P.158Congenital-onset hypertrophic cardiomyopathy and skeletal myopathy with nemaline rods and actin filament aggregates due to likely pathogenic recessive variants in CFL2

Background. PRKAG2 is a rare autosomal dominant syndrome that mainly presents with hypertrophic cardiomyopathy, ventricular preexcitation, and conduction abnormalities. This case report demonstrates that the PRKAG2 mutation presents with various phenotypes already in pediatric patients. Case Summary. We describe the clinical and investigative findings in two families with a PRKAG2 mutation from the different variants in the gene on chromosome 7q36.1, emphasising that the variability of phenotypes and that presentation in childhood is common. Furthermore, we highlight that skeletal myopathy and hypertrophic cardiomyopathy are significant debilitating characteristics of the PRKAG2 mutation. Conclusion. In our report of adult and pediatric patients, early presentation in childhood with hypertrophic cardiomyopathy and skeletal muscle involvement was common, demonstrating the challenges of the clinical management of PRKAG2 mutations.

Download Full-text

Case Report: Identification of Mutations in LAMP2 in Two Chinese Infants With Danon Disease

Frontiers in Genetics ◽

10.3389/fgene.2020.589838 ◽

2021 ◽

Vol 11 ◽

Author(s):

Luyan Zhang ◽

Fan Yang ◽

Mei Chen ◽

Ming Zhou ◽

Tianwei Qian ◽

...

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Genetic Screening ◽

Lysosomal Storage Disorder ◽

Liver Enzymes ◽

Critical Role ◽

Family Counseling ◽

Lysosomal Storage ◽

Danon Disease ◽

Skeletal Myopathy

Danon disease (DD) is a monogenic lysosomal storage disorder characterized by cardiomyopathy, skeletal myopathy, and variable degrees of intellectual disability. It is caused by a deficiency of lysosomal-associated membrane protein 2 (LAMP2). Two unrelated boys who presented with severe hypertrophic cardiomyopathy and elevated levels of liver enzymes, and were diagnosed with Danon disease at a very young age, were investigated. One boy was diagnosed at 4 months old and died soon after; his mother also died of hypertrophic cardiomyopathy shortly after his birth. Another developed hypertrophic cardiomyopathy at 3 months old but reported no significant cardiovascular symptoms during more than 5 years follow-up. Genetic screening found compound variants of LAMP2 and MYH7 in both of them. This report highlights the clinical heterogeneity in DD. The timely identification of LAMP2 mutation plays a critical role in their treatment and family counseling.

Download Full-text

Subclinical skeletal myopathy and incidence of sudden death in patients with hypertrophic cardiomyopathy

Journal of Molecular and Cellular Cardiology ◽

10.1016/s0022-2828(02)90743-1 ◽

2002 ◽

Vol 34 (6) ◽

pp. A5

Author(s):

Aris Anastasaltis ◽

Angelus Rigopoulos ◽

Robert Sepp ◽

Nikos Karandreas ◽

Artemisia Theopistou ◽

...

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Sudden Death ◽

Skeletal Myopathy

Download Full-text

CRISPR-Cas9 generated Pompe knock-in murine model exhibits early-onset hypertrophic cardiomyopathy and skeletal muscle weakness

10.1101/780320 ◽

2019 ◽

Author(s):

Jeffrey Y. Huang ◽

Shih-Hsin Kan ◽

Emilie K. Sandfeld ◽

Nancy D. Dalton ◽

Anthony D. Rangel ◽

...

Keyword(s):

Skeletal Muscle ◽

Hypertrophic Cardiomyopathy ◽

Muscle Weakness ◽

Murine Model ◽

Early Onset ◽

Late Onset ◽

Therapeutic Approaches ◽

Skeletal Myopathy ◽

Skeletal Muscle Weakness ◽

Target Effects

AbstractInfantile-onset Pompe Disease (IOPD), caused by mutations in lysosomal acid alpha-glucosidase (Gaa), manifests rapidly progressive fatal cardiac and skeletal myopathy incompletely attenuated by synthetic GAA intravenous infusions. The currently available murine model does not fully simulate human IOPD, displaying skeletal myopathy with late-onset hypertrophic cardiomyopathy. Bearing a Cre-LoxP induced exonic disruption of the murine Gaa gene, this model is also not amenable to genome-editing based therapeutic approaches. We report the early onset of severe hypertrophic cardiomyopathy in a novel murine IOPD model generated utilizing CRISPR-Cas9 homology-directed recombination to harbor the orthologous Gaa mutation c.1826dupA (p.Y609*), which causes human IOPD. We demonstrate the dual sgRNA approach with a single-stranded oligonucleotide donor is highly specific for the Gaac.1826 locus without genomic off-target effects or rearrangements. Cardiac and skeletal muscle were deficient in Gaa mRNA and enzymatic activity and accumulated high levels of glycogen. The mice demonstrated skeletal muscle weakness but did not experience early mortality. Altogether, these results demonstrate that the CRISPR-Cas9 generated Gaac.1826dupA murine model recapitulates hypertrophic cardiomyopathy and skeletal muscle weakness of human IOPD, indicating its utility for evaluation of novel therapeutics.

