate fibrosis in various tissues. However, the role of this mechanism in the heart, and in the specific case of a PKP2-initiated cardiomyopathy, remains unexplored.Objectives: To investigate the role of ATP/adenosine in the progression of a PKP2-associated cardiomyopathy.Methods: HL1 cells were used to study PKP2- and Connexin43 (Cx43)-dependent ATP release. A cardiac-specific, tamoxifen-activated PKP2 knock-out murine model (PKP2cKO) was used to define the effect of adenosine receptor blockade on the progression of a PKP2-dependent cardiomyopathy.Results: HL1 cells silenced for PKP2 showed increased ATP release compared to control. Knockout of Cx43 in the same cells blunted the effect. PKP2cKO transcriptomic data revealed overexpression of genes involved in adenosine-receptor cascades. Istradefylline (an adenosine 2A receptor blocker) tempered the progression of fibrosis and mechanical failure observed in PKP2cKO mice. In contrast, PSB115, a blocker of the 2B adenosine receptor, showed opposite effects.Conclusion: Paracrine adenosine 2A receptor activation contributes to the progression of fibrosis and impaired cardiac function in animals deficient in PKP2. Given the limitations of the animal model, translation to the case of patients with PKP2 deficiency needs to be done with caution.
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abstract 14942 identification of truncation mutations in PKP2 encoded plakophilin 2 in patients with catecholaminergic polymorphic ventricular tachycardia and decedents with autopsy negative sudden death in the young
Circulation, 2017Co-Authors: Jaeger P Ackerman, Marina Cerrone, Mario Delmar, David J Tester, John R Giudicessi, Nicholas C Ackerman, Michael J AckermanAbstract:Background: Mutations in plakophilin-2 (PKP2) cause arrhythmogenic cardiomyopathy. Recently, a cardiomyocyte-specific PKP2 knockout mouse model revealed that loss of PKP2 markedly reduces expression of genes critical in intracellular calcium handling. The mice, with structurally normal hearts, exhibited isoproterenol-triggered polymorphic ventricular arrhythmias that mimicked catecholaminergic polymorphic ventricular tachycardia (CPVT). Therefore, we speculated that radical PKP2 mutations might underlie some cases of CPVT and exercise-associated autopsy negative sudden death in the young (ANSDY). Methods: A PKP2 gene mutational analysis was performed on DNA from 18 unrelated patients with genotype ( RYR2 , CASQ2, and KCNJ2 ) negative CPVT (9 males, average age at diagnosis 19.6 ± 12.8 years) and 19 decedents with ANSDY during exercise (13 males, average age at death, 14 ± 3 years). Only radical (i.e. frame-shift or nonsense) mutations with a minor allele frequency of ≤ 0.00005 in the genome aggregation database (gnomAD) were considered pathogenic. Results: Radical PKP2 mutations were identified in 5/18 (27.7%) patients with CPVT and 1/19 (5.3%) exercise-related ANSDY cases compared to 96/138,632 (0.069%) individuals in gnomAD (p=3.1 x10 -13 ). A R79X mutation was identified in both a 17-year-old female and a 12-year-old male with syncope while playing soccer. An E85fs mutation was identified in a 28-year-old female with cardiac arrest while jogging. An A418fs mutation was identified in a 19-year-old male with a history of syncope during exercise and a family history of ANSDY. An N634fs mutation was identified in a 16-year-old male that died during football drills. An H689fs mutation was identified in a 15-year-old female with exercise-induced ventricular fibrillation. Cardiac imaging or autopsy demonstrated a structurally normal heart in all patients at the time of diagnosis or sudden death. Conclusions: Our data suggests that the progression of the PKP2-dependent electrical disorder can be independent of structural perturbations and can precipitate sudden cardiac arrest prior to the presence of an overt cardiomyopathy akin to the PKP2 knockout out mouse model. Thus, the CPVT genetic test panel should now include PKP2 .
