Literatura académica sobre el tema "Sarcomeric protein mutation"
Crea una cita precisa en los estilos APA, MLA, Chicago, Harvard y otros
Consulte las listas temáticas de artículos, libros, tesis, actas de conferencias y otras fuentes académicas sobre el tema "Sarcomeric protein mutation".
Junto a cada fuente en la lista de referencias hay un botón "Agregar a la bibliografía". Pulsa este botón, y generaremos automáticamente la referencia bibliográfica para la obra elegida en el estilo de cita que necesites: APA, MLA, Harvard, Vancouver, Chicago, etc.
También puede descargar el texto completo de la publicación académica en formato pdf y leer en línea su resumen siempre que esté disponible en los metadatos.
Artículos de revistas sobre el tema "Sarcomeric protein mutation"
1
Becker, K. David, Kim R. Gottshall, Reed Hickey, Jean-Claude Perriard y Kenneth R. Chien. "Point Mutations in Human β Cardiac Myosin Heavy Chain Have Differential Effects on Sarcomeric Structure and Assembly: An ATP Binding Site Change Disrupts Both Thick and Thin Filaments, Whereas Hypertrophic Cardiomyopathy Mutations Display Normal Assembly". Journal of Cell Biology 137, n.º 1 (7 de abril de 1997): 131–40. http://dx.doi.org/10.1083/jcb.137.1.131.
Texto completoResumen
Hypertrophic cardiomyopathy is a human heart disease characterized by increased ventricular mass, focal areas of fibrosis, myocyte, and myofibrillar disorganization. This genetically dominant disease can be caused by mutations in any one of several contractile proteins, including β cardiac myosin heavy chain (βMHC). To determine whether point mutations in human βMHC have direct effects on interfering with filament assembly and sarcomeric structure, full-length wild-type and mutant human βMHC cDNAs were cloned and expressed in primary cultures of neonatal rat ventricular cardiomyocytes (NRC) under conditions that promote myofibrillogenesis. A lysine to arginine change at amino acid 184 in the consensus ATP binding sequence of human βMHC resulted in abnormal subcellular localization and disrupted both thick and thin filament structure in transfected NRC. Diffuse βMHC K184R protein appeared to colocalize with actin throughout the myocyte, suggesting a tight interaction of these two proteins. Human βMHC with S472V mutation assembled normally into thick filaments and did not affect sarcomeric structure. Two mutant myosins previously described as causing human hypertrophic cardiomyopathy, R249Q and R403Q, were competent to assemble into thick filaments producing myofibrils with well defined I bands, A bands, and H zones. Coexpression and detection of wild-type βMHC and either R249Q or R403Q proteins in the same myocyte showed these proteins are equally able to assemble into the sarcomere and provided no discernible differences in subcellular localization. Thus, human βMHC R249Q and R403Q mutant proteins were readily incorporated into NRC sarcomeres and did not disrupt myofilament formation. This study indicates that the phenotype of myofibrillar disarray seen in HCM patients which harbor either of these two mutations may not be directly due to the failure of the mutant myosin heavy chain protein to assemble and form normal sarcomeres, but may rather be a secondary effect possibly resulting from the chronic stress of decreased βMHC function.
2
Riaz, Muhammad, Jinkyu Park, Lorenzo R. Sewanan, Yongming Ren, Jonas Schwan, Subhash K. Das, Pawel T. Pomianowski et al. "Muscle LIM Protein Force-Sensing Mediates Sarcomeric Biomechanical Signaling in Human Familial Hypertrophic Cardiomyopathy". Circulation 145, n.º 16 (19 de abril de 2022): 1238–53. http://dx.doi.org/10.1161/circulationaha.121.056265.
Texto completoResumen
Background: Familial hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and is typically caused by mutations in genes encoding sarcomeric proteins that regulate cardiac contractility. HCM manifestations include left ventricular hypertrophy and heart failure, arrythmias, and sudden cardiac death. How dysregulated sarcomeric force production is sensed and leads to pathological remodeling remains poorly understood in HCM, thereby inhibiting the efficient development of new therapeutics. Methods: Our discovery was based on insights from a severe phenotype of an individual with HCM and a second genetic alteration in a sarcomeric mechanosensing protein. We derived cardiomyocytes from patient-specific induced pluripotent stem cells and developed robust engineered heart tissues by seeding induced pluripotent stem cell–derived cardiomyocytes into a laser-cut scaffold possessing native cardiac fiber alignment to study human cardiac mechanobiology at both the cellular and tissue levels. Coupled with computational modeling for muscle contraction and rescue of disease phenotype by gene editing and pharmacological interventions, we have identified a new mechanotransduction pathway in HCM, shown to be essential in modulating the phenotypic expression of HCM in 5 families bearing distinct sarcomeric mutations. Results: Enhanced actomyosin crossbridge formation caused by sarcomeric mutations in cardiac myosin heavy chain ( MYH7 ) led to increased force generation, which, when coupled with slower twitch relaxation, destabilized the MLP (muscle LIM protein) stretch-sensing complex at the Z-disc. Subsequent reduction in the sarcomeric muscle LIM protein level caused disinhibition of calcineurin–nuclear factor of activated T-cells signaling, which promoted cardiac hypertrophy. We demonstrate that the common muscle LIM protein–W4R variant is an important modifier, exacerbating the phenotypic expression of HCM, but alone may not be a disease-causing mutation. By mitigating enhanced actomyosin crossbridge formation through either genetic or pharmacological means, we alleviated stress at the Z-disc, preventing the development of hypertrophy associated with sarcomeric mutations. Conclusions: Our studies have uncovered a novel biomechanical mechanism through which dysregulated sarcomeric force production is sensed and leads to pathological signaling, remodeling, and hypertrophic responses. Together, these establish the foundation for developing innovative mechanism-based treatments for HCM that stabilize the Z-disc MLP-mechanosensory complex.
