Epigenetics in LMNA-Related Cardiomyopathy
Abstract
:1. Introduction
2. LMNA-Related Dilated Cardiomyopathy
3. Arrhythmogenic Right Ventricular Cardiomyopathy
4. Left Ventricle Noncompaction Cardiomyopathy
5. Restrictive Cardiomyopathy
6. Molecular Mechanisms Resulting in LMNA-Related Cardiomyopathy Pathogenesis
7. Epigenetics in LMNA-Related CARDIOMYOPATHIES
- Lamina-associated domain reorganization and changes in chromatin architecture in LMNA-related cardiomyopathy.
- The role of Polycomb Group Proteins in LMNA-related cardiomyopathy.
8. Advances in Therapeutic Strategies for LMNA-Related Cardiomyopathy
9. Conclusions and Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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LMNA Mutation | Disease | Clinical Features | References |
---|---|---|---|
p. N195K | DCM | Heart dilatation, fibrosis, arrhythmia, sinus bradycardia, atrioventricular conduction block, and atrial arrhythmias | [26,35] |
p. R225X | DCM | Atrial fibrillation, complete atrioventricular block, ventricular tachyarrhythmia, and heart failure | [36,37] |
p. K117fs | DCM | Atrioventricular block, ventricular tachycardia, atrial fibrillation, arrhythmias at the single-cell level | [38] |
p.c.908_909 delCT | DCM | Atrial fibrillation, sick sinus syndrome, dilated cardiomyopathy | [39] |
p.28insA | DCM | Dilated cardiomyopathy with conduction defects | [40] |
p. T101 | DCM, lipodystrophy, atypical progeroid syndrome | Hypertriglyceridemia, diabetes mellitus, insulin resistance, left ventricular myocyte hypertrophy, interstitial fibrosis | [41,42,43,44] |
p. R377H | EDMD, LGMD, DCM | Muscular dystrophy, atrial fibrillation or flutter; conduction defects | [45,46,47,48] |
p. S143p | DCM | Atrioventricular conduction defects, left ventricular systolic dysfunction and dilatation | [49,50] |
p.H222P | EDMD | Muscle weakness, cardiac arrhythmias | [51] |
p. K219T | DCM | Heart dilatation, atrial fibrillation, atrioventricular block | [52,53] |
p. E161K | DCM | Dilatation, atrial fibrillation, conduction system diseases | [40,54] |
p. R541C | DCM, LVNC | Reduced heart contractility, left ventricle dilatation, polymorphic premature ventricular contraction, diffuse ST-T change | [41,55] |
p. R190W | DCM, LVNC, ARVC | Left ventricular noncompaction, conduction system defect, abnormal activation of ERK1/2 signaling and sarcomeric disorganization | [56,57,58] |
p. R644C | DCM, LVNC, ARVC, | Also leads to lipodystrophy, atypical progeria, phenotypic diversity, and low penetrance associated with the R644C mutation | [59,60] |
p. V445E | LVNC | Ventricular tachycardia/fibrillation | [58] |
p.c.835 delG:p.Glu279ArgfsX201 | RCM | Diastolic dysfunction, biatrial enlargement, atrial fibrillation, skeletal muscle weakness | [61] |
Mouse Model | Gene Targeting Strategy | Disease | Homozygous Phenotype | Heterozygous Phonotype | References |
---|---|---|---|---|---|
Lmna−/− * | Deletion of exons 8-11; a truncated lamin A protein of 54 kDa is still expressed | DCM, EDMD | Retarded postnatal growth, conduction disorders, DCM, EDMD, death by 8 weeks of age | AV conduction defects, both atrial and ventricular arrhythmias; develop DCM by 50 weeks | [64,65] |
Lmna−/− | Deletion of exon 2 | DCM LVNC | Retarded postnatal growth, conduction disorders, DCM, noncompaction, death within 1 month, developmental defects | RV dilatation, RV noncompaction, developmental defects | [62,63] |
Lmna GT−/− | A gene trap cassette inserted upstream of exon 2 of Lmna | N/A | Growth retardation at 2 weeks, impaired postnatal cardiac hypertrophy, skeletal muscle hypotrophy, defects in lipid metabolism | No apparent abnormalities | [66] |
Myh6 cre -Lmna f/f | Conditional deletion of Lmna in cardiomyocytes | DCM | DCM, cardiac dysfunction, conduction defects, ventricular arrhythmias, fibrosis, apoptosis, and premature death within 4 weeks | Develop cardiac dilatation and dysfunction, cardiac arrhythmias, fibrosis in older mice | [67] |
Lamin C only | Deletion of the last 150 nucleotides of exon 11 and the complete intron 11 | N/A | No obvious phenotype | No obvious phenotype | [68] |
Lamin A only | Deletion of introns 10 and 11, the last 30 bp of exon 11, and the first 24 bp of exon 12 | N/A | No apparent abnormalities | N/A | [69] |
