Dextrocardia and symmetric hypertrophic cardiomyopathy with multiple mutations of genes encoding the sarcomere proteins

The etiology of hypertrophic cardiomyopathy (HCM) has been ascribed to mutations in genes encoding sarcomere proteins. In particular, mutations in MYBPC3, a gene which encodes cardiac myosin binding protein-C (cMyBP-C), have been implicated in over one third of HCM cases. Of these mutations, 70% are predicted to result in C′-truncated protein products, which are undetectable in tissue samples. Heterozygous carriers of these truncation mutations exhibit varying penetrance of HCM, with symptoms often occurring later in life. We hypothesize that heterozygous carriers of MYBPC3 mutations, while seemingly asymptomatic, have subtle functional impairments that precede the development of overt HCM. This study compared heterozygous (+/t) knock-in MYBPC3 truncation mutation mice with wild-type (+/+) littermates to determine whether functional alterations occur at the whole-heart or single-cell level before the onset of hypertrophy. The +/t mice show ∼40% reduction in MYBPC3 transcription, but no changes in cMyBP-C level, phosphorylation status, or cardiac morphology. Nonetheless, +/t mice show significantly decreased maximal force development at sarcomere lengths of 1.9 μm (+/t 68.5 ± 4.1 mN/mm2 vs. +/+ 82.2 ± 3.2) and 2.3 μm (+/t 79.2 ± 3.1 mN/mm2 vs. +/+ 95.5 ± 2.4). In addition, heterozygous mice show significant reductions in vivo in the early/after (E/A) (+/t 1.74 ± 0.12 vs. +/+ 2.58 ± 0.43) and E′/A′ (+/t 1.18 ± 0.05 vs. +/+ 1.52 ± 0.15) ratios, indicating diastolic dysfunction. These results suggest that seemingly asymptomatic heterozygous MYBPC3 carriers do suffer impairments that may presage the onset of HCM.

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Protein Quality Control Activation and Microtubule Remodeling in Hypertrophic Cardiomyopathy

Cells ◽

10.3390/cells8070741 ◽

2019 ◽

Vol 8 (7) ◽

pp. 741 ◽

Cited By ~ 2

Author(s):

Dorsch ◽

Schuldt ◽

Remedios ◽

Schinkel ◽

Jong ◽

...

Keyword(s):

Quality Control ◽

Hypertrophic Cardiomyopathy ◽

Protein Quality ◽

Protein Quality Control ◽

Left Ventricular ◽

Microtubule Network ◽

Protein Levels ◽

Tubulin Acetylation ◽

Genes Encoding ◽

Sarcomere Proteins

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder. It is mainly caused by mutations in genes encoding sarcomere proteins. Mutant forms of these highly abundant proteins likely stress the protein quality control (PQC) system of cardiomyocytes. The PQC system, together with a functional microtubule network, maintains proteostasis. We compared left ventricular (LV) tissue of nine donors (controls) with 38 sarcomere mutation-positive (HCMSMP) and 14 sarcomere mutation-negative (HCMSMN) patients to define HCM and mutation-specific changes in PQC. Mutations in HCMSMP result in poison polypeptides or reduced protein levels (haploinsufficiency, HI). The main findings were 1) several key PQC players were more abundant in HCM compared to controls, 2) after correction for sex and age, stabilizing heat shock protein (HSP)B1, and refolding, HSPD1 and HSPA2 were increased in HCMSMP compared to controls, 3) α-tubulin and acetylated α-tubulin levels were higher in HCM compared to controls, especially in HCMHI, 4) myosin-binding protein-C (cMyBP-C) levels were inversely correlated with α-tubulin, and 5) α-tubulin levels correlated with acetylated α-tubulin and HSPs. Overall, carrying a mutation affects PQC and α-tubulin acetylation. The haploinsufficiency of cMyBP-C may trigger HSPs and α-tubulin acetylation. Our study indicates that proliferation of the microtubular network may represent a novel pathomechanism in cMyBP-C haploinsufficiency-mediated HCM.

