J G Seidman

Harvard Medical School, Boston, Massachusetts, United States

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Publications (461)6177.4 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in MYBPC3, the gene encoding cardiac myosin binding protein-C (cMyBP-C), account for ~40% of hypertrophic cardiomyopathy (HCM) cases. Most pathological MYBPC3 mutations encode truncated protein products not found in tissue. Reduced protein levels occur in symptomatic heterozygous human HCM carriers, suggesting haploinsufficiency as an underlying mechanism of disease. However, we do not know if reduced cMyBP-C content results from, or initiates the development of HCM. In previous studies, heterozygous (HET) mice with a MYBPC3 C'-terminal truncation mutation and normal cMyBP-C levels show altered contractile function prior to any overt hypertrophy. Therefore, this study aimed to test whether haploinsufficiency occurs, with decreased cMyBP-C content, following cardiac stress and whether the functional impairment in HET MYBPC3 hearts leads to worsened disease progression. To address these questions, transverse aortic constriction (TAC) was performed on three-month-old wild-type (WT) and HET MYBPC3-truncation mutant mice and then characterized at 4 and 12weeks post-surgery. HET-TAC mice showed increased hypertrophy and reduced ejection fraction compared to WT-TAC mice. At 4weeks post-surgery, HET myofilaments showed significantly reduced cMyBP-C content. Functionally, HET-TAC cardiomyocytes showed impaired force generation, higher Ca(2+) sensitivity, and blunted length-dependent increase in force generation. RNA sequencing revealed several differentially regulated genes between HET and WT groups, including regulators of remodeling and hypertrophic response. Collectively, these results demonstrate that haploinsufficiency occurs in HET MYBPC3 mutant carriers following stress, causing, in turn, reduced cMyBP-C content and exacerbating the development of dysfunction at myofilament and whole-heart levels. Copyright © 2014. Published by Elsevier Ltd.
    Journal of Molecular and Cellular Cardiology 11/2014; · 5.15 Impact Factor
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    Agrawal N, Akbani R, Aksoy BA, Ally A, Arachchi H, Asa SL, Auman JT, Balasundaram M, Balu S, Baylin SB, [......], Zeiger MA, Zeng D, Zenklusen JC, Zhao N, Zhang H, Zhang J, Zhang JJ, Zhang W, Zmuda E, Zou L.
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    ABSTRACT: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Here, we describe the genomic landscape of 496 PTCs. We observed a low frequency of somatic alterations (relative to other carcinomas) and extended the set of known PTC driver alterations to include EIF1AX, PPM1D, and CHEK2 and diverse gene fusions. These discoveries reduced the fraction of PTC cases with unknown oncogenic driver from 25% to 3.5%. Combined analyses of genomic variants, gene expression, and methylation demonstrated that different driver groups lead to different pathologies with distinct signaling and differentiation characteristics. Similarly, we identified distinct molecular subgroups of BRAF-mutant tumors, and multidimensional analyses highlighted a potential involvement of oncomiRs in less-differentiated subgroups. Our results propose a reclassification of thyroid cancers into molecular subtypes that better reflect their underlying signaling and differentiation properties, which has the potential to improve their pathological classification and better inform the management of the disease.
    Cell 10/2014; 159(3):676-90. · 31.96 Impact Factor
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    ABSTRACT: Previous studies have established that a subset of head and neck tumors contains human papillomavirus (HPV) sequences and that HPV-driven head and neck cancers display distinct biological and clinical features. HPV is known to drive cancer by the actions of the E6 and E7 oncoproteins, but the molecular architecture of HPV infection and its interaction with the host genome in head and neck cancers have not been comprehensively described. We profiled a cohort of 279 head and neck cancers with next generation RNA and DNA sequencing and show that 35 (12.5%) tumors displayed evidence of high-risk HPV types 16, 33, or 35. Twenty-five cases had integration of the viral genome into one or more locations in the human genome with statistical enrichment for genic regions. Integrations had a marked impact on the human genome and were associated with alterations in DNA copy number, mRNA transcript abundance and splicing, and both inter- and intrachromosomal rearrangements. Many of these events involved genes with documented roles in cancer. Cancers with integrated vs. nonintegrated HPV displayed different patterns of DNA methylation and both human and viral gene expressions. Together, these data provide insight into the mechanisms by which HPV interacts with the human genome beyond expression of viral oncoproteins and suggest that specific integration events are an integral component of viral oncogenesis.