3
Piroddi, Nicoletta, E. Rosalie Witjas-Paalberends, Claudia Ferrara, Cecilia Ferrantini, Giulia Vitale, Beatrice Scellini, Paul J. M. Wijnker et al. "The homozygous K280N troponin T mutation alters cross-bridge kinetics and energetics in human HCM". Journal of General Physiology 151, n.º 1 (21 de diciembre de 2018): 18–29. http://dx.doi.org/10.1085/jgp.201812160.
Texto completoResumen
Hypertrophic cardiomyopathy (HCM) is a genetic form of left ventricular hypertrophy, primarily caused by mutations in sarcomere proteins. The cardiac remodeling that occurs as the disease develops can mask the pathogenic impact of the mutation. Here, to discriminate between mutation-induced and disease-related changes in myofilament function, we investigate the pathogenic mechanisms underlying HCM in a patient carrying a homozygous mutation (K280N) in the cardiac troponin T gene (TNNT2), which results in 100% mutant cardiac troponin T. We examine sarcomere mechanics and energetics in K280N-isolated myofibrils and demembranated muscle strips, before and after replacement of the endogenous troponin. We also compare these data to those of control preparations from donor hearts, aortic stenosis patients (LVHao), and HCM patients negative for sarcomeric protein mutations (HCMsmn). The rate constant of tension generation following maximal Ca2+ activation (kACT) and the rate constant of isometric relaxation (slow kREL) are markedly faster in K280N myofibrils than in all control groups. Simultaneous measurements of maximal isometric ATPase activity and Ca2+-activated tension in demembranated muscle strips also demonstrate that the energy cost of tension generation is higher in the K280N than in all controls. Replacement of mutant protein by exchange with wild-type troponin in the K280N preparations reduces kACT, slow kREL, and tension cost close to control values. In donor myofibrils and HCMsmn demembranated strips, replacement of endogenous troponin with troponin containing the K280N mutant increases kACT, slow kREL, and tension cost. The K280N TNNT2 mutation directly alters the apparent cross-bridge kinetics and impairs sarcomere energetics. This result supports the hypothesis that inefficient ATP utilization by myofilaments plays a central role in the pathogenesis of the disease.
4
Chun, M. y S. Falkenthal. "Ifm(2)2 is a myosin heavy chain allele that disrupts myofibrillar assembly only in the indirect flight muscle of Drosophila melanogaster." Journal of Cell Biology 107, n.º 6 (1 de diciembre de 1988): 2613–21. http://dx.doi.org/10.1083/jcb.107.6.2613.
Texto completoResumen
Using a combination of molecular and genetic techniques we demonstrate that Ifm(2)2 is an allele of the single-copy sarcomeric myosin heavy chain gene. Flies homozygous for this allele accumulate wild-type levels of mRNA and protein in tubular muscle of adults, but fail to accumulate detectable amounts of myosin heavy chain mRNA or protein in the indirect flight muscle. We propose that the mutation interferes with either transcription of the gene or splicing of the primary transcript in the indirect flight muscle and not in other muscle tissues. Biochemical and electron microscopic analysis of flies homozygous for this mutation has revealed that thick filament assembly is abolished in the indirect flight muscle resulting in the instability of wild-type thick filament proteins. In contrast, thin filament and Z disc assembly are marginally affected. We discuss a working hypothesis for sarcomere assembly and define and experimental approach to test the predictions of this proposed pathway for sarcomere assembly.
5
Clay, Sarah A., Timothy L. Domeier, Laurin M. Hanft, Kerry S. McDonald y Maike Krenz. "Elevated Ca2+ transients and increased myofibrillar power generation cause cardiac hypercontractility in a model of Noonan syndrome with multiple lentigines". American Journal of Physiology-Heart and Circulatory Physiology 308, n.º 9 (1 de mayo de 2015): H1086—H1095. http://dx.doi.org/10.1152/ajpheart.00501.2014.
Texto completoResumen
Noonan syndrome with multiple lentigines (NSML) is primarily caused by mutations in the nonreceptor protein tyrosine phosphatase SHP2 and associated with congenital heart disease in the form of pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM). Our goal was to elucidate the cellular mechanisms underlying the development of HCM caused by the Q510E mutation in SHP2. NSML patients carrying this mutation suffer from a particularly severe form of HCM. Drawing parallels to other, more common forms of HCM, we hypothesized that altered Ca2+ homeostasis and/or sarcomeric mechanical properties play key roles in the pathomechanism. We used transgenic mice with cardiomyocyte-specific expression of Q510E-SHP2 starting before birth. Mice develop neonatal onset HCM with increased ejection fraction and fractional shortening at 4–6 wk of age. To assess Ca2+ handling, isolated cardiomyocytes were loaded with fluo-4. Q510E-SHP2 expression increased Ca2+ transient amplitudes during excitation-contraction coupling and increased sarcoplasmic reticulum Ca2+ content concurrent with increased expression of sarco(endo)plasmic reticulum Ca2+-ATPase. In skinned cardiomyocyte preparations from Q510E-SHP2 mice, force-velocity relationships and power-load curves were shifted upward. The peak power-generating capacity was increased approximately twofold. Transmission electron microscopy revealed that the relative intracellular area occupied by sarcomeres was increased in Q510E-SHP2 cardiomyocytes. Triton X-100-based myofiber purification showed that Q510E-SHP2 increased the amount of sarcomeric proteins assembled into myofibers. In summary, Q510E-SHP2 expression leads to enhanced contractile performance early in disease progression by augmenting intracellular Ca2+ cycling and increasing the number of power-generating sarcomeres. This gives important new insights into the cellular pathomechanisms of Q510E-SHP2-associated HCM.