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plakophilin 2 loss promotes tgf β1 p38 mapk dependent fibrotic gene expression in cardiomyocytes
Journal of Cell Biology, 2016Co-Authors: Mario Delmar, Adi D Dubash, Chen Y Kam, Brian A Aguado, Dipal M Patel, Lonnie D Shea, Kathleen J GreenAbstract:Members of the desmosome protein family are integral components of the cardiac area composita, a mixed junctional complex responsible for electromechanical coupling between cardiomyocytes. In this study, we provide evidence that loss of the desmosomal armadillo protein Plakophilin-2 (PKP2) in cardiomyocytes elevates transforming growth factor β1 (TGF-β1) and p38 mitogen-activated protein kinase (MAPK) signaling, which together coordinate a transcriptional program that results in increased expression of profibrotic genes. Importantly, we demonstrate that expression of Desmoplakin (DP) is lost upon PKP2 knockdown and that restoration of DP expression rescues the activation of this TGF-β1/p38 MAPK transcriptional cascade. Tissues from PKP2 heterozygous and DP conditional knockout mouse models also exhibit elevated TGF-β1/p38 MAPK signaling and induction of fibrotic gene expression in vivo. These data therefore identify PKP2 and DP as central players in coordination of desmosome-dependent TGF-β1/p38 MAPK signaling in cardiomyocytes, pathways known to play a role in different types of cardiac disease, such as arrhythmogenic or hypertrophic cardiomyopathy.
Zhou Songyang - One of the best experts on this subject based on the ideXlab platform.
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oncogenic kinase induced pkm2 tyrosine 105 phosphorylation converts nononcogenic pkm2 to a tumor promoter and induces cancer stem like cells
Cancer Research, 2018Co-Authors: Zhifen Zhou, Lin Zhang, Hong Zhao, Ozgur şahin, Jing Chen, Jean J Zhao, Zhou SongyangAbstract:The role of pyruvate kinase M2 isoform (PKM2) in tumor progression has been controversial. Previous studies showed that PKM2 promoted tumor growth in xenograft models; however, depletion of PKM2 in the Brca1-loss-driven mammary tumor mouse model accelerates tumor formation. Because oncogenic kinases are frequently activated in tumors and PKM2 phosphorylation promotes tumor growth, we hypothesized that phosphorylation of PKM2 by activated kinases in tumor cells confers PKM2 oncogenic function, whereas nonphosphorylated PKM2 is nononcogenic. Indeed, PKM2 was phosphorylated at tyrosine 105 (Y105) and formed oncogenic dimers in MDA-MB-231 breast cancer cells, whereas PKM2 was largely unphosphorylated and formed nontumorigenic tetramers in nontransformed MCF10A cells. PKM2 knockdown did not affect MCF10A cell growth but significantly decreased proliferation of MDA-MB-231 breast cancer cells with tyrosine kinase activation. Multiple kinases that are frequently activated in different cancer types were identified to phosphorylate PKM2-Y105 in our tyrosine kinase screening. Introduction of the PKM2-Y105D phosphomimetic mutant into MCF10A cells induced colony formation and the CD44hi/CD24neg cancer stem-like cell population by increasing Yes-associated protein (YAP) nuclear localization. ErbB2, a strong inducer of PKM2-Y105 phosphorylation, boosted nuclear localization of YAP and enhanced the cancer stem-like cell population. Treatment with the ErbB2 kinase inhibitor lapatinib decreased PKM2-Y105 phosphorylation and cancer stem-like cells, impeding PKM2 tumor-promoting function. Taken together, phosphorylation of PKM2-Y105 by activated kinases exerts oncogenic functions in part via activation of YAP downstream signaling to increase cancer stem-like cell properties.Significance: These findings reveal PKM2 promotes tumorigenesis by inducing cancer stem-like cell properties and clarify the paradox of PKM2's dichotomous functions in tumor progression. Cancer Res; 78(9); 2248-61. ©2018 AACR.