    Proceedings of the National Academy of Sciences of the United States of America. 10/2014;
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    ABSTRACT: Rationale: Holt-Oram syndrome (HOS) is an autosomal dominant heart-hand syndrome caused by mutations in the TBX5 gene. Overexpression of Tbx5 in the chick proepicardial organ (PEO) impaired coronary blood vessel formation. However, the potential activity of Tbx5 in the epicardium itself, and Tbx5's role in mammalian coronary vasculogenesis, remains largely unknown. Objective: To evaluate the consequences of altered Tbx5 gene dosage during PEO and epicardial development in the embryonic chick and mouse. Methods and Results: Retroviral-mediated knockdown or upregulation of Tbx5 expression in the embryonic chick PEO as well as proepicardial-specific deletion of Tbx5 in the embryonic mouse (Tbx5(epi-/-)) impaired normal PEO cell development, inhibited epicardial and coronary blood vessel formation and altered developmental gene expression. The generation of epicardial-derived cells (EPDCs) and their migration into the myocardium was impaired between embryonic day (E) 13.5-15.5 in mutant hearts due to delayed epicardial attachment to the myocardium and subepicardial accumulation of EPDCs. This caused defective coronary vasculogenesis associated with impaired vascular smooth muscle cell recruitment, and reduced invasion of cardiac fibroblasts and endothelial cells into myocardium. In contrast to wildtype hearts that exhibited an elaborate ventricular vascular network, Tbx5(epi-/-) hearts displayed a marked decrease in vascular density that was associated with myocardial hypoxia as exemplified by HIF1α upregulation and increased binding of Hypoxyprobe-1. Tbx5(epi-/-) mice with such myocardial hypoxia exhibited reduced exercise capacity compared to wildtype mice. Conclusions: Our findings support a conserved Tbx5 dose-dependent requirement for both proepicardial and epicardial progenitor cell development in chick and mouse coronary vascular formation.
    Circulation Research 09/2014; · 11.86 Impact Factor
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    ABSTRACT: Rationale: Congenital heart disease (CHD) is among the most common birth defects. Most cases are of unknown etiology. Objective: To determine the contribution of de novo copy number variants (CNVs) in the etiology of sporadic CHD. Methods and Results: We studied 538 CHD trios using genome-wide dense single nucleotide polymorphism (SNP) arrays and/or whole exome sequencing (WES). Results were experimentally validated using digital droplet PCR. We compared validated CNVs in CHD cases to CNVs in 1,301 healthy control trios. The two complementary high-resolution technologies identified 63 validated de novo CNVs in 51 CHD cases. A significant increase in CNV burden was observed when comparing CHD trios with healthy trios, using either SNP array (p=7x10-5, Odds Ratio (OR)=4.6) or WES data (p=6x10-4, OR=3.5) and remained after removing 16% of de novo CNV loci previously reported as pathogenic (p=0.02, OR=2.7). We observed recurrent de novo CNVs on 15q11.2 encompassing CYFIP1, NIPA1, and NIPA2 and single de novo CNVs encompassing DUSP1, JUN, JUP, MED15, MED9, PTPRE SREBF1, TOP2A, and ZEB2, genes that interact with established CHD proteins NKX2-5 and GATA4. Integrating de novo variants in WES and CNV data suggests that ETS1 is the pathogenic gene altered by 11q24.2-q25 deletions in Jacobsen syndrome and that CTBP2 is the pathogenic gene in 10q sub-telomeric deletions. Conclusions: We demonstrate a significantly increased frequency of rare de novo CNVs in CHD patients compared with healthy controls and suggest several novel genetic loci for CHD.
    Circulation Research 09/2014; · 11.86 Impact Factor
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    ABSTRACT: Recent genomic analyses of pathologically defined tumor types identify ''within-a-tissue'' disease sub-types. However, the extent to which genomic sig-natures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head and neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multiplatform classification, while correlated with tissue-of-origin, provides inde-pendent information for predicting clinical outcomes. All data sets are available for data-mining from a uni-fied resource to support further biological discov-eries and insights into novel therapeutic strategies. INTRODUCTION
    Cell 08/2014; · 31.96 Impact Factor
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    ABSTRACT: -The geographic isolation and homogeneous population of Iceland is ideally suited to ascertain clinical and genetic characteristics of hypertrophic cardiomyopathy (HCM) at the population level.