Download Full-text

Abstract 281: Studying Structural And Contractility Defects Of Cardiomyocytes In An In Vitro Model Of Human Hypertrophic Cardiomyopathy

Circulation Research ◽

10.1161/res.113.suppl_1.a281 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Marcelo C Ribeiro ◽

Hedde van Hoorn ◽

Jantine J Monshouwer-Kloots ◽

Christine L Mummery ◽

Thomas Schmidt ◽

...

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Actin Filament ◽

Cardiac Disease ◽

In Vitro Model ◽

Molecular Mechanisms ◽

Imaging Method ◽

Sarcomeric Proteins ◽

Cross Bridges ◽

Vitro Model

Hypertrophic Cardiomyopathy (HCM) is a cardiac disease, morphologically characterized by cardiac hypertrophy, fibrosis and impaired heart function. HCM is primarily associated with mutations in sarcomeric proteins. Mutations in sarcomeric Myosin Binding Protein C (MYBPC3) account for approximately 25% of all HCM patients. The majority of mutations in MYBPC3 are nonsense mutations, predicted to produce truncated proteins. However, instead of truncated proteins, lower levels of full-length protein of MYPBC3 are frequently found in heart samples of patients with mutations in MYBPC3, strongly suggesting that haploinsufficiency is responsible for the cardiac disease phenotype. It has been previously shown that upon ablation of MYBPC3 the myosin cross-bridges are localized closer to the actin filament, suggesting that MYBPC3 functions as a structural restraint, holding a fraction of the myosin heads at a specific distance from the actin filament. We hypothesize that the shortening of the distance between the myosin cross-bridges and the actin filaments is responsible for the increase of stretch activation kinetics leading to an increase in calcium sensitivity and contractile dysfunction. In order to develop a human in vitro model for HCM we mimicked MYBPC3 haploinsufficiency by generating stable lines in human pluripotent stem cells-derived cardiomyocytes (hPSC-CM) in which MYPBC3 protein levels were reduced by 40 to 90% using short-hairpin RNA sequences. To analyze structural and Ca2+ kinetic changes induced by the MYBPC3 knockdown we are using stochastic optical reconstruction microscopy (STORM), a superresolution fluorescence imaging method, to measure the distances between sarcomeric proteins in combination with Ca2+ imaging using a ratiometric method. At a mechanical level we are able to measure total cell force of contraction by measuring the deflection of pillars on a micropillar array generated by control and MYBPC3 knockdown hPS-CM during contraction. In conclusion, we successfully developed a human in vitro model for cardiac MYBPC3 haploinsufficiency in combination with state of the art biophysical and imaging techniques, which will allow us to comprehend the molecular mechanisms responsible for the development of HCM.

Download Full-text

Toward an alignment of the actin molecule within the actin filament

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100075981 ◽

1983 ◽

Vol 41 ◽

pp. 450-451

Author(s):

P.R. Smith ◽

W.E. Fowler ◽

U. Aebi

Keyword(s):

Actin Filament ◽

Diffraction Data ◽

Quantitative Estimate ◽

Molecular Model ◽

Quantitative Comparison ◽

Regulatory Proteins ◽

Essential Information ◽

X Ray ◽

Maximum Resolution ◽

Lack Of Information

An understanding of the specific interactions of actin with regulatory proteins has been limited by the lack of information about the structure of the actin filament. Molecular actin has been studied in actin-DNase I complexes by single crystal X-ray analysis, to a resolution of about 0.6nm, and in the electron microscope where two dimensional actin sheets have been reconstructed to a maximum resolution of 1.5nm. While these studies have shown something of the structure of individual actin molecules, essential information about the orientation of actin in the filament is still unavailable.The work of Egelman & DeRosier has, however, suggested a method which could be used to provide an initial quantitative estimate of the orientation of actin within the filament. This method involves the quantitative comparison of computed diffraction data from single actin filaments with diffraction data derived from synthetic filaments constructed using the molecular model of actin as a building block. Their preliminary work was conducted using a model consisting of two juxtaposed spheres of equal size.

Download Full-text

The 3-Dimensional Molecular Structure of the Actin Filament Revisited

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100119223 ◽

1985 ◽

Vol 43 ◽

pp. 480-481

Author(s):

U. Aebi ◽

R. Millonig ◽

H. Salvo

Keyword(s):

Actin Filament ◽

Supramolecular Assembly ◽

Specimen Preparation ◽

X Ray Diffraction ◽

Single Filament ◽

X Ray ◽

3 Dimensional ◽

Filament Diameter ◽

Preparation Conditions ◽

Apparent Diameter

To date, most 3-D reconstructions of undecorated actin filaments have been obtained from actin filament paracrystal data (for refs, see 1,2). However, due to the fact that (a) the paracrystals may be several filament layers thick, and (b) adjacent filaments may sustantially interdigitate, these reconstructions may be subject to significant artifacts. None of these reconstructions has permitted unambiguous tracing or orientation of the actin subunits within the filament. Furthermore, measured values for the maximal filament diameter both determined by EM and by X-ray diffraction analysis, vary between 6 and 10 nm. Obviously, the apparent diameter of the actin filament revealed in the EM will critically depend on specimen preparation, since it is a rather flexible supramolecular assembly which can easily be bent or distorted. To resolve some of these ambiguities, we have explored specimen preparation conditions which may preserve single filaments sufficiently straight and helically ordered to be suitable for single filament 3-D reconstructions, possibly revealing molecular detail.

Download Full-text