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Unraveling the Genotype‐Phenotype Relationship in Hypertrophic Cardiomyopathy: Obesity‐Related Cardiac Defects as a Major Disease Modifier

Journal of the American Heart Association ◽

10.1161/jaha.120.018641 ◽

2020 ◽

Vol 9 (22) ◽

Author(s):

Edgar E. Nollet ◽

B. Daan Westenbrink ◽

Rudolf A. de Boer ◽

Diederik W. D. Kuster ◽

Jolanda van der Velden

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Disease Burden ◽

Clinical Course ◽

Clinical Findings ◽

Inherited Cardiomyopathy ◽

Genes Encoding ◽

Disease Penetrance ◽

Disease Modifier ◽

Sarcomere Proteins ◽

Recent Cohort

Abstract Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy and is characterized by asymmetric septal thickening and diastolic dysfunction. More than 1500 mutations in genes encoding sarcomere proteins are associated with HCM. However, the genotype‐phenotype relationship in HCM is incompletely understood and involves modification by additional disease hits. Recent cohort studies identify obesity as a major adverse modifier of disease penetrance, severity, and clinical course. In this review, we provide an overview of these clinical findings. Moreover, we explore putative mechanisms underlying obesity‐induced sensitization and aggravation of the HCM phenotype. We hypothesize obesity‐related stressors to impact on cardiomyocyte structure, metabolism, and homeostasis. These may impair cardiac function by directly acting on the primary mutation‐induced myofilament defects and by independently adding to the total cardiac disease burden. Last, we address important clinical and pharmacological implications of the involvement of obesity in HCM disease modification.

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Reconnoitering the Role of Long-Noncoding RNAs in Hypertrophic Cardiomyopathy: A Descriptive Review

International Journal of Molecular Sciences ◽

10.3390/ijms22179378 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9378

Author(s):

Syeda K. Shahzadi ◽

Nerissa Naidoo ◽

Alawi Alsheikh-Ali ◽

Manfredi Rizzo ◽

Ali A. Rizvi ◽

...

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Direct Consequence ◽

Calcium Sensitivity ◽

Biological Processes ◽

Functional Roles ◽

Hereditary Cardiomyopathy ◽

Genes Encoding ◽

Non Coding Rnas ◽

Sarcomere Proteins

Hypertrophic cardiomyopathy (HCM) is the most common form of hereditary cardiomyopathy. It is characterized by an unexplained non-dilated hypertrophy of the left ventricle with a conserved or elevated ejection fraction. It is a genetically heterogeneous disease largely caused by variants of genes encoding for cardiac sarcomere proteins, including MYH7, MYBPC3, ACTC1, TPM1, MYL2, MYL3, TNNI3, and TNNT23. Preclinical evidence indicates that the enhanced calcium sensitivity of the myofilaments plays a key role in the pathophysiology of HCM. Notably, this is not always a direct consequence of sarcomeric variations but may also result from secondary mutation-driven alterations. Long non-coding RNAs (lncRNAs) are a large class of transcripts ≥200 nucleotides in length that do not encode proteins. Compared to coding mRNAs, most lncRNAs are not as well-annotated and their functions are greatly unexplored. Nevertheless, increasing evidence shows that lncRNAs are involved in a variety of biological processes and diseases including HCM. Accumulating evidence has indicated that lncRNAs are dysregulated in HCM, and closely related to sarcomere construction, calcium channeling and homeostasis of mitochondria. In this review, we have summarized the known regulatory and functional roles of lncRNAs in HCM.

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The genetics of hypertrophic cardiomyopathy

Global Cardiology Science and Practice ◽

10.21542/gcsp.2018.36 ◽

2018 ◽

Vol 2018 (3) ◽

Cited By ~ 3

Author(s):

Mohammed Akhtar ◽

Perry Elliott

Keyword(s):

Genetic Testing ◽

Hypertrophic Cardiomyopathy ◽

Treatment Strategies ◽

Glycogen Storage ◽

Calcium Handling ◽

Clinical Role ◽

Genes Encoding ◽

Disease Stratification ◽

Sarcomere Proteins

Hypertrophic cardiomyopathy (HCM) is most commonly transmitted as an autosomal dominant trait, caused by mutations in genes encoding cardiac sarcomere proteins. Other inheritable causes of the disease include mutations in genes coding for proteins important in calcium handling or that form part of the cytoskeleton. At present, the primary clinical role of genetic testing in HCM is to facilitate familial screening to allow the identification of individuals at risk of developing the disease. It is also used to diagnose genocopies, such as lysosomal and glycogen storage disease which have different treatment strategies, rates of disease progression and prognosis. The role of genetic testing in predicting prognosis is limited at present, but emerging data suggest that knowledge of the genetic basis of disease will assume an important role in disease stratification and offer potential targets for disease-modifying therapy in the near future.