6
Marcu, Andreea Sorina, Radu Vătăşescu, Sebastian Onciul, Viorica Rădoi y Ruxandra Jurcuţ. "Intrafamilial Phenotypical Variability Linked to PRKAG2 Mutation—Family Case Report and Review of the Literature". Life 12, n.º 12 (18 de diciembre de 2022): 2136. http://dx.doi.org/10.3390/life12122136.
Texto completoResumen
PRKAG2 syndrome (PS) is a rare, early-onset autosomal dominant phenocopy of sarcomeric hypertrophic cardiomyopathy (HCM), that mainly presents with ventricular pre-excitation, cardiac hypertrophy and progressive conduction system degeneration. Its natural course, treatment and prognosis are significantly different from sarcomeric HCM. The clinical phenotypes of PRKAG2 syndrome often overlap with HCM due to sarcomere protein mutations, causing this condition to be frequently misdiagnosed. The syndrome is caused by mutations in the gene encoding for the γ2 regulatory subunit (PRKAG2) of 5′ Adenosine Monophosphate-Activated Protein Kinase (AMPK), an enzyme that modulates glucose uptake and glycolysis. PRKAG2 mutations (OMIM#602743) are responsible for structural changes of AMPK, leading to an impaired myocyte glucidic uptake, and finally causing storage cardiomyopathy. We describe the clinical and investigative findings in a family with several affected members (NM_016203.4:c.905G>A or p.(Arg302Gln), heterozygous), highlighting the various phenotypes even in the same family, and the utility of genetic testing in diagnosing PS. The particularity of this family case is represented by the fact that the index patient was diagnosed at age 16 with cardiac hypertrophy and ventricular pre-excitation while his mother, by age 42, only had Wolff–Parkinson–White syndrome, without left ventricle hypertrophy. Both the grandmother and the great-grandmother underwent pacemaker implantation at a young age because of conduction abnormalities. Making the distinction between PS and sarcomeric HCM is actionable, given the early-onset of the disease, the numerous life-threatening consequences and the high rate of conduction disorders. In patients who exhibit cardiac hypertrophy coexisting with ventricular pre-excitation, genetic screening for PRKAG2 mutations should be considered.
7
Ojala, Marisa, Chandra Prajapati, Risto-Pekka Pölönen, Kristiina Rajala, Mari Pekkanen-Mattila, Jyrki Rasku, Kim Larsson y Katriina Aalto-Setälä. "Mutation-Specific Phenotypes in hiPSC-Derived Cardiomyocytes Carrying Either Myosin-Binding Protein C Orα-Tropomyosin Mutation for Hypertrophic Cardiomyopathy". Stem Cells International 2016 (2016): 1–16. http://dx.doi.org/10.1155/2016/1684792.
Texto completoResumen
Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disease, which affects the structure of heart muscle tissue. The clinical symptoms include arrhythmias, progressive heart failure, and even sudden cardiac death but the mutation carrier can also be totally asymptomatic. To date, over 1400 mutations have been linked to HCM, mostly in genes encoding for sarcomeric proteins. However, the pathophysiological mechanisms of the disease are still largely unknown. Two founder mutations for HCM in Finland are located in myosin-binding protein C (MYBPC3-Gln1061X) andα-tropomyosin (TPM1-Asp175Asn) genes. We studied the properties of HCM cardiomyocytes (CMs) derived from patient-specific human induced pluripotent stem cells (hiPSCs) carrying eitherMYBPC3-Gln1061XorTPM1-Asp175Asnmutation. Both types of HCM-CMs displayed pathological phenotype of HCM but, more importantly, we found differences between CMs carrying eitherMYBPC3-Gln1061XorTPM1-Asp175Asngene mutation in their cellular size, Ca2+handling, and electrophysiological properties, as well as their gene expression profiles. These findings suggest that even though the clinical phenotypes of the patients carrying eitherMYBPC3-Gln1061XorTPM1-Asp175Asngene mutation are similar, the genetic background as well as the functional properties on the cellular level might be different, indicating that the pathophysiological mechanisms behind the two mutations would be divergent as well.
8
Masum, Md Mohiuddin, Md Abdullah Al Sayeef, Rayhan Shahrear, Devjani Banik, Gonopati Biswas y Zinnat Ara Yesmin. "Hypertrophic Cardiomyopathy: The Molecular Genetics". Faridpur Medical College Journal 14, n.º 1 (26 de marzo de 2020): 44–49. http://dx.doi.org/10.3329/fmcj.v14i1.46168.