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oncogenic kinase induced pkm2 tyrosine 105 phosphorylation converts nononcogenic pkm2 to a tumor promoter and induces cancer stem like cells
Cancer Research, 2018Co-Authors: Zhifen Zhou, Lin Zhang, Hong Zhao, Ozgur şahin, Jing Chen, Jean J Zhao, Zhou SongyangAbstract:The role of pyruvate kinase M2 isoform (PKM2) in tumor progression has been controversial. Previous studies showed that PKM2 promoted tumor growth in xenograft models; however, depletion of PKM2 in the Brca1-loss-driven mammary tumor mouse model accelerates tumor formation. Since oncogenic kinases are frequently activated in tumors and PKM2 phosphorylation promotes tumor growth, we hypothesized that phosphorylation of PKM2 by activated kinases in tumor cells confers PKM2 oncogenic function, whereas non-phosphorylated PKM2 is non-oncogenic. Indeed, PKM2 was phosphorylated at tyrosine 105 (Y105) and formed oncogenic dimers in MDA-MB-231 breast cancer cells, whereas PKM2 was largely unphosphorylated and formed non-tumorigenic tetramers in non-transformed MCF10A cells. PKM2 knockdown did not affect MCF10A cell growth but significantly decreased proliferation of MDA-MB-231 breast cancer cells with tyrosine kinase activation. Multiple kinases that are frequently activated in different cancer types were identified to phosphorylate PKM2-Y105 in our tyrosine kinase screening. Introduction of the PKM2-Y105D phospho-mimetic mutant into MCF10A cells induced colony formation and the CD44hi/CD24neg cancer stem-like cell population by increasing YAP protein nuclear localization. ErbB2, a strong inducer of PKM2-Y105 phosphorylation, boosted nuclear localization of YAP and enhanced the cancer stem-like cell population. Treatment with the ErbB2 kinase inhibitor lapatinib decreased PKM2-Y105 phosphorylation and cancer stem-like cells, impeding PKM2 tumor-promoting function. Taken together, phosphorylation of PKM2-Y105 by activated kinases exerts oncogenic functions in part via activation of YAP downstream signaling to increase cancer stem-like cell properties.
Marina Cerrone - One of the best experts on this subject based on the ideXlab platform.
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transcriptomic coupling of PKP2 with inflammatory and immune pathways endogenous to adult cardiac myocytes
Frontiers in Physiology, 2021Co-Authors: Marta Perezhernandez, Marina Cerrone, Mingliang Zhang, Fengxia Liang, Grecia M Marronlinares, Florencia Schlamp, Adriana Heguy, Chantal J M Van Opbergen, Valeria Mezzano, Mario DelmarAbstract:Plakophilin-2 (PKP2) is classically defined as a component of the desmosome. Besides its role in cell-cell adhesion, PKP2 can modulate transcription through intracellular signals initiated at the site of cell-cell contact. Mutations in PKP2 associate with arrhythmogenic right ventricular cardiomyopathy (ARVC). Recent data demonstrate that inflammation plays a key role in disease progression; other results show an abundance of anti-heart antibodies in patients with confirmed diagnosis of ARVC. Here, we test the hypothesis that, in adult cardiac myocytes, PKP2 transcript abundance is endogenously linked to the abundance of transcripts participating in the inflammatory/immune response. Cardiac-specific, tamoxifen (TAM)-activated PKP2-knockout mice (PKP2cKO) were crossed with a RiboTag line to allow characterization of the ribosome-resident transcriptome of cardiomyocytes after PKP2 knockdown. Data were combined with informatics analysis of human cardiac transcriptome using GTEx. Separately, the presence of non-myocyte cells at the time of analysis was assessed by imaging methods. We identified a large number of transcripts upregulated consequent to PKP2 deficiency in myocytes, inversely correlated with PKP2 abundance in human transcriptomes, and part of functional pathways associated with inflammatory/immune responses. Our data support the concept that PKP2 is transcriptionally linked, in cardiac myocytes, to genes coding for host-response molecules even in the absence of exogenous triggers. Targeted anti-inflammatory therapy may be effective in ARVC.
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plakophilin 2 truncation variants in patients clinically diagnosed with catecholaminergic polymorphic ventricular tachycardia and decedents with exercise associated autopsy negative sudden unexplained death in the young
JACC: Clinical Electrophysiology, 2019Co-Authors: David J Tester, Marina Cerrone, Mario Delmar, Jaeger P Ackerman, John R Giudicessi, Nicholas C Ackerman, Michael J AckermanAbstract:Abstract Objectives This study determined if radical plakophilin-2 (PKP2) variants might underlie some cases of clinically diagnosed catecholaminergic polymorphic ventricular tachycardia (CPVT) and exercise-associated, autopsy-negative sudden unexplained death in the young (SUDY). Background Pathogenic variants in PKP2 cause arrhythmogenic right ventricular cardiomyopathy (ARVC). Recently, a cardiomyocyte-specific PKP2 knockout mouse model revealed that loss of PKP2 markedly reduced expression of genes critical in intracellular calcium handling. The mice with structurally normal hearts exhibited isoproterenol-triggered polymorphic ventricular arrhythmias that mimicked CPVT. Methods A PKP2 gene mutational analysis was performed on DNA from 18 unrelated patients (9 males; average age at diagnosis: 19.6 ± 12.8 years) clinically diagnosed with CPVT but who were RYR2-, CASQ2-, KCNJ2-, and TRDN-negative, and 19 decedents with SUDY during exercise (13 males; average age at death: 14 ± 3 years). Only radical (i.e., frame-shift, canonical splice site, or nonsense) variants with a minor allele frequency of ≤0.00005 in the genome aggregation database (gnomAD) were considered pathogenic. Results Radical PKP2 variants were identified in 5 of 18 (27.7%) CPVT patients and 1 of 19 (5.3%) exercise-related SUDY cases compared with 96 of 138,632 (0.069%) individuals in gnomAD (p = 3.1 × 10−13). Cardiac imaging or autopsy demonstrated a structurally normal heart in all patients at the time of their CPVT diagnosis or sudden death. Conclusions Our data suggested that the progression of the PKP2-dependent electropathy can be independent of structural perturbations and can precipitate exercise-associated sudden cardiac arrest or sudden cardiac death before the presence of overt cardiomyopathy, which clinically mimics CPVT, similar to the PKP2 knockout mouse model. Thus, CPVT and SUDY genetic test panels should now include PKP2.