    Circulation 07/2014; · 15.20 Impact Factor
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    ABSTRACT: Spontaneous calcium release evoking delayed after-depolarization is believed to cause CPVT, a lethal human arrhythmia provoked by exercise or emotional stress. Beta-adrenergic blockers are the drug of choice, but fail to achieve complete arrhythmia control in some patients. These individuals often require flecainide, device implantation and/or sympathetic denervation. To optimize the arrhythmia therapy by pharmacological inhibition of the sympathetic nervous system in the CASQ2(Δ/Δ) mouse model of CPVT2. A heart telemetry device was implanted for continuous ECG recording at rest and during provocation testing. Calcium transients and abnormal calcium release were studied in cardiomyocytes isolated from adult mice. Adrenergic receptor expression was determined by western blotting and confocal microscopy. Adult CASQ2(Δ/Δ) mice suffer from complex ventricular arrhythmia at rest and ventricular tachycardia during treadmill exercise and after epinephrine injection. Beta adrenergic blockers, propranolol and metoprolol attenuated arrhythmia at rest but not after stress. Reserpine had no efficacy in controlling arrhythmia. Agents with alpha blocking activity, phentolamine or labetalol, abolished both exercise and epinephrine-induced arrhythmia. To the contrary, injection of alpha adrenergic agonist phenylephrine reproducibly provoked VT. Isolated cardiomyocytes from CASQ2(Δ/Δ) mice had delayed calcium release waves upon exposure to sympathetic agonists which was abolished by phentolamine. Hearts of calsequestrin mutant mice expressed more alpha adreno-receptor1 compared to controls (p<0.05). We identified a contribution of alpha adrenergic pathway to pathogenesis of catecholamine-induced arrhythmia. Alpha blockade emerges an effective therapy in the murine model of CPVT2 and should be tried in humans resistant to beta blockers.
    Heart rhythm: the official journal of the Heart Rhythm Society 04/2014; · 4.56 Impact Factor
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    ABSTRACT: We report a five-generation family with phenotypically diverse neurodegenerative disease including relentlessly progressive choreoathetoid movements, dysarthria, dysphagia, spastic paralysis, and behavioral dementia in descendants of a 67-year-old woman with amyotrophic lateral sclerosis. Disease onset varied with gender, occurring in male children and adult women. Exome sequence analyses revealed a novel mutation (c.1490C>T, p.P497L) in the ubiquilin-2 gene (UBQLN2) with X-linked inheritance in all studied affected individuals. As ubiquilin-2 positive inclusions were identified in brain we suggest that mutant peptide predisposes to protein misfolding and accumulation. Our findings expand the spectrum of neurodegenerative phenotypes caused by UBQLN2 mutations. ANN NEUROL 2014. © 2014 American Neurological Association
    Annals of Neurology 04/2014; · 11.19 Impact Factor
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    ABSTRACT: Variants in SCN10A, which encodes a voltage-gated sodium channel, are associated with alterations of cardiac conduction parameters and the cardiac rhythm disorder Brugada syndrome; however, it is unclear how SCN10A variants promote dysfunctional cardiac conduction. Here we showed by high-resolution 4C-seq analysis of the Scn10a-Scn5a locus in murine heart tissue that a cardiac enhancer located in Scn10a, encompassing SCN10A functional variant rs6801957, interacts with the promoter of Scn5a, a sodium channel-encoding gene that is critical for cardiac conduction. We observed that SCN5A transcript levels were several orders of magnitude higher than SCN10A transcript levels in both adult human and mouse heart tissue. Analysis of BAC transgenic mouse strains harboring an engineered deletion of the enhancer within Scn10a revealed that the enhancer was essential for Scn5a expression in cardiac tissue. Furthermore, the common SCN10A variant rs6801957 modulated Scn5a expression in the heart. In humans, the SCN10A variant rs6801957, which correlated with slowed conduction, was associated with reduced SCN5A expression. These observations establish a genomic mechanism for how a common genetic variation at SCN10A influences cardiac physiology and predisposes to arrhythmia.