Texto completoResumen
Hypertrophic Cardiomyopathy (HCM) is the common monogenic form familial pathological cardiac hypertrophy. HCM is an important cause of sudden cardiac death in the young adult and a major cause of morbidity in the elderly. We discuss here the molecular genetics and recent advances in the molecular genetics of HCM. HCM became the first cardiac disease for which a molecular genetic mechanism was identified. More than 100 mutations in nine genes, that encoding sarcomeric proteins have been identified in patients with HCM, which had led to the belief that HCM is a disease of contractile sarcomeric proteins of the cardiac muscle. Approximately two-thirds of all HCM cases are caused by the mutation of the myosin heavy chain (MyHC), cardiac troponin T (cTnT) and myosin binding protein-C (MyBP-C). Genotype-phenotype correlation studies suggest that mutations in the MyHC gene are associated with more extensive hypertrophy and a higher risk of SCD as compared to mutations in genes coding for other sarcomeric proteins, such as MyBP-C and cTnT. However, there is a noteworthy variability and factors, such as modifier genes and probably the environmental factors affect the phenotypic expression of HCM. The results of different functional studies suggest that in spite of the variety of the mutations, the initial defects in HCM is abnormal cardiac myocyte function. In this era of genetics and upcoming future of precision medicine, good knowledge of its molecular basis of any disease is crucial for patient management, and HCM is not different.
Faridpur Med. Coll. J. Jan 2019;14(1): 44-49
9
Ahmad, Syed Abrar, Chandrakant Chavan, Rajesh Badani y Varsha Wankhade. "Sarcomeric gene mutations in phenotypic positive hypertrophic cardiomyopathic patients in Indian population". Cellular and Molecular Biology 67, n.º 6 (27 de febrero de 2022): 1–10. http://dx.doi.org/10.14715/cmb/2021.67.6.1.
Texto completoResumen
HCM is a monogenic cardiac disorder with a high risk of sudden cardiac death, heterogeneous phenotypic expression and genetic profile. HCM is expressed as autosomal dominant in fashion with the prevalence of 1:500 in the general population. The main objective of the current study was to unravel the mutation status in sarcomeric genes in urbanizing Pune population. HCM patients were recruited from Bharti hospital and Poona hospital and research centre, Pune after being screened by 2-D echocardiography. DNA was extracted from whole blood samples and PCR amplification was performed for selected exons from pre-selected genes, amplimers of >300 b.p were restriction digested and the SSCP technique was optimized for maximum result output. HCM patients shows the maximum prevalence of mitral regurgitation (23.3%) while the minimum prevalence was left auricular diameter (10%). Maximum variation spectrum was present in MYBPC3 genes as most of them were “benign” type as per Polyphen-2 tool status. Mutations in the MYH7 gene produce a prominent impact on splicing by the creation of a new SRP40 binding site (Exon Splicing Enhancer) as predicted by Human Splicing Finder 3.1. I736T mutation in the MYH7 gene results in replacement of β-strand by α-helix upstream from mutation site which may have a profound impact on protein tertiary structure as predicted by Polyphen-2 tool (probably damaging-1.00). Also, two ‘novel’ mutations and one ‘novel’ variation were reported in the present study. Thus, the MYBPC3 gene shows maximum mutation load among other sarcomeric genes. Double gene mutations do not represent much severe pathophysiology as compared to single gene mutated and genotypic negative HCM patients.
10
Ниязова, С. С., Н. Н. Чакова, С. М. Комиссарова y М. А. Сасинович. "Mutation spectrum in sarcomeric protein genes and their phenotypic features in Belarusian patients with hypertrophic cardiomyopathy". Nauchno-prakticheskii zhurnal «Medicinskaia genetika», n.º 6() (28 de junio de 2019): 21–33. http://dx.doi.org/10.25557/2073-7998.2019.06.21-33.
Texto completoResumen
Введение. Гипертрофическая кардиомиопатия (ГКМП) относится к наследственной патологии, основной причиной которой являются мутации в генах, кодирующих белковые компоненты миофибрильного аппарата кардиомиоцитов, при этом спектр этих генетических изменений имеет популяционные особенности. Целью данного исследования являлось определение спектра мутаций в генах, кодирующих саркомерные белки, у пациентов с ГКМП из Беларуси, а также изучение взаимосвязей между генотипом и фенотипическими проявлениями заболевания. Материалы и методы. В исследование были включены 340 неродственных пациентов с ГКМП, проживающих в Беларуси. Обнаружение мутаций в кодирующих последовательностях генов ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNI3, TNNT2, TNNС1 и TPM1 у 89 пациентов проводили методом высокопроизводительного секвенирования (NGS). Направленный поиск выявленных методом NGS генетических дефектов осуществлялся методом автоматического секвенирования по Сэнгеру, а также с использованием ПЦР-ПДРФ анализа. Результаты. У 51,7% пациентов методом NGS обнаружены мутации в генах: MYBPC3 (20,2%), MYH7 (16,9%), TPM1 (3,4%), ACTC1 (2,3%), MYL2 (1,1%) и TNNC1 (1,1%). У 6,7% индивидуумов встречались две (5,6%) или три (1,1%) замены. Обнаружены новые мутации p.Ala49Asn, p.Val1407Phe в гене MYH7; р.Tyr501Ser, р.Trp1007fs, р.Tyr1043*, р.Pro1066Arg, p.Arg1138fs, р.Pro1181Gln, р.Cys1202Arg в гене MYBPC3. Установлены часто встречающиеся мутации: р.Gln1233*, р.Ser871Alafs, комбинация р.Glu1265Val+р.Cys1266Arg, р.Gln401* и р.Trp1214Arg в гене MYBPC3, p.Arg403Trp, p.Arg663Cys, p.Arg663His, p.Ala729Pro, p.Glu924Lys и p.Glu1356Lys в гене MYH7. По данным ЭхоКГ-исследования носители мутаций в генах белков саркомера, особенно обладатели миссенс-мутаций в гене MYBPC3, имели более выраженную гипертрофию миокарда и раннюю манифестацию заболевания по сравнению с пациентами без мутаций в этих генах. Для носителей наиболее распространенной среди белорусских пациентов мутации р.Gln1233* характерны позднее начало заболевания, умеренная гипертрофия миокарда левого желудочка, частое развитие фибрилляции предсердий. Выводы. Распределение встречаемости мутаций в генах, кодирующих саркомерные белки, у пациентов с ГКМП из Беларуси не отличалось от других европейских популяций. 