The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Christopher Semsarian - One of the best experts on this subject based on the ideXlab platform.
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clinical utility of a phenotype enhanced MYH7 specific variant classification framework in hypertrophic cardiomyopathy genetic testing
Circulation: Genomic and Precision Medicine, 2020Co-Authors: Connor L Mattivi, Christopher Semsarian, Steve R Ommen, Martijn J Bos, Richard D Bagnall, N Nowak, John R Giudicessi, Michael J. AckermanAbstract:Background - Missense variants in the MYH7-encoded beta myosin heavy chain 7 represent a leading cause of hypertrophic cardiomyopathy (HCM). MYH7-specific American College of Medical Genetics and G...
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generation of induced pluripotent stem cells ipscs from a hypertrophic cardiomyopathy patient with the pathogenic variant p val698ala in beta myosin heavy chain MYH7 gene
Stem Cell Research, 2017Co-Authors: Christopher Semsarian, N Nowak, Samantha Barratt Ross, Stuart T FraserAbstract:Induced pluripotent stem cells (iPSCs) were generated from peripheral blood mononuclear cells (PBMCs) isolated from the whole blood of a 43-year-old male with hypertrophic cardiomyopathy (HCM) who carries the pathogenic variant p.Val698Ala in beta-myosin heavy chain (MYH7). Patient-derived PBMCs were reprogrammed using non-integrative episomal vectors containing reprogramming factors OCT4, SOX2, LIN28, KLF4 and L-MYC. iPSCs were shown to express pluripotent markers, have trilineage differentiation potential, carry the pathogenic MYH7 variant p.Val698Ala, have a normal karyotype and no longer carry the episomal reprogramming vector. This line is useful for studying the link between variants in MYH7 and the pathogenesis of HCM.
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clinical features and outcome of hypertrophic cardiomyopathy associated with triple sarcomere protein gene mutations
Journal of the American College of Cardiology, 2010Co-Authors: Francesca Girolami, Christopher Semsarian, Michael J. Ackerman, Massimo Baldi, Melissa L Will, Katia Baldini, Francesca Torricelli, Laura Yeates, Franco Cecchi, Iacopo OlivottoAbstract:Objectives The aim of this study was to describe the clinical profile associated with triple sarcomere gene mutations in a large hypertrophic cardiomyopathy (HCM) cohort. Background In patients with HCM, double or compound sarcomere gene mutation heterozygosity might be associated with earlier disease onset and more severe outcome. The occurrence of triple mutations has not been reported. Methods A total of 488 unrelated index HCM patients underwent screening for myofilament gene mutations by direct deoxyribonucleic acid sequencing of 8 genes, including myosin binding protein C (MYBPC3), beta-myosin heavy chain (MYH7), regulatory and essential light chains (MYL2, MYL3), troponin-T (TNNT2), troponin-I (TNNI3), alpha-tropomyosin (TPM1), and actin (ACTC). Results Of the 488 index patients, 4 (0.8%) harbored triple mutations, as follows: MYH7-R869H, MYBPC3-E258K, and TNNI3-A86fs in a 32-year-old woman; MYH7-R723C, MYH7-E1455X, and MYBPC3-E165D in a 46-year old man; MYH7-R869H, MYBPC3-K1065fs, and MYBPC3-P371R in a 45-year old woman; and MYH7-R1079Q, MYBPC3-Q969X, and MYBPC3-R668H in a 50-year old woman. One had a history of resuscitated cardiac arrest, and 3 had significant risk factors for sudden cardiac death, prompting the insertion of an implantable cardioverter-defibrillator in all, with appropriate shocks in 2 patients. Moreover, 3 of 4 patients had a severe phenotype with progression to end-stage HCM by the fourth decade, requiring cardiac transplantation (n = 1) or biventricular pacing (n = 2). The fourth patient, however, had clinically mild disease. Conclusions Hypertrophic cardiomyopathy caused by triple sarcomere gene mutations was rare but conferred a remarkably increased risk of end-stage progression and ventricular arrhythmias, supporting an association between multiple sarcomere defects and adverse outcome. Comprehensive genetic testing might provide important insights to risk stratification and potentially indicate the need for differential surveillance strategies based on genotype.