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Table_1_Blockade of the Adenosine 2A Receptor Mitigates the Cardiomyopathy Induced by Loss of Plakophilin-2 Expression.XLS
2018Co-Authors: Marina Cerrone, Mingliang Zhang, Chantal J M Van Opbergen, Kabir Malkani, Natasha Irrera, Toon A. B. Van Veen, Bruce Cronstein, Mario DelmarAbstract:Background: Mutations in plakophilin-2 (PKP2) are the most common cause of familial Arrhythmogenic Right Ventricular Cardiomyopathy, a disease characterized by ventricular arrhythmias, sudden death, and progressive fibrofatty cardiomyopathy. The relation between loss of PKP2 expression and structural cardiomyopathy remains under study, though paracrine activation of pro-fibrotic intracellular signaling cascades is a likely event. Previous studies have indicated that ATP release into the intracellular space, and activation of adenosine receptors, can regulate fibrosis in various tissues. However, the role of this mechanism in the heart, and in the specific case of a PKP2-initiated cardiomyopathy, remains unexplored.Objectives: To investigate the role of ATP/adenosine in the progression of a PKP2-associated cardiomyopathy.Methods: HL1 cells were used to study PKP2- and Connexin43 (Cx43)-dependent ATP release. A cardiac-specific, tamoxifen-activated PKP2 knock-out murine model (PKP2cKO) was used to define the effect of adenosine receptor blockade on the progression of a PKP2-dependent cardiomyopathy.Results: HL1 cells silenced for PKP2 showed increased ATP release compared to control. Knockout of Cx43 in the same cells blunted the effect. PKP2cKO transcriptomic data revealed overexpression of genes involved in adenosine-receptor cascades. Istradefylline (an adenosine 2A receptor blocker) tempered the progression of fibrosis and mechanical failure observed in PKP2cKO mice. In contrast, PSB115, a blocker of the 2B adenosine receptor, showed opposite effects.Conclusion: Paracrine adenosine 2A receptor activation contributes to the progression of fibrosis and impaired cardiac function in animals deficient in PKP2. Given the limitations of the animal model, translation to the case of patients with PKP2 deficiency needs to be done with caution.