84,9% обнаруженных мутаций локализовано в генах MYBPC3 и MYH7. Background. Hypertrophic cardiomyopathy (HCM) is a hereditary pathology, the main cause of which is mutations in the genes encoding the protein components of the myofibril apparatus of cardiomyocytes, and the spectrum of these genetic changes has population features. The aim of the study was to determine the spectrum of mutations in the genes encoding sarcomeric proteins in patients with HCM from Belarus, as well as to study the association between the genotype and the phenotypic manifestations of the disease. Materials and methods. The study included 340 unrelated patients with HCM from Belarus. Mutation detection in the coding sequences of ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNI3, TNNT2, TNNС1 и TPM1 genes was performed by next generation sequencing (NGS) in 89 patients. The directed search for genetic defects detected by the NGS method was carried out by the automatic sequencing method using Sanger and PCR-RFLP analysis. Results. The NGS method allowed to detect mutations in the genes of 51,7% of patients: MYBPC3 (20,2%), MYH7 (16,9%), TPM1 (3,4%), ACTC1 (2,3%), MYL2 (1,1 %) and TNNC1 (1,1%). In 6,7% of individuals two (5,6%) or three (1,1%) substitutions were observed. New mutations were found: p.Ala49Asn, p.Val1407Phe in the MYH7 gene; p.Tyr501Ser, p.Trp1007fs, p.Tyr1043*, p.Pro1066Arg, p.Arg1138fs, p.Pro1181Gln, р.Cys1202Arg in the MYBPC3 gene. The most frequently occurring mutations were identified: p.Gln1233*, p.Ser871Alafs, the combination of the р.Glu1265Val + p.Cys1266Arg, R.Gln401*, and Trp1214Arg in the MYBPC3 gene, p.Glu924Lys and p.Glu1356Lys in the MYH7 gene. According to the ECG study, carriers of mutations in sarcomere protein genes, especially with missense mutations in the MYBPC3 gene, had more severe myocardial hypertrophy and early disease manifestation then patients without mutations in those genes. The p.Gln1233* mutation was the most common among Belarusian patients and characterized by late onset of the disease, mild left ventricular myocardial hypertrophy and the more frequent development of atrial fibrillation. Conclusions. In general, the distribution of mutations in the genes encoding sarcomeric proteins in patients with HCM from Belarus didn’t differ from other European populations. 84,9% of the detected mutations were localized in MYBPC3 and MYH7 genes.
Tesis sobre el tema "Sarcomeric protein mutation"
1
Bohman, Lova. "Pathological Mechanisms of Sarcomere Mutations in the Disease Hypertrophic Cardiomyopathy : A Review". Thesis, Linköpings universitet, Institutionen för fysik, kemi och biologi, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-176045.
Texto completoResumen
Hypertrophic cardiomyopathy is a heart disease that is characterized by an enlarged heart muscle. Mutations to sarcomere proteins in the muscle fibers give rise to the disease, and this review aims to compile the mechanisms by which the mutations cause the disease phenotype. β-myosin heavy chain mutants affect the thick filament structure and contraction velocity of the muscle. Mutations to the myosin-binding protein C produces truncated proteins with decreased expression in the cells. Troponin T mutants cause myofibrillar disarray, alters affinity to α-tropomyosin, and are linked to a higher risk of sudden death. Troponin I is an unpredictable mutant that needs to be further researched but is thought to cause regulatory problems. Mutations to α-tropomyosin and the regulatory myosin light chain both affect the Ca2+-affinity of the proteins and leads to contractile problems. Hypercontractility as a result of the mutations seems to be the primary cause of the disease. Hypertrophic cardiomyopathy is linked to sudden death, and factors such as a family history of sudden death, multiple simultaneous mutations, unexplained syncope, non-sustained ventricular tachycardia, abnormal blood pressure response and extreme hypertrophy (>30 mm) heightens the risk of a sudden death. An increased knowledge about the disease will aid in the mission to better the treatments for the affected, but further investigation of pathological pathways needs to be performed.
2
FERRARA, CLAUDIA. "Impact of sarcomeric protein mutations associated to myopathies on the mechanics and energetics of myofibril contraction". Doctoral thesis, 2013. http://hdl.handle.net/2158/803892.
Texto completoResumen
The effect of mutations of two different sarcomeric proteins, cardiac troponin T (cTnT) and skeletal nebuline on biophysical properties of crossbridge cicle on myofibrils were investigated.
Mechanical and kinetic properties of myofibrils from a human cardiac and a neonatal skeletal murine biopsies, were analized and explained using the same 2-state model of acto-myosin interaction proposed by Brenner in 1988.
Libros sobre el tema "Sarcomeric protein mutation"
1
Pinto, Jose Renato y P. Bryant Chase, eds. Connecting Sarcomere Protein Mutations to Pathogenesis in Myopathies. Frontiers Media SA, 2020. http://dx.doi.org/10.3389/978-2-88963-921-2.
Texto completo
2
Garcia-Pavia, Pablo y Fernando Dominguez. Left ventricular non-compaction: genetics and embryology. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198784906.003.0362.