    The Journal of clinical investigation 03/2014; · 15.39 Impact Factor
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    ABSTRACT: The transcriptome is subject to multiple changes during pathogenesis, including the use of alternate 5' start-sites that can affect transcription levels and output. Current RNA sequencing techniques can assess mRNA levels, but do not robustly detect changes in 5' start-site use. Here, we developed a transcriptome sequencing strategy that detects genome-wide changes in start-site usage (5'RNA-Seq) and applied this methodology to identify regulatory events that occur in hypertrophic cardiomyopathy (HCM). Compared with transcripts from WT mice, 92 genes had altered start-site usage in a mouse model of HCM, including four-and-a-half LIM domains protein 1 (Fhl1). HCM-induced altered transcriptional regulation of Fhl1 resulted in robust myocyte expression of a distinct protein isoform, a response that was conserved in humans with genetic or acquired cardiomyopathies. Genetic ablation of Fhl1 in HCM mice was deleterious, which suggests that Fhl1 transcriptional changes provide salutary effects on stressed myocytes in this disease. Because Fhl1 is a chromosome X-encoded gene, stress-induced changes in its transcription may contribute to gender differences in the clinical severity of HCM. Our findings indicate that 5'RNA-Seq has the potential to identify genome-wide changes in 5' start-site usage that are associated with pathogenic phenotypes.
    The Journal of clinical investigation 02/2014; · 15.39 Impact Factor
  • Diane Fatkin, Christine E Seidman, Jonathan G Seidman
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    ABSTRACT: Cardiomyopathies are a heterogeneous group of heart muscle diseases associated with heart failure, arrhythmias, and death. Genetic variation has a critical role in the pathogenesis of cardiomyopathies, and numerous single-gene mutations have been associated with distinctive cardiomyopathy phenotypes. Contemporaneously with these discoveries, there has been enormous growth of genome-wide sequencing studies in large populations, data that show extensive genomic variation within every individual. The considerable allelic diversity in cardiomyopathy genes and in genes predicted to impact clinical expression of disease mutations indicates the need for a more nuanced interpretation of single-gene mutation in cardiomyopathies. These findings highlight the need to find new ways to interpret the functional significance of suites of genetic variants, as well as the need for new disease models that take global genetic variant burdens, epigenetic factors, and cardiac environmental factors into account.
    Cold Spring Harbor Perspectives in Medicine 01/2014; 4(1). · 7.56 Impact Factor
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    ABSTRACT: CRISPR/Cas9 has demonstrated a high-efficiency in site-specific gene targeting. However, potential off-target effects of the Cas9 nuclease represent a major safety concern for any therapeutic application. Here, we knock out the Tafazzin gene by CRISPR/Cas9 in human-induced pluripotent stem cells with 54% efficiency. We combine whole-genome sequencing and deep-targeted sequencing to characterise the off-target effects of Cas9 editing. Whole-genome sequencing of Cas9-modified hiPSC clones detects neither gross genomic alterations nor elevated mutation rates. Deep sequencing of in silico predicted off-target sites in a population of Cas9-treated cells further confirms high specificity of Cas9. However, we identify a single high-efficiency off-target site that is generated by a common germline single-nucleotide variant (SNV) in our experiment. Based on in silico analysis, we estimate a likelihood of SNVs creating off-target sites in a human genome to be ~1.5-8.5%, depending on the genome and site-selection method, but also note that mutations might be generated at these sites only at low rates and may not have functional consequences. Our study demonstrates the feasibility of highly specific clonal ex vivo gene editing using CRISPR/Cas9 and highlights the value of whole-genome sequencing before personalised CRISPR design.
    Nature Communications 01/2014; 5:5507. · 10.74 Impact Factor
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    ABSTRACT: Two distinct alleles in the gene encoding apolipoprotein L1 (APOL1), a major component of HDL, confer protection against Trypanosoma brucei rhodesiense infection and also increase risk for chronic kidney disease (CKD). Approximately 14% of African-Americans carry two APOL1 risk alleles, accounting for the high CKD burden in this population. We tested whether APOL1 risk alleles significantly increase risk for atherosclerotic cardiovascular disease (CVD) in African-Americans. We sequenced APOL1 in 1959 randomly selected African American participants in the Jackson Heart Study (JHS) and evaluated associations between APOL1 genotypes and renal and cardiovascular phenotypes. Previously identified association between APOL1 genotypes and CKD were confirmed (p=2.4 x 10-6). Among JHS participants with two APOL1 risk alleles, we observed increased risk for CVD (50/763 events among participants without vs. 37/280 events among participants with two risk alleles; odds ratio (OR): 2.17, p=9.4 x 10-4). We replicated this novel association of APOL1 genotype with CVD in Women's Health Initiative (WHI) participants (66/292 events among participants without vs. 37/101 events among participants with two risk alleles; OR: 1.98, p=8.37 x 10-3; JHS and WHI combined, p=8.5 x 10-5; OR: 2.12). The increased risk for CVD conferred by APOL1 alleles was robust to correction for both traditional CVD risk factors and CKD. APOL1 variants contribute to atherosclerotic CVD risk, indicating a genetic component to cardiovascular health disparities in individuals of African ancestry. The considerable population of African Americans with two APOL1 risk alleles may benefit from intensive interventions to reduce CVD.