Pre-lamin A only | Deletion of intron 10 | N/A | No apparent abnormalities | N/A | [69] |
Lmna N195K | Missense mutation in exon 3 | DCM | DCM, conduction defects, fibrosis, minor growth retardation, increased heart weight, death at 12–14 weeks | No obvious phenotype | [35] |
Lmna R225X | Nonsense mutation at exon 4 causing premature truncation of both lamin A and lamin C | DCM | Retarded postnatal growth, conduction disorders, dilated cardiomyopathy, AV node fibrosis, death within postnatal 2 weeks | No apparent abnormalities | [36] |
Lmna E82K | Transgenic mice expressing Lmna E82K under the control of | DCM | N/A | DCM, conduction defects, fibrosis, increased heart weight | [70] |
Lmna ∆K32 | Deletion of lysine 32 of lamin A/C in exon 1 | DCM | Retarded postnatal growth, striated muscle maturation delay, metabolic defects including reduced adipose tissue and hypoglycemia, death within 3 weeks | Develop a progressive cardiac dysfunction and DCM | [71,72,73] |
Lmna R541C | Missense mutation in exon 10 | DCM | Ventricular dilatation and reduced systolic function | N/A | [55] |
Lmna H222P | Missense mutation in exon 4 | EDMD DCM | Heart dilatation, conduction defects, increased fibrosis, hypertrophy defects, death by 9 months of age, developmental defects | No apparent abnormalities | [74,75,76] |
Lmna M317K | Transgenic mice expressing Lmna M317K missense mutation under the control of | EDMD | N/A | Increased eosinophilia and fragmentation of cardiomyofibrils, nuclear pyknosis and edema without fibrosis or significant inflammation, death at 2–7 weeks of age | [77] |
Lmna D300N | Transgenic mice expressing Lmna D300N; Myh6-tTA mice | DCM | N/A | Heart dilatation, increased heart-to-body-weight ratio, fibrosis, death within two months | [78] |
Lmna L530P | Missense mutation in exon 9 | HGPS | Loss of subcutaneous fat, reduction in growth rate, and death by 4 weeks of age | No apparent abnormalities | [79] |
Lmna G609G | Point mutation in exon 11 | HGPS | Shortened life span, reduced body weight, bone and cardiovascular abnormalities, death at an average of 100 days | Develop a similar phenotype to homozygotes but at an older age, average death at 242 days | [80] |
Lmna HG | Deletion of introns 10–11 and last 150 nucleotides of exon 11 | HGPS | Growth retardation osteoporosis, micrognathia, loss of adipose tissue, death by 3–4 weeks of age | Similar phenotype to homozygotes but less severe, death by 21 weeks | [81] |
Lmna nHG | Deletion of introns 10 and 11 and the last 150 bp of exon 11 together with an exchange of cysteine to serine in the CaaX motif | HGPS | Weight loss, reduced subcutaneous and abdominal fat by 4–8 weeks of age, death at 17 weeks of age | Similar spectrum of disease phenotypes as Lmna HG/+ mice but less severe, death by 36 weeks of age | [82] |
csmHG | Deletion of introns 10 and 11 and the last 150 bp of exon 11, three-nucleotide deletion (the isoleucine in progerin’s CaaX motif) | HGPS | No bone phenotype, normal body weight and survival | No bone disease, normal body weight and survival | [83] |
G608G BAC | 164-kb BAC carrying mutated G608G human LMNA | HGPS | N/A | Progressive loss of vascular smooth muscle cells | [84] |
tetop_LAG608G | Targeted expression of the lamin A G608G minigene using the keratin 5 transactivator | HGPS | N/A | Growth retardation, skin and teeth abnormalities, fibrosis, loss of hypodermal adipocytes | [85] |
Keratin14-progerin | Vector expressing progerin in epidermis under the control of the keratin 14 promoter | HGPS | N/A | Severe abnormalities in skin keratinocyte nuclei, including nuclear envelope lobulation and decreased nuclear circularity | [86] |
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Wang, Y.; Dobreva, G. Epigenetics in LMNA-Related Cardiomyopathy. Cells 2023, 12, 783. https://doi.org/10.3390/cells12050783
Wang Y, Dobreva G. Epigenetics in LMNA-Related Cardiomyopathy. Cells. 2023; 12(5):783. https://doi.org/10.3390/cells12050783
Chicago/Turabian StyleWang, Yinuo, and Gergana Dobreva. 2023. "Epigenetics in LMNA-Related Cardiomyopathy" Cells 12, no. 5: 783. https://doi.org/10.3390/cells12050783