Amelioration of X-Linked Related Autophagy Failure in Danon Disease With DNA Methylation Inhibitor

Ng, Kwong‐Man; Mok, Pamela Y.; Butler, Amy W.; Ho, Joseph; Choi, Shing Wan; Lee, Yee-Ki; Lai, Wing‐Hon; Au, Ka-Wing; Lau, YL; Wong, L.C.; Esteban, Miguel A.; Siu, Chung‐Wah; Sham, Pak C.; Colman, Alan; Tse, Hung‐Fat

doi:10.1161/circulationaha.115.019847

Cited by 44 publications

(43 citation statements)

References 32 publications

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“…Cell models of LAMP‐2 deficiency showed accumulation of LC3‐vacuoles, myofibrillar disorganization , decreased localization of LC3‐lysosomes, and ATG14 and VAMP8 , suggesting inhibited fusion between autophagic vacuoles and lysosomes .…”

Section: Pathogenetic Mechanismmentioning

confidence: 99%

“…Myopathic changes at EMG were sometimes associated with signs of myotonia , which may lead to a misdiagnosis of myotonic dystrophy . Since electrical myotonia can be observed in other vacuolar myopathies such as Pompe disease , by analogy, it is possible that intracytoplasmic vacuoles (derived from the sarcolemma) in myocytes may contribute to myotonic discharges in DD.…”

Section: Clinical Features In Male Patientsmentioning

confidence: 99%

“…Many patients had hepatomegaly (36% of cases) , overt hepatopathy or increased liver enzyme levels from childhood .…”

Section: Clinical Features In Male Patientsmentioning

confidence: 99%

“…Immunohistochemistry in explanted hearts showed LAMP‐2 absent either in 40–60% of cardiomyocytes (random XCI pattern) or in 60–75% of cardiomyocytes (unfavourably skewed XCI) . Sometimes, LAMP‐2‐negative cardiomyocytes showed significant hypertrophy compared to LAMP‐2 positive cardiomyocytes .…”

Section: Tissue Pathology and Lamp‐2 Protein Testing In Female Patientsmentioning

confidence: 99%

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Review: Danon disease: Review of natural history and recent advances

Cenacchi

Papa

Pegoraro

et al. 2019

Neuropathology Appl Neurobio

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Danon disease is a severe multisystem disorder clinically characterized by hypertrophic cardiomyopathy, skeletal myopathy and mental retardation in male patients, and by a milder phenotype (predominantly involving cardiac muscle) in female patients. The disease is inherited as an X‐linked dominant trait. The primary deficiency of lysosome‐associated membrane protein‐2 (LAMP‐2) causes disruption of autophagy, leading to an impaired fusion of lysosomes to autophagosomes and biogenesis of lysosomes. We surveyed over 500 Danon disease patients reported in the literature from the first description to the present, in order to summarize the clinical, pathological and molecular data and treatment perspectives. An early molecular diagnosis is of crucial importance for genetic counselling and for therapeutic interventions: in male patients, the prognosis is poor due to rapid progression towards heart failure, and only heart transplantation modifies the disease course.

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Section: Pathogenetic Mechanismmentioning

confidence: 99%

Section: Clinical Features In Male Patientsmentioning

confidence: 99%

“…Many patients had hepatomegaly (36% of cases) , overt hepatopathy or increased liver enzyme levels from childhood .…”

Section: Clinical Features In Male Patientsmentioning

confidence: 99%

Section: Tissue Pathology and Lamp‐2 Protein Testing In Female Patientsmentioning

confidence: 99%

See 2 more Smart Citations

Review: Danon disease: Review of natural history and recent advances

Cenacchi

Papa

Pegoraro

et al. 2019

Neuropathology Appl Neurobio

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“…Human induced pluripotent stem cells (hiPSC) generated from individual patients who harbor a specific mutation have been exploited to elucidate the pathogenic mechanisms of various cardiovascular diseases. [14][15][16][17][18][19] The hiPSC technology is expected to revolutionize the concept of precision medicine by providing a steady supply of patient-specific functional cells for preclinical testing in order to identify the most effective and safest personalized strategies for a particular individual. 20 In fact, the US Food and Drug Administration has recently examined ways in which hiPSC-derived cardiomyocytes can be used in preclinical investigation of the potential risks in metabolic pathways or proarrhythmia events.…”

mentioning

confidence: 99%

Modeling Treatment Response for Lamin A/C Related Dilated Cardiomyopathy in Human Induced Pluripotent Stem Cells