F. C. Howarth - One of the best experts on this subject based on the ideXlab platform.
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P400Effects of a sucrose-enriched diet on the pattern of gene expression, contraction and Ca2+ transport in Goto-Kakizaki type 2 diabetic rat heart
Cardiovascular Research, 2014Co-Authors: F. C. Howarth, K. Parekh, M. A. Qureshi, E El Nebrisi, Petrilla Jayaprakash, Thomas E. AdrianAbstract:There has been a spectacular rise in the global prevalence of type 2 diabetes mellitus and cardiovascular disease is the major cause of morbidity and mortality in diabetic patients. A variety of diastolic and systolic dysfunctions have been demonstrated in type 2 diabetic heart. The consumption of sugar-sweetened beverages has been linked to rising rates of obesity which in turn is a risk factor for development of type 2 diabetes mellitus. The effects of a sucrose-enriched diet on the pattern of gene expression, contraction and calcium transport in the Goto-Kakizaki (GK) type 2 diabetic rat heart have been investigated. Genes encoding cardiac muscle proteins (MYH7, Mybpc3, Myl1, Myl3, Mylpf), intercellular proteins (Gja4), cell membrane transport (Atp1b1), calcium channels (Cacna1c, Cacna1g, Cacnb1), potassium channels (Kcnj11) were upregulated and genes encoding potassium channels (Kcnb1) were downregulated in GK compared to Control rats. Genes encoding cardiac muscle proteins (Myh6, Mybpc3, Tnn2), intercellular proteins (Gja1, Gja4), intracellular calcium transport (Atp2a1, Ryr2), cell membrane transport (Atp1a2, Atp1b1), potassium channel (Kcnj2, Kcnj8) proteins were upregulated and genes encoding cardiac muscle proteins (MYH7) were downregulated in Control/Sucrose compared to Control rats. Genes encoding cardiac muscle proteins (MYH7), potassium channel (Kcnj11) proteins were downregulated in GK/Sucrose compared to Control rats. Amplitude of shortening was reduced in myocytes from Control/Sucrose compared to Control and in GK/Sucrose compared to GK rats. Amplitude of the calcium transient was increased in myocytes from Control/Sucrose compared to Control and decreased in GK/Sucrose compared to GK rats. Subtle alterations in the pattern of expression of genes encoding a variety of cardiac muscle proteins are associated with changes in shortening and intracellular calcium transport in ventricular myocytes from GK type 2 diabetic and Control rats fed a sucrose-enriched diet.
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effects of a sucrose enriched diet on the pattern of gene expression contraction and ca2 transport in goto kakizaki type 2 diabetic rat heart
Experimental Physiology, 2014Co-Authors: E M Gaber, K. Parekh, M. A. Qureshi, Petrilla Jayaprakash, Thomas E. Adrian, F. C. HowarthAbstract:New Findings What is the central question of this study? Poor diet is a risk factor for development of type 2 diabetes mellitus and its associated complications. In this study, the effects of sucrose-enriched diet on the pattern of gene expression, contraction and Ca2+ transport in type 2 diabetic heart are explored. What is the main finding and its importance? The altered pattern of gene expression in type 2 diabetic hearts was further altered in diabetic and control rats that received a sucrose-enriched diet, and these alterations were associated with changes in ventricular myocyte shortening and Ca2+ transport. There has been a spectacular rise in the global prevalence of type 2 diabetes mellitus (T2DM), and cardiovascular disease is the major cause of morbidity and mortality in diabetic patients. A variety of diastolic and systolic dysfunctions have been demonstrated in type 2 diabetic heart. The consumption of sugar-sweetened beverages has been linked to rising rates of obesity, which in turn is a risk factor for development of T2DM. In this study, the effects of a sucrose-enriched diet on the pattern of gene expression, contraction and Ca2+ transport in the Goto–Kakizaki T2DM rat heart were investigated. Genes encoding cardiac muscle proteins (MYH7, Mybpc3, Myl1, Myl3 and Mylpf), intercellular proteins (Gja4), cell membrane transport (Atp1b1), calcium channels (Cacna1c, Cacna1g and Cacnb1) and potassium channels (Kcnj11) were upregulated and genes encoding potassium channels (Kcnb1) were downregulated in GK compared with control rats. Genes encoding cardiac muscle proteins (Myh6, Mybpc3 and Tnn2), intercellular proteins (Gja1 and Gja4), intracellular Ca2+ transport (Atp2a1 and Ryr2), cell membrane transport (Atp1a2 and Atp1b1) and potassium channel proteins (Kcnj2 and Kcnj8) were upregulated and genes encoding cardiac muscle proteins (MYH7) were downregulated in control rats fed sucrose compared with control rats. Genes encoding cardiac muscle proteins (MYH7) and potassium channel proteins (Kcnj11) were downregulated in control and GK rats fed sucrose compared with control and GK rats, respectively. The amplitude of shortening was reduced in myocytes from the control–sucrose group compared with control rats and in the GK–sucrose group compared with GK rats. The amplitude of the Ca2+ transient was increased in myocytes from control–sucrose compared with control rats and decreased in GK–sucrose compared with GK rats. Subtle alterations in the pattern of expression of genes encoding a variety of cardiac muscle proteins are associated with changes in shortening and intracellular Ca2+ transport in ventricular myocytes from GK T2DM and control rats fed a sucrose-enriched diet.