Texto completoResumen
Left ventricular non-compaction (LVNC) is a rare disorder that is considered an ‘unclassified cardiomyopathy’ by the European Society of Cardiology. Several different gene mutations related to LVNC have been identified, involving sarcomeric, cytoskeletal, Z-line, ion channel, mitochondrial, and signalling proteins. However, there is broad genetic overlap between LVNC and other inherited cardiac diseases such as dilated cardiomyopathy and hypertrophic cardiomyopathy. LVNC could also be part of multisystemic genetic entities such as Barth syndrome, or accompany congenital heart defects.
3
Cardim, Nuno, Denis Pellerin y Filipa Xavier Valente. Hypertrophic cardiomyopathy. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780198726012.003.0042.
Texto completoResumen
Hypertrophic cardiomyopathy is a common inherited heart disease caused by genetic mutations in cardiac sarcomeric proteins. Although most patients are asymptomatic and many remain undiagnosed, the clinical presentation and natural history include sudden cardiac death, heart failure, and atrial fibrillation. Echocardiography plays an essential role in the diagnosis, serial monitoring, prognostic stratification, and family screening. Advances in Doppler myocardial imaging and deformation analysis have improved preclinical diagnosis as well as the differential diagnosis of left ventricular hypertrophy. Finally, echocardiography is closely involved in patient selection and in intraoperative guidance and monitoring of septal reduction procedures. This chapter describes the pathophysiology, clinical presentation, role of echocardiography, morphological features, differential diagnosis, diagnostic criteria in first-degree relatives, echo guidance for the treatment of symptomatic left ventricular outflow tract obstruction, and follow-up and monitoring of patients with hypertrophic cardiomyopathy.
Capítulos de libros sobre el tema "Sarcomeric protein mutation"
1
Kamisago, Mitsuhiro, Joachim P. Schmitt, Dennis McNamara, Christine Seidman y J. G. Seidman. "Sarcomere Protein Gene Mutations and Inherited Heart Disease: A β Cardiac Myosin Heavy Chain Mutation Causing Endocardial Fibroelastosis and Heart Failure". En Novartis Foundation Symposia, 176–95. Chichester, UK: John Wiley & Sons, Ltd, 2008. http://dx.doi.org/10.1002/0470029331.ch11.
Texto completo
2
Charron, Philippe y Carole Maupain. "Genetics of cardiomyopathies: hypertrophic cardiomyopathy". En ESC CardioMed, 688–91. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198784906.003.0154.
Texto completoResumen
Hypertrophic cardiomyopathy is characterized by the presence of increased left ventricular wall thickness that is not solely explained by abnormal loading conditions (such as hypertension or valvular disease). Hypertrophic cardiomyopathy is a genetic disease, usually with an autosomal dominant inheritance. About 35–60% of patients with hypertrophic cardiomyopathy carry a pathogenic mutation in sarcomeric protein genes. Most mutations are observed in genes encoding beta-myosin heavy chain (MYH7), cardiac myosin binding protein C (MYBPC3), or cardiac troponin T (TNNT2). Non-sarcomeric genetic causes exist, especially in children (Pompe disease, Noonan syndrome, or Friedreich ataxia). In adults, non-sarcomeric genetic causes include metabolic storage diseases such as Danon disease (LAMP2 gene), Fabry disease (GLA gene), left ventricular hypertrophy associated with Wolff–Parkinson–White syndrome (PRKAG2 gene), familial amyloidosis (TTR gene), and mitochondrial cardiomyopathies.
3
F. Wieczorek, David. "Cardiomyopathy: Getting Bigger All the Time - Lessons Learned about Heart Disease from Tropomyosin". En Cardiomyopathy - Disease of the Heart Muscle [Working Title]. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.95509.
Texto completoResumen
In 1990, John and Christine Seidman uncovered the genetic association between mutations in sarcomeric contractile proteins and hypertrophic cardiomyopathy. Since then, the increase in knowledge and understanding of this disease has increased exponentially. Although pathologies associated with the various cardiomyopathies are vastly different, in some cases, the same proteins are causative, but with different genetic mutations. The focus of this article will be on hypertrophic and dilated cardiomyopathies, which are often caused by mutations in sarcomeric contractile proteins. Tropomyosin, a thin filament protein, serves as a paradigm to illustrate how different mutations within the same protein can generate the hypertrophic or dilated cardiomyopathic condition. As such, the significant advances in information derived from basic science investigations has led to the development of novel therapeutics in the treatment of these pathological diseases. This article will illustrate linkages which occur to bridge scientific advances to clinical treatments in cardiomyopathic patients.
4
Lopes, Luis Rocha. "Dilated cardiomyopathy: genetics". En ESC CardioMed, 1467–73. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198784906.003.0355.
Texto completoResumen
The genetic background of dilated cardiomyopathy is characterized by heterogeneity. Truncating mutations in titin (TTN), responsible for around 20% of cases, have recently been recognized as the most prevalent genetic cause of dilated cardiomyopathy. Other important causal genes are LMNA (coding for the nuclear envelope protein, lamin A/C) and sarcomere protein genes, such as beta-myosin heavy chain (MYH7) and troponin T (TNNT2). Other loci, including genes that code for cytoskeleton, Z-disc, and membrane-associated proteins, are each responsible for a lower percentage of cases. Current consensus recommendations propose genetic testing in the presence of familial forms of the disease or when certain phenotype characteristics, such as conduction disease or a family history of sudden cardiac death, are present. Some causal genes are associated with a worse prognosis. This is most strongly established for LMNA, where the presence of a disease-causing mutation, together with certain clinical risk factors, is an indication for an implantable cardioverter defibrillator.
5
Akhtar, Mohammed Majid y Luis Rocha Lopes. "Hypertrophic cardiomyopathy: genetics". En ESC CardioMed, 1443–50. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198784906.003.0350.