    Circulation Research 12/2013; · 11.86 Impact Factor
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    ABSTRACT: We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) on the basis of multidimensional and comprehensive characterization, including mtDNA and whole-genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared with other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT upregulation in cancer distinct from previously observed amplifications and point mutations.
    Cancer Cell. 12/2013; 26(3):319-330.
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    ABSTRACT: -Integrin-linked kinase (ILK) is a serine-threonine kinase that has been linked to human and experimental heart failure, but its role in the heart is not fully understood. -To define the role of cardiomyocyte ILK, we generated cardiac-specific ILK knockout mice (CSILK-KO) using α-MHC-driven Cre expression. CSILK-KO spontaneously developed lethal dilated cardiomyopathy and heart failure with an early increase in apoptosis, fibrosis, and cardiac inflammation. To identify downstream effectors, we used deep sequence analysis of gene expression (DSAGE) to compare comprehensive transcriptional profiles of CSILK-KO and WT hearts from 10 day old mice before the development of cardiac dysfunction. ~2x10(6) cDNA clones from each genotype were sequenced, corresponding to 33,274 independent transcripts. 93 genes were altered, using nominal thresholds of >1.4-fold change and p<0.001. The most highly upregulated gene was osteopontin (47-fold increase, p=9.6x10(-45)), an inflammatory chemokine implicated in heart failure pathophysiology. ILK also regulated osteopontin expression in cardiomyocytes in vitro. Importantly, blocking antibodies to osteopontin mitigated but did not fully rescue the functional decline in CSILK-KO mice. -Cardiomyocyte-specific ILK deletion leads to a lethal cardiomyopathy characterized by cardiomyocyte death, fibrosis, and inflammation. Comprehensive profiling identifies ILK-dependent transcriptional effects and implicates osteopontin as a contributor to these phenotypes.
    Circulation Heart Failure 12/2013; · 6.68 Impact Factor
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    ABSTRACT: Genome sequencing can identify individuals in the general population who harbor rare coding variants in genes for Mendelian disorders and who may consequently have increased disease risk. Previous studies of rare variants in phenotypically extreme individuals display ascertainment bias and may demonstrate inflated effect-size estimates. We sequenced seven genes for maturity-onset diabetes of the young (MODY) in well-phenotyped population samples (n = 4,003). We filtered rare variants according to two prediction criteria for disease-causing mutations: reported previously in MODY or satisfying stringent de novo thresholds (rare, conserved and protein damaging). Approximately 1.5% and 0.5% of randomly selected individuals from the Framingham and Jackson Heart Studies, respectively, carry variants from these two classes. However, the vast majority of carriers remain euglycemic through middle age. Accurate estimates of variant effect sizes from population-based sequencing are needed to avoid falsely predicting a substantial fraction of individuals as being at risk for MODY or other Mendelian diseases.
    Nature Genetics 10/2013; · 35.21 Impact Factor
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    ABSTRACT: Dominant mutations in sarcomere proteins such as the myosin heavy chains (MHC) are the leading genetic causes of human hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy. We found that expression of the HCM-causing cardiac MHC gene (Myh6) R403Q mutation in mice can be selectively silenced by an RNA interference (RNAi) cassette delivered by an adeno-associated virus vector. RNAi-transduced MHC(403/+) mice developed neither hypertrophy nor myocardial fibrosis, the pathologic manifestations of HCM, for at least 6 months. Because inhibition of HCM was achieved by only a 25% reduction in the levels of the mutant transcripts, we suggest that the variable clinical phenotype in HCM patients reflects allele-specific expression and that partial silencing of mutant transcripts may have therapeutic benefit.
    Science 10/2013; 342(6154):111-114. · 31.20 Impact Factor
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    ABSTRACT: The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile.