Thomas E. Adrian - One of the best experts on this subject based on the ideXlab platform.
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P400Effects of a sucrose-enriched diet on the pattern of gene expression, contraction and Ca2+ transport in Goto-Kakizaki type 2 diabetic rat heart
Cardiovascular Research, 2014Co-Authors: F. C. Howarth, K. Parekh, M. A. Qureshi, E El Nebrisi, Petrilla Jayaprakash, Thomas E. AdrianAbstract:There has been a spectacular rise in the global prevalence of type 2 diabetes mellitus and cardiovascular disease is the major cause of morbidity and mortality in diabetic patients. A variety of diastolic and systolic dysfunctions have been demonstrated in type 2 diabetic heart. The consumption of sugar-sweetened beverages has been linked to rising rates of obesity which in turn is a risk factor for development of type 2 diabetes mellitus. The effects of a sucrose-enriched diet on the pattern of gene expression, contraction and calcium transport in the Goto-Kakizaki (GK) type 2 diabetic rat heart have been investigated. Genes encoding cardiac muscle proteins (MYH7, Mybpc3, Myl1, Myl3, Mylpf), intercellular proteins (Gja4), cell membrane transport (Atp1b1), calcium channels (Cacna1c, Cacna1g, Cacnb1), potassium channels (Kcnj11) were upregulated and genes encoding potassium channels (Kcnb1) were downregulated in GK compared to Control rats. Genes encoding cardiac muscle proteins (Myh6, Mybpc3, Tnn2), intercellular proteins (Gja1, Gja4), intracellular calcium transport (Atp2a1, Ryr2), cell membrane transport (Atp1a2, Atp1b1), potassium channel (Kcnj2, Kcnj8) proteins were upregulated and genes encoding cardiac muscle proteins (MYH7) were downregulated in Control/Sucrose compared to Control rats. Genes encoding cardiac muscle proteins (MYH7), potassium channel (Kcnj11) proteins were downregulated in GK/Sucrose compared to Control rats. Amplitude of shortening was reduced in myocytes from Control/Sucrose compared to Control and in GK/Sucrose compared to GK rats. Amplitude of the calcium transient was increased in myocytes from Control/Sucrose compared to Control and decreased in GK/Sucrose compared to GK rats. Subtle alterations in the pattern of expression of genes encoding a variety of cardiac muscle proteins are associated with changes in shortening and intracellular calcium transport in ventricular myocytes from GK type 2 diabetic and Control rats fed a sucrose-enriched diet.