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Pleiotropic Phenotypes Associated With PKP2 Variants
Frontiers Media S.A., 2018Co-Authors: Valeria Novelli, Kabir Malkani, Marina CerroneAbstract:Plakophilin-2 (PKP2) is a component of the desmosome complex and known for its role in cell-cell adhesion. Recently, alterations in the PKP2 gene have been associated with different inherited cardiac conditions including Arrythmogenic Cardiomyopathy (ACM or ARVC), Brugada syndrome (BrS), and idiopathic ventricular fibrillation to name the most relevant. However, the assessment of pathogenicity regarding the genetic variations associated with PKP2 is still a challenging task: the gene has a positive Residual Variation Intolerance Score and the potential deleterious role of several of its variants has been disputed. Limitations in facilitating interpretation and annotations of these variants are seen in the lack of segregation and clinical data in the control population of reference. In this review, we will provide a summary of all the currently available genetic information related to the PKP2 gene, including different phenotypes, ClinVar annotations and data from large control database. Our goal is to provide a literature review that could help clinicians and geneticists in interpreting the role of PKP2 variants in the context of heritable sudden death syndromes. Limitations of current algorithms and data repositories will be discussed
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abstract 14942 identification of truncation mutations in PKP2 encoded plakophilin 2 in patients with catecholaminergic polymorphic ventricular tachycardia and decedents with autopsy negative sudden death in the young
Circulation, 2017Co-Authors: Jaeger P Ackerman, Marina Cerrone, Mario Delmar, David J Tester, John R Giudicessi, Nicholas C Ackerman, Michael J AckermanAbstract:Background: Mutations in plakophilin-2 (PKP2) cause arrhythmogenic cardiomyopathy. Recently, a cardiomyocyte-specific PKP2 knockout mouse model revealed that loss of PKP2 markedly reduces expression of genes critical in intracellular calcium handling. The mice, with structurally normal hearts, exhibited isoproterenol-triggered polymorphic ventricular arrhythmias that mimicked catecholaminergic polymorphic ventricular tachycardia (CPVT). Therefore, we speculated that radical PKP2 mutations might underlie some cases of CPVT and exercise-associated autopsy negative sudden death in the young (ANSDY). Methods: A PKP2 gene mutational analysis was performed on DNA from 18 unrelated patients with genotype ( RYR2 , CASQ2, and KCNJ2 ) negative CPVT (9 males, average age at diagnosis 19.6 ± 12.8 years) and 19 decedents with ANSDY during exercise (13 males, average age at death, 14 ± 3 years). Only radical (i.e. frame-shift or nonsense) mutations with a minor allele frequency of ≤ 0.00005 in the genome aggregation database (gnomAD) were considered pathogenic. Results: Radical PKP2 mutations were identified in 5/18 (27.7%) patients with CPVT and 1/19 (5.3%) exercise-related ANSDY cases compared to 96/138,632 (0.069%) individuals in gnomAD (p=3.1 x10 -13 ). A R79X mutation was identified in both a 17-year-old female and a 12-year-old male with syncope while playing soccer. An E85fs mutation was identified in a 28-year-old female with cardiac arrest while jogging. An A418fs mutation was identified in a 19-year-old male with a history of syncope during exercise and a family history of ANSDY. An N634fs mutation was identified in a 16-year-old male that died during football drills. An H689fs mutation was identified in a 15-year-old female with exercise-induced ventricular fibrillation. Cardiac imaging or autopsy demonstrated a structurally normal heart in all patients at the time of diagnosis or sudden death. Conclusions: Our data suggests that the progression of the PKP2-dependent electrical disorder can be independent of structural perturbations and can precipitate sudden cardiac arrest prior to the presence of an overt cardiomyopathy akin to the PKP2 knockout out mouse model. Thus, the CPVT genetic test panel should now include PKP2 .
Ans C P Wiesfeld - One of the best experts on this subject based on the ideXlab platform.
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detection of genomic deletions of PKP2 in arrhythmogenic right ventricular cardiomyopathy
Clinical Genetics, 2013Co-Authors: Jason D Roberts, Ans C P Wiesfeld, Dennis Dooijes, Johanna C Herkert, Julie Rutberg, Sarah M Nikkel, Robert M Gow, J P Van Tintelen, Michael H GollobAbstract:Roberts JD, Herkert JC, Rutberg J, Nikkel SM, Wiesfeld ACP, Dooijes D, Gow RM, van Tintelen JP, Gollob MH. Detection of genomic deletions of PKP2 in arrhythmogenic right ventricular cardiomyopathy. Clin Genet 2013: 83: 452-456. (C) John Wiley & Sons A/S. Published by Blackwell Publishing Ltd, 2012 Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disease that predominantly affects the right ventricle and is associated with ventricular arrhythmias that may lead to sudden cardiac death. Mutations within at least seven separate genes have been identified to cause ARVC, however a genetic culprit remains elusive in approximately 50% of cases. Although negative genetic testing may be secondary to pathogenic mutations within undiscovered genes, an alternative explanation may be the presence of large deletions or duplications involving known genes. These large copy number variants may not be detected with standard clinical genetic testing which is presently limited to direct DNA sequencing. We describe two cases of ARVC possessing large deletions involving plakophilin-2 (PKP2) identified with microarray analysis and/or multiplex ligation-dependent probe amplification (MLPA) that would have been classified as genotype negative with standard clinical genetic testing. A deletion of the entire coding region of PKP2 excluding exon 1 was identified in patient 1 and his son. In patient 2, MLPA analysis of PKP2 revealed deletion of the entire gene with subsequent microarray analysis demonstrating a de novo 7.9Mb deletion of chromosome 12p12.1p11.1. These findings support screening for large copy number variants in clinically suspected ARVC cases without clear disease causing mutations following initial sequencing analysis.