Texto completoResumen
Hypertrophic cardiomyopathy is most commonly transmitted as an autosomal dominant trait, caused by mutations in genes encoding cardiac sarcomere and associated proteins. Knowledge of the genetic pathophysiology of the disease has advanced significantly since the initial identification of a point mutation in the beta-myosin heavy chain (MYH7) gene in 1990. Other genetic causes of the disease include mutations in genes coding for proteins implicated in calcium handling or which form part of the cytoskeleton. The recent emergence of next-generation sequencing allows quicker and less expensive identification of causative mutations. However, a causative mutation is not identified in up to 50% of probands. At present, the primary clinical role of genetic testing in hypertrophic cardiomyopathy is in the context of familial screening, allowing the identification of those at risk of developing the condition. Genetic testing can also be used to exclude genocopies, particularly in the presence of certain diagnostic ‘red flag’ features, where lysosomal, glycogen storage, neuromuscular or Ras-MAPK pathway disorders may be suspected. The role of individual mutations in predicting prognosis is limited at present. However, the higher incidence of sudden cardiac death in the presence of a family history of such, suggests that genetics play a significant role in determining outcome. With an increased understanding of the impact of these mutations on a cellular level and on longer-term clinical outcomes, the aim in future for gene and mutation specific prognosis or potential disease-modifying therapy is closer.
6
Akhtar, Mohammed Majid y Luis Rocha Lopes. "Hypertrophic cardiomyopathy: genetics". En ESC CardioMed, 1443–50. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198784906.003.0350_update_001.
Texto completoResumen
Hypertrophic cardiomyopathy is most commonly transmitted as an autosomal dominant trait, caused by mutations in genes encoding cardiac sarcomere and associated proteins. Knowledge of the genetic pathophysiology of the disease has advanced significantly since the initial identification of a point mutation in the beta-myosin heavy chain (MYH7) gene in 1990. Other genetic causes of the disease include mutations in genes coding for proteins implicated in calcium handling or which form part of the cytoskeleton. The recent emergence of next-generation sequencing allows quicker and less expensive identification of causative mutations. However, a causative mutation is not identified in up to 50% of probands. At present, the primary clinical role of genetic testing in hypertrophic cardiomyopathy is in the context of familial screening, allowing the identification of those at risk of developing the condition. Genetic testing can also be used to exclude genocopies, particularly in the presence of certain diagnostic ‘red flag’ features, where lysosomal, glycogen storage, neuromuscular or Ras-MAPK pathway disorders may be suspected. The role of individual mutations in predicting prognosis is limited at present. However, the higher incidence of sudden cardiac death in the presence of a family history of such, suggests that genetics play a significant role in determining outcome. With an increased understanding of the impact of these mutations on a cellular level and on longer-term clinical outcomes, the aim in future for gene and mutation specific prognosis or potential disease-modifying therapy is closer.
7
M. Harvey, Evan, Murad Almasri y Hugo R. Martinez. "Genetics of Cardiomyopathy". En Cardiomyopathy - Disease of the Heart Muscle [Working Title]. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.97010.
Texto completoResumen
Cardiomyopathies (CMs) encompass a heterogeneous group of structural and functional (systolic and diastolic) abnormalities of the myocardium and are either confined to the cardiovascular system or are part of a systemic disorder. CMs represent a leading cause of morbidity and mortality and account for a significant percentage of death and cardiac transplantation. The 2006 American Heart Association (AHA) classification grouped CMs into primary (genetic, mixed, or acquired) or secondary (i.e., infiltrative or autoimmune). In 2008, the European Society of Cardiology classification proposed subgrouping CM into familial or genetic and nonfamilial or nongenetic forms. In 2013, the World Heart Federation recommended the MOGES nosology system, which incorporates a morpho-functional phenotype (M), organ(s) involved (O), the genetic inheritance pattern (G), an etiological annotation (E) including genetic defects or underlying disease/substrates, and the functional status (S) of a particular patient based on heart failure symptoms. Rapid advancements in the biology of cardio-genetics have revealed substantial genetic and phenotypic heterogeneity in myocardial disease. Given the variety of disciplines in the scientific and clinical fields, any desired classification may face challenges to obtaining consensus. Nonetheless, the heritable phenotype-based CM classification offers the possibility of a simple, clinically useful diagnostic scheme. In this chapter, we will describe the genetic basis of dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), arrhythmogenic cardiomyopathy (ACM), LV noncompaction cardiomyopathy (LVNC), and restrictive cardiomyopathy (RCM). Although the descriptive morphologies of these types of CM differ, an overlapping phenotype is frequently encountered within the CM types and arrhythmogenic pathology in clinical practice. CMs appear to originate secondary to disruption of “final common pathways.” These disruptions may have purely genetic causes. For example, single gene mutations result in dysfunctional protein synthesis causing downstream dysfunctional protein interactions at the level of the sarcomere and a CM phenotype. The sarcomere is a complex with multiple protein interactions, including thick myofilament proteins, thin myofilament proteins, and myosin-binding proteins. In addition, other proteins are involved in the surrounding architecture of the sarcomere such as the Z-disk and muscle LIM proteins. One or multiple genes can exhibit tissue-specific function, development, and physiologically regulated patterns of expression for each protein. Alternatively, multiple mutations in the same gene (compound heterozygosity) or in different genes (digenic heterozygosity) may lead to a phenotype that may be classic, more severe, or even overlapping with other disease forms.