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effects of a sucrose enriched diet on the pattern of gene expression contraction and ca2 transport in goto kakizaki type 2 diabetic rat heart
Experimental Physiology, 2014Co-Authors: E M Gaber, K. Parekh, M. A. Qureshi, Petrilla Jayaprakash, Thomas E. Adrian, F. C. HowarthAbstract:New Findings What is the central question of this study? Poor diet is a risk factor for development of type 2 diabetes mellitus and its associated complications. In this study, the effects of sucrose-enriched diet on the pattern of gene expression, contraction and Ca2+ transport in type 2 diabetic heart are explored. What is the main finding and its importance? The altered pattern of gene expression in type 2 diabetic hearts was further altered in diabetic and control rats that received a sucrose-enriched diet, and these alterations were associated with changes in ventricular myocyte shortening and Ca2+ transport. There has been a spectacular rise in the global prevalence of type 2 diabetes mellitus (T2DM), and cardiovascular disease is the major cause of morbidity and mortality in diabetic patients. A variety of diastolic and systolic dysfunctions have been demonstrated in type 2 diabetic heart. The consumption of sugar-sweetened beverages has been linked to rising rates of obesity, which in turn is a risk factor for development of T2DM. In this study, the effects of a sucrose-enriched diet on the pattern of gene expression, contraction and Ca2+ transport in the Goto–Kakizaki T2DM rat heart were investigated. Genes encoding cardiac muscle proteins (MYH7, Mybpc3, Myl1, Myl3 and Mylpf), intercellular proteins (Gja4), cell membrane transport (Atp1b1), calcium channels (Cacna1c, Cacna1g and Cacnb1) and potassium channels (Kcnj11) were upregulated and genes encoding potassium channels (Kcnb1) were downregulated in GK compared with control rats. Genes encoding cardiac muscle proteins (Myh6, Mybpc3 and Tnn2), intercellular proteins (Gja1 and Gja4), intracellular Ca2+ transport (Atp2a1 and Ryr2), cell membrane transport (Atp1a2 and Atp1b1) and potassium channel proteins (Kcnj2 and Kcnj8) were upregulated and genes encoding cardiac muscle proteins (MYH7) were downregulated in control rats fed sucrose compared with control rats. Genes encoding cardiac muscle proteins (MYH7) and potassium channel proteins (Kcnj11) were downregulated in control and GK rats fed sucrose compared with control and GK rats, respectively. The amplitude of shortening was reduced in myocytes from the control–sucrose group compared with control rats and in the GK–sucrose group compared with GK rats. The amplitude of the Ca2+ transient was increased in myocytes from control–sucrose compared with control rats and decreased in GK–sucrose compared with GK rats. Subtle alterations in the pattern of expression of genes encoding a variety of cardiac muscle proteins are associated with changes in shortening and intracellular Ca2+ transport in ventricular myocytes from GK T2DM and control rats fed a sucrose-enriched diet.
Michael J. Ackerman - One of the best experts on this subject based on the ideXlab platform.
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clinical utility of a phenotype enhanced MYH7 specific variant classification framework in hypertrophic cardiomyopathy genetic testing
Circulation: Genomic and Precision Medicine, 2020Co-Authors: Connor L Mattivi, Christopher Semsarian, Steve R Ommen, Martijn J Bos, Richard D Bagnall, N Nowak, John R Giudicessi, Michael J. AckermanAbstract:Background - Missense variants in the MYH7-encoded beta myosin heavy chain 7 represent a leading cause of hypertrophic cardiomyopathy (HCM). MYH7-specific American College of Medical Genetics and G...
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clinical utility of a phenotype enhanced MYH7 specific variant classification framework in hypertrophic cardiomyopathy genetic testing
Journal of the American College of Cardiology, 2019Co-Authors: Connor L Mattivi, John R Giudicessi, Martijn Bos, Michael J. AckermanAbstract:Missense variants in the MYH7 -encoded beta myosin heavy chain 7 represent a leading cause of hypertrophic cardiomyopathy (HCM). MYH7 -specific American College of Medical Genetics and Genomics (ACMG) variant classification guidelines were released recently, but have yet to be assessed independently
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clinical features and outcome of hypertrophic cardiomyopathy associated with triple sarcomere protein gene mutations
Journal of the American College of Cardiology, 2010Co-Authors: Francesca Girolami, Christopher Semsarian, Michael J. Ackerman, Massimo Baldi, Melissa L Will, Katia Baldini, Francesca Torricelli, Laura Yeates, Franco Cecchi, Iacopo OlivottoAbstract:Objectives The aim of this study was to describe the clinical profile associated with triple sarcomere gene mutations in a large hypertrophic cardiomyopathy (HCM) cohort. Background In patients with HCM, double or compound sarcomere gene mutation heterozygosity might be associated with earlier disease onset and more severe outcome. The occurrence of triple mutations has not been reported. Methods A total of 488 unrelated index HCM patients underwent screening for myofilament gene mutations by direct deoxyribonucleic acid sequencing of 8 genes, including myosin binding protein C (MYBPC3), beta-myosin heavy chain (MYH7), regulatory and essential light chains (MYL2, MYL3), troponin-T (TNNT2), troponin-I (TNNI3), alpha-tropomyosin (TPM1), and actin (ACTC). Results Of the 488 index patients, 4 (0.8%) harbored triple mutations, as follows: MYH7-R869H, MYBPC3-E258K, and TNNI3-A86fs in a 32-year-old woman; MYH7-R723C, MYH7-E1455X, and MYBPC3-E165D in a 46-year old man; MYH7-R869H, MYBPC3-K1065fs, and MYBPC3-P371R in a 45-year old woman; and MYH7-R1079Q, MYBPC3-Q969X, and MYBPC3-R668H in a 50-year old woman. One had a history of resuscitated cardiac arrest, and 3 had significant risk factors for sudden cardiac death, prompting the insertion of an implantable cardioverter-defibrillator in all, with appropriate shocks in 2 patients. Moreover, 3 of 4 patients had a severe phenotype with progression to end-stage HCM by the fourth decade, requiring cardiac transplantation (n = 1) or biventricular pacing (n = 2). The fourth patient, however, had clinically mild disease. Conclusions Hypertrophic cardiomyopathy caused by triple sarcomere gene mutations was rare but conferred a remarkably increased risk of end-stage progression and ventricular arrhythmias, supporting an association between multiple sarcomere defects and adverse outcome. Comprehensive genetic testing might provide important insights to risk stratification and potentially indicate the need for differential surveillance strategies based on genotype.