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arrhythmogenic right ventricular dysplasia cardiomyopathy pathogenic desmosome mutations in index patients predict outcome of family screening dutch arrhythmogenic right ventricular dysplasia cardiomyopathy genotype phenotype follow up study
Circulation, 2011Co-Authors: Moniek G P J Cox, Ans C P Wiesfeld, Jasper J Van Der Smagt, Maartje Noorman, Irene M Van Langen, Paul A Van Der Zwaag, Christian Van Der Werf, Zahir A Bhuiyan, Paul G A Volders, Douwe E AtsmaAbstract:Background— Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an autosomal dominant inherited disease with incomplete penetrance and variable expression. Causative mutations in genes encoding 5 desmosomal proteins are found in ≈50% of ARVD/C index patients. Previous genotype-phenotype relation studies involved mainly overt ARVD/C index patients, so follow-up data on relatives are scarce. Methods and Results— One hundred forty-nine ARVD/C index patients (111 male patients; age, 49±13 years) according to 2010 Task Force criteria and 302 relatives from 93 families (282 asymptomatic; 135 male patients; age, 44±13 years) were clinically and genetically characterized. DNA analysis comprised sequencing of plakophilin-2 ( PKP2 ), desmocollin-2, desmoglein-2, desmoplakin, and plakoglobin and multiplex ligation-dependent probe amplification to identify large deletions in PKP2. Pathogenic mutations were found in 87 index patients (58%), mainly truncating PKP2 mutations, including 3 cases with multiple mutations. Multiplex ligation-dependent probe amplification revealed 3 PKP2 exon deletions. ARVD/C was diagnosed in 31% of initially asymptomatic mutation-carrying relatives and 5% of initially asymptomatic relatives of index patients without mutation. Prolonged terminal activation duration was observed more than negative T waves in V1 to V3, especially in mutation-carrying relatives <20 years of age. In 45% of screened families, ≥1 affected relatives were identified (90% with mutations). Conclusions— Pathogenic desmosomal gene mutations, mainly truncating PKP2 mutations, underlie ARVD/C in the majority (58%) of Dutch index patients and even 90% of familial cases. Additional multiplex ligation-dependent probe amplification analysis contributed to discovering pathogenic mutations underlying ARVD/C. Discovering pathogenic mutations in index patients enables those relatives who have a 6-fold increased risk of ARVD/C diagnosis to be identified. Prolonged terminal activation duration seems to be a first sign of ARVD/C in young asymptomatic relatives. # Clinical Perspective {#article-title-38}
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arrhythmogenic right ventricular dysplasia cardiomyopathy pathogenic desmosome mutations in index patients predict outcome of family screening dutch arrhythmogenic right ventricular dysplasia cardiomyopathy genotype phenotype follow up study
Circulation, 2011Co-Authors: Moniek G P J Cox, Ans C P Wiesfeld, Jasper J Van Der Smagt, Maartje Noorman, Irene M Van Langen, Paul A Van Der Zwaag, Christian Van Der Werf, Zahir A Bhuiyan, Paul G A Volders, Douwe E AtsmaAbstract:textabstractBackground-: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an autosomal dominant inherited disease with incomplete penetrance and variable expression. Causative mutations in genes encoding 5 desmosomal proteins are found in ≈50% of ARVD/C index patients. Previous genotype-phenotype relation studies involved mainly overt ARVD/C index patients, so follow-up data on relatives are scarce. Methods and Results-: One hundred forty-nine ARVD/C index patients (111 male patients; age, 49±13 years) according to 2010 Task Force criteria and 302 relatives from 93 families (282 asymptomatic; 135 male patients; age, 44±13 years) were clinically and genetically characterized. DNA analysis comprised sequencing of plakophilin-2 (PKP2), desmocollin-2, desmoglein-2, desmoplakin, and plakoglobin and multiplex ligation-dependent probe amplification to identify large deletions in PKP2. Pathogenic mutations were found in 87 index patients (58%), mainly truncating PKP2 mutations, including 3 cases with multiple mutations. Multiplex ligation-dependent probe amplification revealed 3 PKP2 exon deletions. ARVD/C was diagnosed in 31% of initially asymptomatic mutation-carrying relatives and 5% of initially asymptomatic relatives of index patients without mutation. Prolonged terminal activation duration was observed more than negative T waves in V1 to V3, especially in mutation-carrying relatives <20 years of age. In 45% of screened families, ≥1 affected relatives were identified (90% with mutations). Conclusions-: Pathogenic desmosomal gene mutations, mainly truncating PKP2 mutations, underlie ARVD/C in the majority (58%) of Dutch index patients and even 90% of familial cases. Additional multiplex ligation-dependent probe amplification analysis contributed to discovering pathogenic mutations underlying ARVD/C. Discovering pathogenic mutations in index patients enables those relatives who have a 6-fold increased risk of ARVD/C diagnosis to be identified. Prolonged terminal activation duration seems to be a first sign of ARVD/C in young asymptomatic relatives.