8
Purevjav, Enkhsaikhan y Jeffrey A. Towbin. "The Z-Disk Final Common Pathway in Cardiomyopathies". En Cardiomyopathy - Disease of the Heart Muscle [Working Title]. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.97532.
Texto completoResumen
The sarcomeres represent the essential contractile units of the cardiac myocyte and are bordered by two Z-lines (disks) that are made by various proteins. The cardiac Z-disk is recognized as one of the nodal points in cardiomyocyte structural organization, mechano-sensation and signal transduction. Rapid progress in molecular and cellular biology has significantly improved the knowledge about pathogenic mechanisms and signaling pathways involved in the development of inherited cardiomyopathies. Genetic insult resulting in expression of mutated proteins that maintain the structure of the heart can perturb cardiac function. The primary mutation in the cardiac contractile apparatus or other subcellular complexes can lead to cardiac pathology on a tissue level, resulting in organ and organism level pathophysiology. The “final common pathway” hypothesis interpreting the genetic basis and molecular mechanisms involved in the development of cardiomyopathies suggests that mutations in cardiac genes encoding proteins with similar structure, function, or location and operating in the same pathway, are responsible for a particular phenotype of cardiomyopathy with unique morpho-histological remodeling of the heart. This chapter will describe genetic abnormalities of cardiac Z-disk and related “final common pathways” that are triggered by a Z-disk genetic insult leading to heart muscle diseases. In addition, animal models carrying mutations in Z-disk proteins will be described.
9
Garcia-Pavia, Pablo y Fernando Dominguez. "Left ventricular non-compaction: genetics and embryology". En ESC CardioMed, 1505–9. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198784906.003.0362_update_001.
Texto completoResumen
Left ventricular non-compaction (LVNC) is a rare disorder that is considered an ‘unclassified cardiomyopathy’ by the European Society of Cardiology. Several different gene mutations related to LVNC have been identified, involving sarcomeric, cytoskeletal, Z-line, ion channel, mitochondrial, and signalling proteins. However, there is broad genetic overlap between LVNC and other inherited cardiac diseases such as dilated cardiomyopathy and hypertrophic cardiomyopathy. LVNC could also be part of multisystemic genetic entities such as Barth syndrome, or accompany congenital heart defects.
10
Pantazis, Antonis. "Hypertrophic Cardiomyopathy". En Manual of Cardiovascular Medicine, 313–20. Oxford University Press, 2021. http://dx.doi.org/10.1093/med/9780198850311.003.0038.
Texto completoResumen
Hypertrophic cardiomyopathy is a myocardial disease that is usually caused by mutations in the genes encoding for contractile proteins of the myocytes (i.e. sarcomeric proteins) leading in most cases to marked myocardial hypertrophy, fibrosis, and supraventricular and ventricular arrhythmias that may trigger cardiac arrest and sudden cardiac death. The diagnosis is commonly made clinically, based on ECG features and with imaging, in particular echocardiography and cardiac MRI. The management involves negative inotropic and chronotropic drugs such as calcium antagonists (diltiazem and verapamil) and beta blockers as well as, in certain cases, with symptomatic left ventricular outflow tract obstruction, catheter-based alcohol-septal ablation, or surgical septal myectomy. To prevent sudden cardiac death ICDs are recommended depending on the risk profile.
Actas de conferencias sobre el tema "Sarcomeric protein mutation"
1
Athayde, Natália Merten y Alzira Alves de Siqueira Carvalho. "The heart of myofibrillary myopathy". En XIII Congresso Paulista de Neurologia. Zeppelini Editorial e Comunicação, 2021. http://dx.doi.org/10.5327/1516-3180.457.
Texto completoResumen
Context: Myofibrillar myopathies (MFM) represent a heterogeneous group of disorders of skeletal and cardiac muscle caused by mutations in genes that encode proteins of sarcomere. Diagnosis is a challenge due to clinical and genetic variability. Case report: Woman, 36 years old, presenting stumbles and falls for 3 years evolving with proximal limb weakness. At age 30, she fainted and a cardiac pacemaker was implanted. Non-consanguineous parents. Neurological exam: proximal and distal weakness in lower limbs and distal atrophy; osteotendinous reflexes normal. Bilateral scapula alata. Exams: CPK = 457 U / l; EMG: myopathic pattern. Muscle MRI: diffuse and heterogeneous fatty degeneration, marked in sartorius, gracilis and semitedinous. Panel NGS myopathies: pathogenic variant, c.1175T> C, missense in heterozygosis in desmin gene. CONCLUSION: The diagnosis of MFM is based on the morphological findings of muscle biopsy with the presence of protein aggregates as a determining factor. Currently, genetic testing by NGS has facilitated early diagnosis allowing for a more appropriate clinical approach. The desmin gene was the first one described to be associated with this group of myopathies. It encodes the desmin protein, a member of the intermediate filament family present in cardiac and skeletal muscle. Several phenotypes are related to desmin gene: isolated dilated cardiomyopathy; scapuloperoneal weakness and distoproximal weakness with cardiac alterations. Desminopathy is a rare cause of cardiomyopathy and / or myopathy. The diagnosis should be thought in patient with muscle weakness and cardiac changes.
2
Prodanovic, Momcilo, Boban Stojanovic, Danica Prodanovic, Nenad Filipovic y Srboljub M. Mijailovich. "Computational Modeling of Sarcomere Protein Mutations and Drug Effects on Cardiac Muscle Behavior". En 2021 IEEE 21st International Conference on Bioinformatics and Bioengineering (BIBE). IEEE, 2021. http://dx.doi.org/10.1109/bibe52308.2021.9635428.
Texto completo