Anders Oldfors - One of the best experts on this subject based on the ideXlab platform.
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embryonic myosin heavy chain mutations cause distal arthrogryposis and developmental myosin myopathy that persists postnatally
JAMA Neurology, 2008Co-Authors: Homa Tajsharghi, Eva Kimber, Annakarin Kroksmark, Ragnar Jerre, Mar Tulinius, Anders OldforsAbstract:Background: Myosin is a molecular motor and the essential part of the thick filament of striated muscle. The expression of myosin heavy-chain (MyHC) isoforms is developmentally regulated. The embryonic isoform encoded from MYH3 (OMIM *160720) is expressed during fetal life. Recently, mutations in MYH3 were demonstrated to be associated with congenital joint contractures, that is, Freeman-Sheldon and Sheldon-Hall syndromes, which are both distal arthrogryposis syndromes. Mutations in other MyHC isoforms cause myopathy. It is unknown whether MYH3 mutations cause myopathy because muscle tissue has not been studied. Objectives: To determine whether novel MYH3 mutations are associated with distal arthrogryposis and to demonstrate myopathic changes in muscle biopsy specimens from 4 patients with distal arthrogryposis and MYH3 mutations. Design: In a cohort of patients with distal arthrogryposis, we analyzed the entire coding sequence of MYH3. Muscle biopsy specimens were obtained, and in addition to morphologic analysis, the expression of MyHC isoforms was investigated at the protein and transcript levels. Results: We identified patients from 3 families with novel MYH3 mutations. These mutations affect developmentally conserved residues that are located in different regions of the adenosine triphosphate-binding pocket of the MyHC head. The embryonic (MYH3) isoform was not detected in any of the muscle biopsy samples, indicating a normal developmental downregulation of MYH3 in these patients. However, morphologic analysis of muscle biopsy specimens from the 4 patients revealed mild and variable myopathic features and a pathologic upregulation of the fetal MyHC isoform (MYH8) in 1 patient. Conclusions: Distal arthrogryposis associated with MYH3 mutations is secondary to myosin myopathy, and postnatal muscle manifestations are variable.
