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Christine E. Seidman - One of the best experts on this subject based on the ideXlab platform.

  • An abnormal Ca2+ response in mutant sarcomere protein–mediated Familial Hypertrophic Cardiomyopathy
    The Journal of clinical investigation, 2000
    Co-Authors: Diane Fatkin, Christine E. Seidman, Frederick J. Schoen, Christopher Semsarian, Bradley K Mcconnell, James O Mudd, Ivan G P Moskowitz, Michael Giewat, Jon G. Seidman
    Abstract:

    Dominant-negative sarcomere protein gene mutations cause Familial Hypertrophic Cardiomyopathy (FHC), a disease characterized by left-ventricular hypertrophy, angina, and dyspnea that can result in sudden death. We report here that a murine model of FHC bearing a cardiac myosin heavy-chain gene missense mutation (αMHC403/+), when treated with calcineurin inhibitors or a K+-channel agonist, developed accentuated hypertrophy, worsened histopathology, and was at risk for early death. Despite distinct pharmacologic targets, each agent augmented diastolic Ca2+ concentrations in wild-type cardiac myocytes; αMHC403/+ myocytes failed to respond. Pretreatment with a Ca2+-channel antagonist abrogated diastolic Ca2+ changes in wild-type myocytes and prevented the exaggerated Hypertrophic response of treated αMHC403/+ mice. We conclude that FHC-causing sarcomere protein gene mutations cause abnormal Ca2+ responses that initiate a Hypertrophic response. These data define an important Ca2+-dependent step in the pathway by which mutant sarcomere proteins trigger myocyte growth and remodel the heart, provide definitive evidence that environment influences progression of FHC, and suggest a rational therapeutic approach to this prevalent human disease.

  • an abnormal ca2 response in mutant sarcomere protein mediated Familial Hypertrophic Cardiomyopathy
    Journal of Clinical Investigation, 2000
    Co-Authors: Diane Fatkin, Christine E. Seidman, Frederick J. Schoen, Christopher Semsarian, Bradley K Mcconnell, James O Mudd, Ivan G P Moskowitz, Michael Giewat
    Abstract:

    Dominant-negative sarcomere protein gene mutations cause Familial Hypertrophic Cardiomyopathy (FHC), a disease characterized by left-ventricular hypertrophy, angina, and dyspnea that can result in sudden death. We report here that a murine model of FHC bearing a cardiac myosin heavy-chain gene missense mutation (αMHC403/+), when treated with calcineurin inhibitors or a K+-channel agonist, developed accentuated hypertrophy, worsened histopathology, and was at risk for early death. Despite distinct pharmacologic targets, each agent augmented diastolic Ca2+ concentrations in wild-type cardiac myocytes; αMHC403/+ myocytes failed to respond. Pretreatment with a Ca2+-channel antagonist abrogated diastolic Ca2+ changes in wild-type myocytes and prevented the exaggerated Hypertrophic response of treated αMHC403/+ mice. We conclude that FHC-causing sarcomere protein gene mutations cause abnormal Ca2+ responses that initiate a Hypertrophic response. These data define an important Ca2+-dependent step in the pathway by which mutant sarcomere proteins trigger myocyte growth and remodel the heart, provide definitive evidence that environment influences progression of FHC, and suggest a rational therapeutic approach to this prevalent human disease.

  • Altered regulatory function of two Familial Hypertrophic Cardiomyopathy troponin T mutants.
    Biochemistry, 1999
    Co-Authors: Poushali Mukherjea, Christine E. Seidman, Jonathan G. Seidman, Lily Tong, Sarah E. Hitchcock-degregori
    Abstract:

    Mutations in the gene encoding human cardiac troponin T can cause Familial Hypertrophic Cardiomyopathy, a disease that is characterized by ventricular hypertrophy and sudden, premature death. Tropo...