    Nature Genetics 09/2013; 45(10):1113-20. · 35.21 Impact Factor
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    ABSTRACT: Humans and genetically engineered mice with recessively inherited CPVT develop arrhythmia which may arise due to malfunction or degradation of calsequestrin (CASQ2). We investigated the relation between protein level and arrhythmia severity in CASQ2D307H/D307H (D307H), compared to CASQ2Δ/Δ (KO) and wild type (WT) mice. CASQ2 expression and Ca(2+) transients were recorded in cardiomyocytes from neonatal or adult mice. Arrhythmia was studied in vivo using heart rhythm telemetry at rest, exercise and after epinephrine injection. CASQ2 protein was absent in KO heart. Neonatal D307H and WT hearts expressed significantly less CASQ2 protein than the level found in the adult WT. Adult D307H expressed only 20% of CASQ2 protein found in WT. Spontaneous Ca(2+) release was more prevalent in neonatal KO cardiomyocytes (89%) compared to 33-36% of either WT or D307H respectively, p<0.001. Adult cardiomyocytes from both mutant mice had more Ca(2+) abnormalities compared to control (KO: 82%, D307H 63%, WT 12%, p<0.01). Calcium oscillations were most common in KO cardiomyocytes. We then treated mice with bortezomib to inhibit CASQ2D307H degradation. Bortezomib increased CASQ2 expression in D307H hearts by ∼50% (p<0.05). Bortezomib-treated D307H mice had lower CPVT prevalence and less premature ventricular beats during peak exercise. No benefit against arrhythmia was observed in bortezomib treated KO mice. These results indicate that the mutant CASQ2D307H protein retains some of its physiological function. Its expression decreases with age and is inversely related to arrhythmia severity. Preventing the degradation of mutant protein should be explored as a possible therapeutic strategy in appropriate CPVT2 patients.
    Biochemical pharmacology 09/2013; · 4.25 Impact Factor

Publication Stats

27k Citations
6,177.40 Total Impact Points

Institutions

  • 1983–2014
    • Harvard Medical School
      • • Department of Genetics
      • • Department of Medicine
      Boston, Massachusetts, United States
    • Harvard University
      • Department of Chemistry and Chemical Biology
      Cambridge, MA, United States
  • 2007–2013
    • Tel Aviv University
      Tell Afif, Tel Aviv, Israel
  • 2004–2013
    • University of Vermont
      • Department of Molecular Physiology and Biophysics
      Burlington, VT, United States
  • 1991–2013
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 1989–2012
    • Boston Children's Hospital
      • • Division of Genetics
      • • Division of Infectious Diseases
      Boston, MA, United States
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
  • 1987–2012
    • Brigham and Women's Hospital
      • • Center for Brain Mind Medicine
      • • Department of Medicine
      Boston, MA, United States
  • 2011
    • University of Chicago
      • Department of Pediatrics
      Chicago, IL, United States
  • 2010
    • The University of Tokyo
      • Faculty & Graduate School of Medicine
      Tokyo, Tokyo-to, Japan
  • 2001–2009
    • Minneapolis Heart Institute
      Minneapolis, Minnesota, United States
  • 2005–2008
    • University of Pittsburgh
      • Department of Medicine
      Pittsburgh, Pennsylvania, United States
  • 2003
    • University of Pennsylvania
      Philadelphia, Pennsylvania, United States
  • 1999
    • Weill Cornell Medical College
      • Division of Cardiology
      New York City, New York, United States
  • 1996–1999
    • Massachusetts Eye and Ear Infirmary
      • Department of Otolaryngology
      Boston, MA, United States
  • 1995
    • Chang Gung Memorial Hospital
      T’ai-pei, Taipei, Taiwan
  • 1994
    • Medical Research Council (UK)
      Londinium, England, United Kingdom
  • 1986–1992
    • Massachusetts General Hospital
      • Department of Medicine
      Boston, Massachusetts, United States
    • Massachusetts Institute of Technology
      • Department of Biology
      Cambridge, Massachusetts, United States
  • 1990–1991
    • LSU Medical Center
      • Department of Medicine
      Shreveport, Louisiana, United States
  • 1988
    • Sinai Hospital
      Baltimore, Maryland, United States
  • 1984
    • Joslin Diabetes Center
      Boston, Massachusetts, United States
  • 1981
    • National Cancer Institute (USA)
      • Laboratory of Cell Biology
      Maryland, United States
  • 1977–1980
    • National Institute of Child Health and Human Development
      Maryland, United States
  • 1978
    • National Institutes of Health
      • Molecular Targets Laboratory
      Bethesda, MD, United States