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new skeletal myopathy and cardiomyopathy associated with a missense mutation in MYH7
Neurology, 2007Co-Authors: Niklas Darin, Homa Tajsharghi, Ingegerd Ostmansmith, Thomas Gilljam, Anders OldforsAbstract:MYH7 encodes slow/β-cardiac myosin heavy chain (MyHC), which is expressed in type 1 fibers of skeletal muscle and in the heart. Pathogenic mutations in MYH7 are common causes of familial hypertrophic cardiomyopathy (FHCM, OMIM 160760) and dilated cardiomyopathy (FDCM, OMIM 160760). These mutations are most frequently located in the globular head of MyHC I but also in the rod. Some mutations in the distal rod region of MyHC 1 cause myosin storage myopathy (OMIM 608358),1 and some mutations in the middle and proximal rod region of MyHC 1 cause Laing early-onset distal myopathy (MPD1, OMIM 160500).2,3 These myopathies are usually not associated with cardiomyopathy. Here we report a mutation in the globular head of slow/β-cardiac myosin associated with distal myopathy and mild cardiomyopathy. See appendix E-1 on the Neurology Web site at www.neurology.org. This boy is the only child of Tanzanian immigrants. The father is healthy. According to the father, the mother has had no obvious muscle weakness, but a maternal aunt in Tanzania has distal muscle …
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homozygous mutation in MYH7 in myosin storage myopathy and cardiomyopathy
Neurology, 2007Co-Authors: Homa Tajsharghi, Anders Oldfors, Dominic P Macleod, Michael SwashAbstract:Myosin storage myopathy (MSM) associated with mutations in MYH7 encoding for slow/β-cardiac myosin heavy chain (MyHC) occurs sporadically or shows autosomal dominant inheritance.1–4 MSM is usually associated with severe skeletal muscle weakness, but cardiomyopathy is typically not present. We describe a patient with MSM in whom there was a homozygous mutation (Glu1,883Lys) in MYH7 . The parents were second cousins, and three of their children developed progressive MSM with respiratory muscle weakness and hypertrophic cardiomyopathy. This British family consisted of four siblings, three of whom were affected; the parents were second cousins. There was no family history of muscle weakness. The father died with a stroke at age 58 and the mother with myocardial infarct at age 70. ### Case 1. Exertional dyspnea commenced in late adolescence for this patient. She presented at age 26 in heart failure, with elevated jugular venous pressure (8 cm), soft systolic murmur at the left sternal edge, and fourth heart sound. She was short (height 141 cm), with thoracic scoliosis. Lung function tests revealed a restrictive deficit. EKG showed right bundle branch block, right axis deviation, and sinus tachycardia. Echocardiography and cardiac catheterization revealed hypertrophic, nonobstructive cardiomyopathy with elevated right ventricular pressure (40 mm Hg systolic) and a restrictive right and left ventricular pattern. Five years later, she developed an acute supraventricular dysrthythmia. …
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mutations and sequence variation in the human myosin heavy chain iia gene myh2
European Journal of Human Genetics, 2005Co-Authors: Homa Tajsharghi, Niklas Darin, Elham Rekabdar, Marten Kyllerman, J Wahlstrom, Tommy Martinsson, Anders OldforsAbstract:We recently described a new autosomal dominant myopathy associated with a missense mutation in the myosin heavy chain (MyHC) IIa gene (MYH2). In this study, we performed mutation analysis of MYH2 in eight Swedish patients with familial myopathy of unknown cause. In two of the eight index cases, we identified novel heterozygous missense mutations in MYH2, one in each case: V970I and L1061V. The mutations were located in subfragment 2 of the MyHC and they changed highly conserved residues. Most family members carrying the mutations had signs and symptoms consisting mainly of mild muscle weakness and myalgia. In addition, we analyzed the extent and distribution of nucleotide variation in MYH2 in 50 blood donors, who served as controls, by the complete sequencing of all 38 exons comprising the coding region. We identified only six polymorphic sites, five of which were synonymous polymorphisms. One variant, which occurred at an allele frequency of 0.01, was identical to the L1061V that was also found in one of the families with myopathy. The results of the analysis of normal variation indicate that there is strong selective pressure against mutations in MYH2. On the basis of these results, we suggest that MyHC genes should be regarded as candidate genes in cases of hereditary myopathies of unknown etiology.
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myosin storage myopathy associated with a heterozygous missense mutation in MYH7
Annals of Neurology, 2003Co-Authors: Homa Tajsharghi, Christopher Lindberg, Larseric Thornell, Bjorn Lindvall, K G Henriksson, Anders OldforsAbstract:Myosin constitutes the major part of the thick filaments in the contractile apparatus of striated muscle. MYH7 encodes the slow/beta-cardiac myosin heavy chain (MyHC), which is the main MyHC isoform in slow, oxidative, type 1 muscle fibers of skeletal muscle. It is also the major MyHC isoform of cardiac ventricles. Numerous missense mutations in the globular head of slow/beta-cardiac MyHC are associated with familial hypertrophic cardiomyopathy. We identified a missense mutation, Arg1845Trp, in the rod region of slow/beta-cardiac MyHC in patients with a skeletal myopathy from two different families. The myopathy was characterized by muscle weakness and wasting with onset in childhood and slow progression, but no overt cardiomyopathy. Slow, oxidative, type 1 muscle fibers showed large inclusions consisting of slow/beta-cardiac MyHC. The features were similar to a previously described entity: hyaline body myopathy. Our findings indicate that the mutated residue of slow/beta-cardiac MyHC is essential for the assembly of thick filaments in skeletal muscle. We propose the term myosin storage myopathy for this disease.