  • Familial Hypertrophic Cardiomyopathy and atrial fibrillation caused by arg663his beta cardiac myosin heavy chain mutation
    American Journal of Cardiology, 1999
    Co-Authors: James E Gruver, Christine E. Seidman, J G Seidman, Barry J Maron, Diane Fatkin, Alfred G Dodds, Joseph Kisslo
    Abstract:

    Abstract More than 40 different β–cardiac myosin heavy chain (β-MHC) missense mutations have been identified that cause Familial Hypertrophic Cardiomyopathy (FHC). Some of these are recognized to have important clinical manifestations, such as an increased incidence of sudden death. We report that the β-MHC missense mutation Arg663His causes predominant cardiac morphology and atrial fibrillation. Longitudinal clinical evaluations were performed in a kindred with FHC. The nucleotide sequence of the β-MHC gene was analyzed to define the causal mutation. A missense mutation in the β-MHC gene, Arg663His, was identified in 24 individuals. Clinical studies demonstrated modest left ventricular hypertrophy in affected individuals, predominantly localized in the proximal segment of the interventricular septum, which increased (average = 40 ± 8%) during 7 years of follow-up. Results showed that 47% of Arg663His adults (age >16 years) with ventricular hypertrophy developed atrial fibrillation, significantly more (p

  • Altered Crossbridge Kinetics in the αMHC403/+ Mouse Model of Familial Hypertrophic Cardiomyopathy
    Circulation research, 1999
    Co-Authors: E. Blanchard, Jon G. Seidman, Christine E. Seidman, Martin M. Lewinter, David W. Maughan
    Abstract:

    Abstract—A mutation in the cardiac β-myosin heavy chain, Arg403Gln (R403Q), causes a severe form of Familial Hypertrophic Cardiomyopathy (FHC) in humans. We used small-amplitude (0.25%) length-perturbation analysis to examine the mechanical properties of skinned left ventricular papillary muscle strips from mouse hearts bearing the R403Q mutation in the α-myosin heavy chain (αMHC403/+). Myofibrillar disarray with variable penetrance occurred in the left ventricular free wall of the αMHC403/+ hearts. In resting strips (pCa 8), dynamic stiffness was ≈40% greater than in wild-type strips, consistent with elevated diastolic stiffness reported for murine hearts with FHC. At pCa 6 (submaximal activation), strip isometric tension was ≈3 times higher than for wild-type strips, whereas at pCa 5 (maximal activation), tension was marginally lower. At submaximal calcium activation the characteristic frequencies of the work-producing (b) and work-absorbing (c) steps of the crossbridge were less in αMHC403/+ strips tha...

Hugh Watkins - One of the best experts on this subject based on the ideXlab platform.

  • Investigation of a truncated cardiac troponin T that causes Familial Hypertrophic Cardiomyopathy: Ca(2+) regulatory properties of reconstituted thin filaments depend on the ratio of mutant to wild-type protein.
    Circulation research, 2000
    Co-Authors: Charles Redwood, Karin Lohmann, Wu Bing, Giovanna Esposito, Kathryn Elliott, Hassan Abdulrazzak, A Knott, Ian Purcell, Steven B. Marston, Hugh Watkins
    Abstract:

    Abstract—Familial Hypertrophic Cardiomyopathy (HCM) is caused by mutations in at least 8 contractile protein genes, most commonly β myosin heavy chain, myosin binding protein C, and cardiac troponi...

  • mutations in the gene for cardiac myosin binding protein c and late onset Familial Hypertrophic Cardiomyopathy
    The New England Journal of Medicine, 1998
    Co-Authors: Hideshi Niimura, William J Mckenna, Robert Roberts, Hugh Watkins, Linda L Bachinski, Somkiat Sangwatanaroj, Albert E Chudley, A Kristinsson, M Sole, Barry J Maron
    Abstract:

    Background Mutations in the gene for cardiac myosin-binding protein C account for approximately 15 percent of cases of Familial Hypertrophic Cardiomyopathy. The spectrum of disease-causing mutations and the associated clinical features of these gene defects are unknown. Methods DNA sequences encoding cardiac myosin-binding protein C were determined in unrelated patients with Familial Hypertrophic Cardiomyopathy. Mutations were found in 16 probands, who had 574 family members at risk of inheriting these defects. The genotypes of these family members were determined, and the clinical status of 212 family members with mutations in the gene for cardiac myosin-binding protein C was assessed. Results Twelve novel mutations were identified in probands from 16 families. Four were missense mutations; eight defects (insertions, deletions, and splice mutations) were predicted to truncate cardiac myosin-binding protein C. The clinical expression of either missense or truncation mutations was similar to that observed ...

  • Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White syndrome maps to a locus on chromosome 7q3.
    The Journal of clinical investigation, 1995
    Co-Authors: Calum A. Macrae, Susan Kass, Hugh Watkins, L Thierfelder, N Ghaisas, Stacey Donnelly, Craig T. Basson, R Anan, Kate Mcgarry, E Rowland
    Abstract:

    We have mapped a disease locus for Wolff-Parkinson-White syndrome (WPW) and Familial Hypertrophic Cardiomyopathy (FHC) segregating in a large kindred to chromosome 7 band q3. Although WPW syndrome and FHC have been observed in members of the same family in prior studies, the relationship between these two diseases has remained enigmatic. A large family with 25 surviving individuals who are affected by one or both of these conditions was studied. The disease locus is closely linked to loci D7S688, D7S505, and D7S483 (maximum two point LOD score at D7S505 was 7.80 at theta = 0). While four different FHC loci have been described this is the first locus that can be mutated to cause both WPW and/or FHC.

  • Molecular Genetics: New Mutations that Cause Familial Hypertrophic Cardiomyopathy
    Developments in Cardiovascular Medicine, 1995
    Co-Authors: Calum A. Macrae, Jon G. Seidman, Hugh Watkins, Ludwig H. Theirfelder, Ryuchiro Anan, Christine E. Seidman
    Abstract:

    Since the description of the first genetic locus for Familial Hypertrophic Cardiomyopathy (FHC; Cardiomyopathy, Hypertrophic, or CMH1) on chromosome 14, our molecular understanding of the syndrome has extended greatly [1] Mutations in the cardiac β myosin heavy chain (PMHC) gene have been shown to cause FHC at this locus [2,3]. The α cardiac myosin heavy chain gene does not appear to cause any FHC [4]. Over 30 discrete βMHC gene missense mutations have now been documented, and individual mutations have been shown to be associated with disparate risks of sudden cardiac death [5]. The precise mechanisms by which myosin mutations cause FHC is not yet known, but abnormalities of myofibrillar assembly in vitro have been demonstrated [6]. Homologous recombination is being used to generate mouse models for β myosin missense mutations that will help to answer these questions definitively.

  • alpha tropomyosin and cardiac troponin t mutations cause Familial Hypertrophic Cardiomyopathy a disease of the sarcomere
    Cell, 1994
    Co-Authors: Hans-peter Vosberg, William J Mckenna, Hugh Watkins, L Thierfelder, Calum A. Macrae, Roger Lamas, J G Seldman
    Abstract:

    We demonstrate that missense mutations (Asp175Asn; Glu180Gly) in the alpha-tropomyosin gene cause Familial Hypertrophic Cardiomyopathy (FHC) linked to chromosome 15q2. These findings implicated components of the troponin complex as candidate genes at other FHC loci, particularly cardiac troponin T, which was mapped in this study to chromosome 1q. Missense mutations (Ile79Asn; Arg92Gln) and a mutation in the splice donor sequence of intron 15 of the cardiac troponin T gene are also shown to cause FHC. Because alpha-tropomyosin and cardiac troponin T as well as beta myosin heavy chain mutations cause the same phenotype, we conclude that FHC is a disease of the sarcomere. Further, because the splice site mutation is predicted to function as a null allele, we suggest that abnormal stoichiometry of sarcomeric proteins can cause cardiac hypertrophy.

Christopher Semsarian - One of the best experts on this subject based on the ideXlab platform.

  • Peripheral blood derived induced pluripotent stem cells (iPSCs) from a female with Familial Hypertrophic Cardiomyopathy.
    Stem cell research, 2017
    Co-Authors: Samantha Barratt Ross, Stuart T. Fraser, Richard D. Bagnall, Christopher Semsarian
    Abstract:

    Induced pluripotent stem cells (iPSCs) were generated from peripheral blood mononuclear cells (PBMCs) obtained from a 62-year-old female with Familial Hypertrophic Cardiomyopathy (HCM). PBMCs were reprogrammed to a pluripotent state following transfection with non-integrative episomal vectors carrying reprogramming factors OCT4, SOX2, LIN28, KLF4 and L-MYC. iPSCs were shown to express pluripotency markers, possess trilineage differentiation potential, carry rare variants identified in DNA isolated directly from the patient's whole blood, have a normal karyotype and no longer carry episomal vectors for reprogramming. This line is a useful resource for identifying unknown genetic causes of HCM.