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desmoglein 2 and desmocollin 2 mutations in dutch arrhythmogenic right ventricular dysplasia cardiomypathy patients results from a multicenter study
Circulation-cardiovascular Genetics, 2009Co-Authors: Zakirul Alam Bhuiyan, Jan D.h. Jongbloed, Paola M. Lombardi, Meyke Schouten, Roselie Jongbloed, Marcel R Nelen, Ans C P Wiesfeld, Jasper J Van Der Smagt, Moniek G P J Cox, Marleen Van WolferenAbstract:Background— This study aimed to evaluate the prevalence and type of mutations in the major desmosomal genes, Plakophilin-2 ( PKP2 ), Desmoglein-2 ( DSG2 ), and Desmocollin-2 ( DSC2 ), in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) patients. We also aimed to distinguish relevant clinical and ECG parameters. Methods and Results— Clinical evaluation was performed according to the Task Force Criteria (TFC). We analyzed the genes in (a) 57 patients who fulfilled the ARVD/C TFC (TFC+), (b) 28 patients with probable ARVD/C (1 major and 1 minor, or 3 minor criteria), and (c) 31 patients with 2 minor or 1 major criteria. In the TFC+ ARVD/C group, 23 patients (40%) had PKP2 mutations, 4 (7%) had DSG2 mutations, and 1 patient (2%) carried a mutation in DSC2 , whereas 1 patient (2%) had a mutation in both DSG2 and DSC2 . Among the DSG2 and DSC2 mutation-positive TFC+ ARVD/C probands, 2 carried compound heterozygous mutations and 1 had digenic mutations. In probable ARVD/C patients and those with 2 minor or 1 major criteria for ARVD/C, mutations were less frequent and they were all heterozygous. Negative T waves in the precordial leads were observed more ( P PKP2 mutation carriers. Conclusions— Mutations in DSG2 and DSC2 are together less prevalent (10%) than PKP2 mutations (40%) in Dutch TFC+ ARVD/C patients. Interestingly, biallelic or digenic DSC2 and/or DSG2 mutations are frequently identified in TFC+ ARVD/C patients, suggesting that a single mutation is less likely to cause a full-blown ARVD/C phenotype. Negative T waves on ECG were prevalent among mutation carriers ( P
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plakophilin 2 mutations are the major determinant of familial arrhythmogenic right ventricular dysplasia cardiomyopathy
Circulation, 2006Co-Authors: Peter J Van Tintelen, Roselie Jongbloed, Ans C P Wiesfeld, Jasper J Van Der Smagt, Mark M Entius, Zahurul A Bhuiyan, Arthur A M Wilde, Ludolf G Boven, Marcel M A M Mannens, Irene M Van LangenAbstract:Background— Mutations in the plakophilin-2 gene (PKP2) have been found in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC). Hence, genetic screening can potentially be a valuable tool in the diagnostic workup of patients with ARVC. Methods and Results— To establish the prevalence and character of PKP2 mutations and to study potential differences in the associated phenotype, we evaluated 96 index patients, including 56 who fulfilled the published task force criteria. In addition, 114 family members from 34 of these 56 ARVC index patients were phenotyped. In 24 of these 56 ARVC patients (43%), 14 different (11 novel) PKP2 mutations were identified. Four different mutations were found more than once; haplotype analyses revealed identical haplotypes in the different mutation carriers, suggesting founder mutations. No specific genotype-phenotype correlations could be identified, except that negative T waves in V2 and V3 occurred more often in PKP2 mutation carriers (P<0.05). Of th...