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Myosins and pathology: genetics and biology.

Acta Biochimica Polonica ◽

10.18388/abp.2002_3739 ◽

2002 ◽

Vol 49 (4) ◽

pp. 789-804 ◽

Cited By ~ 34

Author(s):

Maria Jolanta Redowicz

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Myosin Heavy Chain ◽

Inner Ear ◽

Heavy Chain ◽

Hair Cells ◽

Familial Hypertrophic Cardiomyopathy ◽

Light Chains ◽

Myosin Isoforms ◽

Cardiac Myosin ◽

Genes Encoding

This article summarizes current knowledge on the genetics and possible molecular mechanisms of Human pathologies resulted from mutations within the genes encoding several myosin isoforms. Mutations within the genes encoding some myosin isoforms have been found to be responsible for blindness (myosins III and VIIA), deafness (myosins I, IIA, IIIA, VI, VIIA and XV) and familial hypertrophic cardiomyopathy (beta cardiac myosin heavy chain and both the regulatory and essential light chains). Myosin III localizes predominantly to photoreceptor cells and is proved to be engaged in the vision process in Drosophila. In the inner ear, myosin I is postulated to play a role as an adaptive motor in the tip links of stereocilia of hair cells, myosin IIA seems to be responsible for stabilizing the contacts between adjacent inner ear hair cells, myosin VI plays a role as an intracellular motor transporting membrane structures within the hair cells while myosin VIIA most probably participates in forming links between neighbouring stereocilia and myosin XV probably stabilizes the stereocilia structure. About 30% of patients with familial hypertrophic cardiomyopathy have mutations within the genes encoding the beta cardiac myosin heavy chain and both light chains that are grouped within the regions of myosin head crucial for its functions. The alterations lead to the destabilization of sarcomeres and to a decrease of the myosin ATPase activity and its ability to move actin filaments.

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Hypertrophic cardiomyopathy: genetics

ESC CardioMed ◽

10.1093/med/9780198784906.003.0350 ◽

2018 ◽

pp. 1443-1450

Author(s):

Mohammed Majid Akhtar ◽

Luis Rocha Lopes

Keyword(s):

Genetic Testing ◽

Hypertrophic Cardiomyopathy ◽

Mapk Pathway ◽

Glycogen Storage ◽

Cellular Level ◽

Causative Mutation ◽

Clinical Role ◽

Genes Encoding ◽

Associated Proteins

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.

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A Novel Myosin Essential Light Chain Mutation Causes Hypertrophic Cardiomyopathy with Late Onset and Low Expressivity

Biochemistry Research International ◽

10.1155/2012/685108 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 18

Author(s):

Paal Skytt Andersen ◽

Paula Louise Hedley ◽

Stephen P. Page ◽

Petros Syrris ◽

Johanna Catharina Moolman-Smook ◽

...

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Light Chain ◽

Late Onset ◽

Large Family ◽

Left Ventricular ◽

Cascade Screening ◽

Essential Light Chain ◽

Mutation Carriers ◽

Genes Encoding ◽

The Mean

Hypertrophic cardiomyopathy (HCM) is caused by mutations in genes encoding sarcomere proteins. Mutations inMYL3, encoding the essential light chain of myosin, are rare and have been associated with sudden death. Both recessive and dominant patterns of inheritance have been suggested. We studied a large family with a 38-year-old asymptomatic HCM-affected male referred because of a murmur. The patient had HCM with left ventricular hypertrophy (max WT 21 mm), a resting left ventricular outflow gradient of 36 mm Hg, and left atrial dilation (54 mm). Genotyping revealed heterozygosity for a novel missense mutation, p.V79I, inMYL3. The mutation was not found in 300 controls, and the patient had no mutations in 10 sarcomere genes. Cascade screening revealed a further nine heterozygote mutation carriers, three of whom had ECG and/or echocardiographic abnormalities but did not fulfil diagnostic criteria for HCM. The penetrance, if we consider this borderline HCM the phenotype of the p.V79I mutation, was 40%, but the mean age of the nonpenetrant mutation carriers is 15, while the mean age of the penetrant mutation carriers is 47. The mutation affects a conserved valine replacing it with a larger isoleucine residue in the region of contact between the light chain and the myosin lever arm. In conclusion,MYL3mutations can present with low expressivity and late onset.