  • DNA testing in Familial Hypertrophic Cardiomyopathy: clinical and laboratory implications
    Clinical genetics, 2008
    Co-Authors: R.v. Smart, Christopher Semsarian, J A French, Richmond W. Jeremy, David R. Richmond, L. Cheung, D. A. Ross, R. J. Trent
    Abstract:

    Counselling and clinical assessment in Familial Hypertrophic Cardiomyopathy (FHC) is difficult, particularly in the young, since echocardiographic and ECG changes may not be diagnostic and clinical severity can vary. From 1990, when the beta-cardiac myosin heavy chain gene was implicated in the aetiology of FHC, considerable information about the molecular genetics of this disorder has emerged. However, an important question facing health professionals is the practical significance of DNA testing in FHC. The present study describes a DNA-based approach to screening for five commonly reported mutations involving the beta-cardiac myosin heavy chain gene. Approximately 11% of randomly selected families had an abnormality detected.

  • Genetic screening of calcium regulation genes in Familial Hypertrophic Cardiomyopathy.
    Journal of molecular and cellular cardiology, 2007
    Co-Authors: Christine L Chiu, Molly Tebo, Jodie Ingles, Laura Yeates, Jonathan W. Arthur, Joanne M. Lind, Christopher Semsarian
    Abstract:

    Abstract Genes encoding Ca2+ regulatory proteins responsible for Ca2+ homeostasis have been suggested as possible candidates for FHC. Mutations in sarcomere genes account for approximately 50% of all FHC cases indicating other genes, including those involved in Ca2+ handling, may account for the remainder. The aim of this study was to identify causative mutations in genes involved in Ca2+ regulation in patients with Familial Hypertrophic Cardiomyopathy (FHC). An Australian cohort of 252 unrelated Familial Hypertrophic Cardiomyopathy patients were screened for mutations in the Ca2+ regulatory genes, sorcin (SRI), calstabin (FKBP1B), calsequestrin (CASQ2), phospholamban (PLN), sarcolipin (SLN), calreticulin (CALR3) and calmodulin (CALM). A total of 17 exonic DNA variants were identified in the 7 Ca2+ regulatory genes studied, of which 4 were considered of pathogenic significance. Two novel mutations in the CALR3 gene were identified (Lys82Arg, Arg73Gln) and one truncation mutation in the PLN gene (Leu39Ter). A variant was also identified in the CASQ2 gene (Asp63Glu). These four variants were all novel, resulted in changes in conserved amino acids and were not identified in a normal population. In conclusion, mutations in Ca2+ handling genes are an infrequent but important cause of FHC. DNA variants in Ca2+ genes may also be involved as modifying factors in phenotype development. Further evaluation of the role of defects in Ca2+ regulation will shed light on the molecular pathogenesis of FHC.

  • Abnormal cardiac response to exercise in a murine model of Familial Hypertrophic Cardiomyopathy
    International journal of cardiology, 2006
    Co-Authors: Lan Nguyen, Jessica Chung, Lien Lam, Tatiana Tsoutsman, Christopher Semsarian
    Abstract:

    Clinical outcome in Familial Hypertrophic Cardiomyopathy (FHC) may be influenced by modifying factors such as exercise. Transgenic mice which overexpress the human disease-causing cTnI gene mutation, Gly203Ser (designated cTnI-G203S), develop all the characteristic phenotypic features of FHC. To study the modifying effect of exercise in early disease, mice underwent swimming exercise at an early age prior to the development of the FHC phenotype. In non-transgenic and cTnI-wt mice, swimming resulted in a significant increase in left ventricular wall thickness and contractility on echocardiography, consistent with a physiological Hypertrophic response to exercise. In contrast, cTnI-G203S mice showed no increase in these parameters, indicating an abnormal response to exercise. The lack of a physiological response to exercise may indicate an important novel mechanistic insight into the role of exercise in triggering adverse events in FHC.

  • an abnormal ca2 response in mutant sarcomere protein mediated Familial Hypertrophic Cardiomyopathy
    Journal of Clinical Investigation, 2000
    Co-Authors: Diane Fatkin, Christine E. Seidman, Frederick J. Schoen, Christopher Semsarian, Bradley K Mcconnell, James O Mudd, Ivan G P Moskowitz, Michael Giewat
    Abstract:

    Dominant-negative sarcomere protein gene mutations cause Familial Hypertrophic Cardiomyopathy (FHC), a disease characterized by left-ventricular hypertrophy, angina, and dyspnea that can result in sudden death. We report here that a murine model of FHC bearing a cardiac myosin heavy-chain gene missense mutation (αMHC403/+), when treated with calcineurin inhibitors or a K+-channel agonist, developed accentuated hypertrophy, worsened histopathology, and was at risk for early death. Despite distinct pharmacologic targets, each agent augmented diastolic Ca2+ concentrations in wild-type cardiac myocytes; αMHC403/+ myocytes failed to respond. Pretreatment with a Ca2+-channel antagonist abrogated diastolic Ca2+ changes in wild-type myocytes and prevented the exaggerated Hypertrophic response of treated αMHC403/+ mice. We conclude that FHC-causing sarcomere protein gene mutations cause abnormal Ca2+ responses that initiate a Hypertrophic response. These data define an important Ca2+-dependent step in the pathway by which mutant sarcomere proteins trigger myocyte growth and remodel the heart, provide definitive evidence that environment influences progression of FHC, and suggest a rational therapeutic approach to this prevalent human disease.

Jonathan G. Seidman - One of the best experts on this subject based on the ideXlab platform.

  • Altered regulatory function of two Familial Hypertrophic Cardiomyopathy troponin T mutants.
    Biochemistry, 1999
    Co-Authors: Poushali Mukherjea, Christine E. Seidman, Jonathan G. Seidman, Lily Tong, Sarah E. Hitchcock-degregori
    Abstract:

    Mutations in the gene encoding human cardiac troponin T can cause Familial Hypertrophic Cardiomyopathy, a disease that is characterized by ventricular hypertrophy and sudden, premature death. Tropo...

  • Altered cardiac excitation-contraction coupling in mutant mice with Familial Hypertrophic Cardiomyopathy.
    The Journal of clinical investigation, 1999
    Co-Authors: Wei Dong Gao, Christine E. Seidman, Jonathan G. Seidman, Néstor G. Pérez, Eduardo Marbán
    Abstract:

    Excitation‐contraction coupling in cardiac muscle of Familial Hypertrophic Cardiomyopathy (FHC) remains poorly understood, despite the fact that the genetic alterations are well defined. We characterized calcium cycling and contractile activation in trabeculae from a mutant mouse model of FHC (Arg403Gln knockin, α-myosin heavy chain). Wild-type mice of the same strain and age (~20 weeks old) served as controls. During twitch contractions, peak intracellular Ca 2+ ([Ca 2+ ]i) was higher in mutant muscles than in the wild-type (P 0.003), with no changes in the [Ca 2+ ]i required for 50% activation or maximal Ca 2+ -activated force. Thus, calcium cycling and myofilament properties are both altered in FHC mutant mice: more Ca 2+ is mobilized to generate force, but this does not suffice to maintain contractility at high stimulation rates.

  • Electrophysiological abnormalities and arrhythmias in alpha MHC mutant Familial Hypertrophic Cardiomyopathy mice.
    The Journal of clinical investigation, 1997
    Co-Authors: Charles I. Berul, Christine E. Seidman, Jonathan G. Seidman, Michael Christe, Mark Aronovitz, Michael E. Mendelsohn
    Abstract:

    A new mouse cardiac electrophysiology method was used to study mice harboring an alpha-myosin heavy chain Arg403Gln missense mutation (alpha-MHC403/+), which results in histological and hemodynamic abnormalities characteristic of Familial Hypertrophic Cardiomyopathy (FHC) and sudden death of uncertain etiology during exercise. Wild-type animals had completely normal cardiac electrophysiology. In contrast, FHC mice demonstrated (a) electrocardiographic abnormalities including prolonged repolarization intervals and rightward axis; (b) electrophysiological abnormalities including heterogeneous ventricular conduction properties and prolonged sinus node recovery time; and (c) inducible ventricular ectopy. These data identify distinct electrophysiologic abnormalities in FHC mice with a specific alpha-myosin mutation, and also validate a novel method to explore in vivo the relationship between specific genotypes and their electrophysiologic phenotypes.

  • A Mouse Model of Familial Hypertrophic Cardiomyopathy
    Science (New York N.Y.), 1996
    Co-Authors: Anja Geisterfer-lowrance, Christine E. Seidman, Michael Christe, David A. Conner, Joanne S. Ingwall, Frederick J. Schoen, Jonathan G. Seidman
    Abstract:

    A mouse model of Familial Hypertrophic Cardiomyopathy (FHC) was generated by the introduction of an Arg 403 → Gln mutation into the α cardiac myosin heavy chain (MHC) gene. Homozygous αMHC 403/403 mice died 7 days after birth, and sedentary heterozygous αMHC 403/+ mice survived for 1 year. Cardiac histopathology and dysfunction in the αMHC 403/+ mice resembled human FHC. Cardiac dysfunction preceded histopathologic changes, and myocyte disarray, hypertrophy, and fibrosis increased with age. Young male αMHC 403/+ mice showed more evidence of disease than did their female counterparts. Preliminary results suggested that exercise capacity may have been compromised in the αMHC 403/+ mice. This mouse model may help to define the natural history of FHC.