Lee

Lau

Cai

et al. 2017

JAHA

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BackgroundPrecision medicine is an emerging approach to disease treatment and prevention that takes into account individual variability in the environment, lifestyle, and genetic makeup of patients. Patient‐specific human induced pluripotent stem cells hold promise to transform precision medicine into real‐life clinical practice. Lamin A/C (LMNA)‐related cardiomyopathy is the most common inherited cardiomyopathy in which a substantial proportion of mutations in the LMNA gene are of nonsense mutation. PTC124 induces translational read‐through over the premature stop codon and restores production of the full‐length proteins from the affected genes. In this study we generated human induced pluripotent stem cells‐derived cardiomyocytes from patients who harbored different LMNA mutations (nonsense and frameshift) to evaluate the potential therapeutic effects of PTC124 in LMNA‐related cardiomyopathy.Methods and ResultsWe generated human induced pluripotent stem cells lines from 3 patients who carried distinctive mutations (R225X, Q354X, and T518fs) in the LMNA gene. The cardiomyocytes derived from these human induced pluripotent stem cells lines reproduced the pathophysiological hallmarks of LMNA‐related cardiomyopathy. Interestingly, PTC124 treatment increased the production of full‐length LMNA proteins in only the R225X mutant, not in other mutations. Functional evaluation experiments on the R225X mutant further demonstrated that PTC124 treatment not only reduced nuclear blebbing and electrical stress‐induced apoptosis but also improved the excitation‐contraction coupling of the affected cardiomyocytes.ConclusionsUsing cardiomyocytes derived from human induced pluripotent stem cells carrying different LMNA mutations, we demonstrated that the effect of PTC124 is codon selective. A premature stop codon UGA appeared to be most responsive to PTC124 treatment.

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In situ nuclear DNA methylation in dilated cardiomyopathy: an endomyocardial biopsy study

et al. 2020

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Aims Although distinct DNA methylation patterns have been reported, its localization and roles remain to be defined in heart failure. We investigated the cellular and subcellular localization of DNA methylation and its pathophysiological significance in human failing hearts. Methods and results Using left ventricular (LV) endomyocardial biopsy specimens from 75 patients with dilated cardiomyopathy (DCM; age: 58 ± 14 years old, %female: 32%) and 20 patients without heart failure (controls; age: 56 ± 17 years old, %female: 45%), we performed immunohistochemistry and immunoelectron microscopy for methylated DNA, 5methylcytosine (5-mC). We next investigated possible relations of the incidence of 5-mC-positive (%5-mC + ) cardiomyocytes with clinicopathological parameters. Immunopositivity for 5-mC was detected in the cardiomyocytes and other cell types. The %5-mC + cardiomyocytes was significantly greater in DCM hearts than in controls (57 ± 13% in DCM vs. 25 ± 12% in controls, P < 0.0001). The localization of 5-mC immunopositivity in cardiomyocyte nuclei coincided well with that of heterochromatin, as confirmed by immunoelectron microscopy. Substantial DNA methylation was also observed in interstitial noncardiomyocytes, but the incidences did not differ between control and DCM hearts (39 ± 7.9% in DCM vs. 41 ± 10% in controls, P = 0.4099). In DCM patients, the %5-mC + cardiomyocytes showed a significant inverse correlation with LV functional parameters such as heart rate (r = 0.2391, P = 0.0388), end-diastolic pressure (r = 0.2397, P = 0.0397), and ejection fraction (r = À0.2917, P = 0.0111) and a positive correlation with LV dilatation (volume index at diastole; r = 0.2442, P = 0.0347; and volume index at systole; r = 0.3136, P = 0.0062) and LV hypertrophy (mass index; r = 0.2287, P = 0.0484)-that is, LV remodelling parameters. No significant correlations between DNA methylation and the histological parameters of the biopsies, including cardiomyocyte hypertrophy, fibrosis, and inflammatory cell infiltration, were noted. Conclusions The present study revealed increased nuclear DNA methylation in cardiomyocytes, but not other cell types, from DCM hearts, with predominant localization in the heterochromatin. Its significant relations with LV functional and remodelling parameters imply a pathophysiological significance of DNA methylation in heart failure.

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Amelioration of X-Linked Related Autophagy Failure in Danon Disease With DNA Methylation Inhibitor

Abstract: Our iPSC-CM platform provides novel mechanistic and therapeutic insights into the contribution of random X chromosome inactivation to disease phenotype in X-linked Danon disease.

Cited by 44 publications

References 32 publications

Review: Danon disease: Review of natural history and recent advances

Review: Danon disease: Review of natural history and recent advances

Modeling Treatment Response for Lamin A/C Related Dilated Cardiomyopathy in Human Induced Pluripotent Stem Cells

In situ nuclear DNA methylation in dilated cardiomyopathy: an endomyocardial biopsy study

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