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An Unusual Presentation of a Myocardial Crypt in Hypertrophic Cardiomyopathy

Case Reports in Cardiology ◽

10.1155/2014/737052 ◽

2014 ◽

Vol 2014 ◽

pp. 1-3

Author(s):

Danny A. J. P. van de Sande ◽

Jan Hoogsteen ◽

Luc J. H. J. Theunissen

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Interventricular Septum ◽

Positive Family History ◽

Phenotypic Expression ◽

Anterior Wall ◽

Left Ventricular ◽

Genes Encoding ◽

History Of ◽

Basal Septum ◽

Myocardial Crypts

Hypertrophic cardiomyopathy (HCM) is a common inherited cardiovascular disease with prevalence of 0.2% in the population. More than 1000 mutations in more than 10 genes encoding for proteins of the cardiac sarcomere have been identified. Cardiac magnetic resonance imaging (CMR) is used to characterize left ventricular morphology with great precision in patients with HCM and it identifies unique structural abnormalities in patients with HCM. We present a case of a 56-year-old man who had positive family history of HCM who was a carrier of the genetic MYH-7 2770 G > C, exon 23 mutation. Transthoracic echocardiography showed thickening of the interventricular septum (16 mm) and in particular the basal septum. CMR confirmed the diagnosis of HCM in the anteroseptal myocardium with a thickness of 23 mm and also revealed large and deep myocardial crypts in the anterior wall. These myocardial crypts are rarely found in the so-called genotype positive and phenotype positive patients, as in our case. Also the crypts in this case are deeper and wider than those reported in other cases. So in conclusion, this case reveals an uncommon finding of a myocardial crypt at an unusual myocardial site with the unusual morphology in a patient with genotypic and phenotypic expression of hypertrophic cardiomyopathy.

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HYPERTROPHIC CARDIOMYOPATHY IN ELDERLY PEOPLE

Arterial’naya Gipertenziya (Arterial Hypertension) ◽

10.18705/1607-419x-2013-19-6-502-505 ◽

2013 ◽

Vol 19 (6) ◽

pp. 502-505 ◽

Cited By ~ 1

Author(s):

A. A. Poliakova ◽

E. N. Semernin ◽

A. A. Streltcova ◽

A. A. Kostareva ◽

A. Ya. Gudkova

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Disease Risk ◽

Clinical Manifestations ◽

The Elderly ◽

Population Based ◽

Left Ventricular ◽

Full Cohort ◽

The Usa ◽

Sarcomere Proteins ◽

The Impact

Hypertrophic cardiomyopathy (HCM) is a leader in genetic structure of cardiovascular system. According to modern concepts, hypertrophic cardiomyopathy associated with mutations of sarcomere proteins is just one of the reasons leading to the left ventricular hypertrophy (LVH). Hypertrophic phenotype is also observed in a number of genetically and non-genetically related diseases. According to population-based studies conducted in the USA, Europe and Japan, the prevalence of HCM is 1:500. Apparently, the data obtained in these studies and based primarily on the phenotypic screening cannot be extrapolated to the full cohort of patients with HCM and reflect the general incidence of hypertrophic phenotype in different populations. There are some publications on the prevalence of HCM in the structure of LVH of unknown cause in children and adolescents. The features of the clinical course of HCM, risk stratification of sudden cardiac death (SCD), medical management in young and middle age are studied. At the same time elderly patients with unexplained LVH are the least studied cohort. Study of the natural history of the disease, risk factors for adverse events, including the SCD, the impact of comorbidity on the clinical manifestations of HCM in the elderly will contribute better understanding of this pathology, as well as a number of other diseases occurring under the guise of HCM. This can help to develop the algorithms for diagnosis, prediction criteria and management of LVH of unknown cause.

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