  • Functional analysis of myosin missense mutations in Familial Hypertrophic Cardiomyopathy.
    Proceedings of the National Academy of Sciences of the United States of America, 1994
    Co-Authors: Anthony J. Straceski, Christine E. Seidman, Jonathan G. Seidman, Anja Geisterfer-lowrance, Leslie A. Leinwand
    Abstract:

    Abstract To analyze potential functional consequences of myosin heavy chain (MHC) mutations identified in patients with Familial Hypertrophic Cardiomyopathy (FHC), we have assessed the stability of the mutant MHCs and their ability to form thick filaments. Constructs encoding wild-type rat alpha MHC and seven corresponding FHC missense mutants were transfected into COS cells. Immunoblot analysis suggested that FHC mutations do not grossly alter protein stability. Wild-type alpha MHC transfected into COS cells forms structures previously shown to be arrays of thick filaments, which also resemble myosin structures observed early in differentiation of muscle cells. Surprisingly, up to 29% of COS cells transfected with the FHC mutants failed to form filamentous structures. To assess whether this phenotype was specific for the FHC mutants and not generalizable to any myosin mutation, COS cells were transfected with a construct encoding an MHC with a 168-amino acid deletion of the hinge/rod region. This deletion construct formed filamentous structures with the same frequency as wild-type MHC. Biochemical analysis of one FHC mutant (Arg-249-->Gln) demonstrates that the structures formed by the mutant are solubilized at a lower ionic strength than those formed by wild-type MHC. We conclude that although the FHC mutant MHC is not labile, its assembly properties may be impaired.

William J Mckenna - One of the best experts on this subject based on the ideXlab platform.

  • mutations in the gene for cardiac myosin binding protein c and late onset Familial Hypertrophic Cardiomyopathy
    The New England Journal of Medicine, 1998
    Co-Authors: Hideshi Niimura, William J Mckenna, Robert Roberts, Hugh Watkins, Linda L Bachinski, Somkiat Sangwatanaroj, Albert E Chudley, A Kristinsson, M Sole, Barry J Maron
    Abstract:

    Background Mutations in the gene for cardiac myosin-binding protein C account for approximately 15 percent of cases of Familial Hypertrophic Cardiomyopathy. The spectrum of disease-causing mutations and the associated clinical features of these gene defects are unknown. Methods DNA sequences encoding cardiac myosin-binding protein C were determined in unrelated patients with Familial Hypertrophic Cardiomyopathy. Mutations were found in 16 probands, who had 574 family members at risk of inheriting these defects. The genotypes of these family members were determined, and the clinical status of 212 family members with mutations in the gene for cardiac myosin-binding protein C was assessed. Results Twelve novel mutations were identified in probands from 16 families. Four were missense mutations; eight defects (insertions, deletions, and splice mutations) were predicted to truncate cardiac myosin-binding protein C. The clinical expression of either missense or truncation mutations was similar to that observed ...

  • Abnormal skeletal muscle bioenergetics in Familial Hypertrophic Cardiomyopathy.
    Heart (British Cardiac Society), 1997
    Co-Authors: Campbell H. Thompson, William J Mckenna, Graham J. Kemp, D. J. Taylor, Michael A. Conway, Bheeshma Rajagopalan, A. O'donoghue, Peter Styles, G. K. Radda
    Abstract:

    OBJECTIVE: To determine the skeletal muscle metabolic manifestations of Familial Hypertrophic Cardiomyopathy. DESIGN: A case-control study. SETTING: 31P magnetic resonance spectroscopy of the calf muscle was performed on volunteers from a centre specialising in Familial Hypertrophic Cardiomyopathy. PATIENTS: Five patients with abnormal beta myosin heavy chain protein in cardiac and skeletal muscle and five patients with a troponin T abnormality in cardiac muscle were compared with healthy controls. RESULTS: High energy phosphate metabolism in vivo was examined in a non-invasive manner. In resting muscle, the beta myosin heavy chain group had a higher ratio of phosphocreatine to ATP concentration (4.51 (SD 0.17)) than either the troponin T group (3.88 (0.42)) or controls (n = 16; 4.04 (0.40)). Exercise duration was reduced compared to controls, and during the fourth minute of exercise phosphocreatine depletion and muscle acidification were greater in both patient groups. After exercise, the recovery of phosphocreatine-an index of oxidative metabolic capacity of the muscle-was slower in the beta myosin heavy chain group (mean half time 0.65 (0.08) minutes) than in the troponin T group (0.60 (0.17) minutes) or controls (0.48 (0.14) minutes). CONCLUSIONS: Exercise metabolism was abnormal in both groups of subjects, and the affected contractile protein determined the metabolic changes in muscle at rest and during recovery. In patients with abnormal beta myosin heavy chain protein, there was a decrease in oxidative capacity consistent with the reduction in mitochondria reported in muscle biopsy studies of similar patients.

  • alpha tropomyosin and cardiac troponin t mutations cause Familial Hypertrophic Cardiomyopathy a disease of the sarcomere
    Cell, 1994
    Co-Authors: Hans-peter Vosberg, William J Mckenna, Hugh Watkins, L Thierfelder, Calum A. Macrae, Roger Lamas, J G Seldman
    Abstract:

    We demonstrate that missense mutations (Asp175Asn; Glu180Gly) in the alpha-tropomyosin gene cause Familial Hypertrophic Cardiomyopathy (FHC) linked to chromosome 15q2. These findings implicated components of the troponin complex as candidate genes at other FHC loci, particularly cardiac troponin T, which was mapped in this study to chromosome 1q. Missense mutations (Ile79Asn; Arg92Gln) and a mutation in the splice donor sequence of intron 15 of the cardiac troponin T gene are also shown to cause FHC. Because alpha-tropomyosin and cardiac troponin T as well as beta myosin heavy chain mutations cause the same phenotype, we conclude that FHC is a disease of the sarcomere. Further, because the splice site mutation is predicted to function as a null allele, we suggest that abnormal stoichiometry of sarcomeric proteins can cause cardiac hypertrophy.

  • A Familial Hypertrophic Cardiomyopathy locus maps to chromosome 15q2.
    Proceedings of the National Academy of Sciences of the United States of America, 1993
    Co-Authors: L Thierfelder, William J Mckenna, Hugh Watkins, Calum A. Macrae, J. Tomfohrde, Marshall V. Williams, K. Bohm, G. Noeske, M. Schlepper, Anne M. Bowcock
    Abstract:

    We report that a gene responsible for Familial Hypertrophic Cardiomyopathy (FHC) in a kindred with a mild degree of cardiac hypertrophy maps to chromosome 15q2. The gene encoding cardiac actin, located on chromosome 15q, was analyzed and excluded as a candidate for FHC at this locus. Two additional families with typical FHC were studied and the disorder in one also maps to the chromosome 15q2 locus. The maximum combined multipoint logarithm of odds score in the two linked families is 6.02. Although these two kindreds reside in the same country, we believe that their disorder is caused by independent mutations in the 15q2 locus because of the clinical and genotypic differences between affected individuals. Mutations in at least four loci can cause FHC: chromosomes 14q1 (beta cardiac myosin heavy chain gene), 1q3, and 15q2 and another unidentified locus, suggesting substantial genetic heterogeneity.

  • The Molecular Genetics of Familial Hypertrophic Cardiomyopathy
    Cardiomyopathies, 1993
    Co-Authors: Hugh Watkins, C. E. Seidman, William J Mckenna
    Abstract:

    Ever since its initial description, Hypertrophic Cardiomyopathy has been identified as a condition which is frequently inherited in a Familial fashion. Teare’s original account in 1958 [1] describes nine cases of sudden death which include a brother and sister from the same family. The subsequent report [2] of the three generation pedigree of the family of these two siblings showed hypertophic Cardiomyopathy segregating in a manner consistent with an autosomal dominant trait. Demonstration of a Mendelian form of inheritance implied that Familial Hypertrophic Cardiomyopathy (FHC) was the result of a single gene disorder. This conclusion was supported by a number of clinical reports, from the early 1960s onwards, of single pedigrees showing autosomal dominant transmission of FHC [3–7].