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oncogenic kinase induced pkm2 tyrosine 105 phosphorylation converts nononcogenic pkm2 to a tumor promoter and induces cancer stem like cells
Cancer Research, 2018Co-Authors: Zhifen Zhou, Lin Zhang, Hong Zhao, Ozgur şahin, Jing Chen, Jean J Zhao, Zhou SongyangAbstract:The role of pyruvate kinase M2 isoform (PKM2) in tumor progression has been controversial. Previous studies showed that PKM2 promoted tumor growth in xenograft models; however, depletion of PKM2 in the Brca1-loss-driven mammary tumor mouse model accelerates tumor formation. Because oncogenic kinases are frequently activated in tumors and PKM2 phosphorylation promotes tumor growth, we hypothesized that phosphorylation of PKM2 by activated kinases in tumor cells confers PKM2 oncogenic function, whereas nonphosphorylated PKM2 is nononcogenic. Indeed, PKM2 was phosphorylated at tyrosine 105 (Y105) and formed oncogenic dimers in MDA-MB-231 breast cancer cells, whereas PKM2 was largely unphosphorylated and formed nontumorigenic tetramers in nontransformed MCF10A cells. PKM2 knockdown did not affect MCF10A cell growth but significantly decreased proliferation of MDA-MB-231 breast cancer cells with tyrosine kinase activation. Multiple kinases that are frequently activated in different cancer types were identified to phosphorylate PKM2-Y105 in our tyrosine kinase screening. Introduction of the PKM2-Y105D phosphomimetic mutant into MCF10A cells induced colony formation and the CD44hi/CD24neg cancer stem-like cell population by increasing Yes-associated protein (YAP) nuclear localization. ErbB2, a strong inducer of PKM2-Y105 phosphorylation, boosted nuclear localization of YAP and enhanced the cancer stem-like cell population. Treatment with the ErbB2 kinase inhibitor lapatinib decreased PKM2-Y105 phosphorylation and cancer stem-like cells, impeding PKM2 tumor-promoting function. Taken together, phosphorylation of PKM2-Y105 by activated kinases exerts oncogenic functions in part via activation of YAP downstream signaling to increase cancer stem-like cell properties.Significance: These findings reveal PKM2 promotes tumorigenesis by inducing cancer stem-like cell properties and clarify the paradox of PKM2's dichotomous functions in tumor progression. Cancer Res; 78(9); 2248-61. ©2018 AACR.
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oncogenic kinase induced pkm2 tyrosine 105 phosphorylation converts nononcogenic pkm2 to a tumor promoter and induces cancer stem like cells
Cancer Research, 2018Co-Authors: Zhifen Zhou, Lin Zhang, Hong Zhao, Ozgur şahin, Jing Chen, Jean J Zhao, Zhou SongyangAbstract:The role of pyruvate kinase M2 isoform (PKM2) in tumor progression has been controversial. Previous studies showed that PKM2 promoted tumor growth in xenograft models; however, depletion of PKM2 in the Brca1-loss-driven mammary tumor mouse model accelerates tumor formation. Since oncogenic kinases are frequently activated in tumors and PKM2 phosphorylation promotes tumor growth, we hypothesized that phosphorylation of PKM2 by activated kinases in tumor cells confers PKM2 oncogenic function, whereas non-phosphorylated PKM2 is non-oncogenic. Indeed, PKM2 was phosphorylated at tyrosine 105 (Y105) and formed oncogenic dimers in MDA-MB-231 breast cancer cells, whereas PKM2 was largely unphosphorylated and formed non-tumorigenic tetramers in non-transformed MCF10A cells. PKM2 knockdown did not affect MCF10A cell growth but significantly decreased proliferation of MDA-MB-231 breast cancer cells with tyrosine kinase activation. Multiple kinases that are frequently activated in different cancer types were identified to phosphorylate PKM2-Y105 in our tyrosine kinase screening. Introduction of the PKM2-Y105D phospho-mimetic mutant into MCF10A cells induced colony formation and the CD44hi/CD24neg cancer stem-like cell population by increasing YAP protein nuclear localization. ErbB2, a strong inducer of PKM2-Y105 phosphorylation, boosted nuclear localization of YAP and enhanced the cancer stem-like cell population. Treatment with the ErbB2 kinase inhibitor lapatinib decreased PKM2-Y105 phosphorylation and cancer stem-like cells, impeding PKM2 tumor-promoting function. Taken together, phosphorylation of PKM2-Y105 by activated kinases exerts oncogenic functions in part via activation of YAP downstream signaling to increase cancer stem-like cell properties.