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AOP: 550
Title
Increased LMNA gene mutation leading to heart failure
Short name
Graphical Representation
Point of Contact
Contributors
- Young Jun Kim
Coaches
OECD Information Table
OECD Project # | OECD Status | Reviewer's Reports | Journal-format Article | OECD iLibrary Published Version |
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This AOP was last modified on December 03, 2024 09:32
Revision dates for related pages
Page | Revision Date/Time |
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Increased LMNA Mutation | December 02, 2024 03:34 |
Structural changes in lamin A/C | November 20, 2024 08:52 |
Altered Signaling Pathways | February 13, 2024 07:31 |
Increased,Cardiac fibrosis | September 01, 2021 20:39 |
Heart failure | December 03, 2024 10:15 |
LMNA Mutation leads to Structural changes in lamin A/C | November 20, 2024 09:36 |
Structural changes in lamin A/C leads to Altered Signaling | November 20, 2024 09:36 |
Altered Signaling leads to Increased,Cardiac fibrosis | November 20, 2024 09:37 |
Increased,Cardiac fibrosis leads to Heart failure | November 21, 2024 07:25 |
Ethyl methanesulfonate | November 29, 2016 18:42 |
Polycyclic aromatic hydrocarbons (PAHs) | February 09, 2017 15:43 |
Arsenic | April 27, 2021 00:15 |
Cadmium | October 25, 2017 08:33 |
Ionizing Radiation | May 07, 2019 12:12 |
UV-B and UV-C | November 20, 2024 09:44 |
Bleomycin | October 29, 2019 13:08 |
Camptothecin | November 20, 2024 09:45 |
Abstract
The LMNA gene, encoding lamin A/C, is essential for maintaining nuclear envelope integrity and regulating gene expression. Mutations in LMNA are well-established causes of various diseases collectively termed laminopathies, which include hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy, and muscular dystrophies. Among these, HCM, characterized by abnormal thickening of the cardiac muscle, has been extensively linked to inherited LMNA mutations. However, the role of chemical-induced mutations in the LMNA gene as a contributing factor to HCM remains an emerging area of research. Chemicals and environmental agents with mutagenic properties can induce DNA damage and mutations in critical genes like LMNA through several mechanisms, including oxidative stress, direct mutagenesis, and epigenetic dysregulation. Oxidative stress, often driven by reactive oxygen species (ROS), can damage DNA bases, while alkylating agents and other mutagens can directly induce point mutations, insertions, or deletions. Furthermore, chemicals that alter epigenetic markers may dysregulate LMNA expression or splicing, potentially contributing to pathological outcomes. LMNA mutations compromise nuclear structural integrity and disrupt critical signal transduction pathways in cardiac myocytes, which are particularly sensitive to mechanical stress. These disruptions can lead to hypertrophic remodeling, fibrosis, and inflammation, all of which are hallmark features of HCM. Additionally, LMNA mutations may result in aberrant chromatin organization, leading to the dysregulated expression of genes vital for cardiac function. Despite these insights, the link between chemical exposure and LMNA-associated HCM is focused on the underlying mechanisms and the implications for environmental risk factors and therapeutic strategies. Understanding this Key event relationship may provide critical insights into risk assessment to chemicals
AOP Development Strategy
Context
The development of an Adverse Outcome Pathway (AOP) for chemical-induced LMNA gene mutation leading to hypertrophic cardiomyopathy (HCM) requires a systematic approach to identify, screen, and assess data relevant to the key events (KEs) and their key event relationships (KERs). This AOP aims to link chemical exposure to molecular initiating events (MIEs), intermediate KEs, and ultimately, adverse outcomes (AOs), providing a mechanistic basis for regulatory applications and research.
Strategy
1. Identification of Relevant Data
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Literature Mining:
- Search for studies linking chemical exposures to LMNA mutations using databases like PubMed, Scopus, and Web of Science. Keywords such as “LMNA mutation,” “hypertrophic cardiomyopathy,” “chemical-induced mutation,” and “genotoxicity” guide the process.
- Focus on experimental and epidemiological evidence that connects genotoxic chemicals to molecular changes in the LMNA gene and downstream effects on cardiomyocytes.
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Data Repositories:
- Explore toxicology databases such as Tox21, ToxCast, and MutageneDB for high-throughput screening data on chemicals that induce oxidative stress, mutagenesis, or epigenetic alterations impacting the LMNA gene.
- Search the Adverse Outcome Pathway Knowledge Base (AOP-KB) for related pathways or existing KEs that may overlap with this AOP.
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Expert Consultation:
- Collaborate with researchers in genomics, cardiology, and toxicology to identify unpublished or emerging studies focusing on LMNA mutations and cardiomyopathies.
2. Screening of Data
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Relevance Filtering:
- Select data demonstrating a direct link between chemical exposure and LMNA-related cellular changes (e.g., DNA damage, mutation hotspots, epigenetic modifications).
- Prioritize studies using human cardiomyocytes or animal models that mimic human cardiac physiology.
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Mechanistic Alignment:
- Focus on studies that describe key mechanisms, such as oxidative stress or direct mutagenesis, leading to LMNA dysfunction. Data connecting LMNA structural defects to hypertrophic remodeling in cardiac myocytes are particularly valuable.
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Dose-Response Evidence:
- Include studies providing dose-response data to establish quantitative relationships between chemical exposure, LMNA mutations, and downstream cardiac effects.
3. Quality Assessment of Data
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Weight of Evidence (WoE) Framework:
- Evaluate evidence based on:
- Biological Plausibility: Ensure consistency with known mechanisms of genotoxicity and cardiac hypertrophy.
- Empirical Support: Assess data for reproducibility across independent studies.
- Concordance: Verify that observed key events occur in a logical sequence from MIE (LMNA mutation) to AO (HCM).
- Quantitative Data: Identify data supporting dose-response or temporal relationships between KEs and KERs.
- Evaluate evidence based on:
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Experimental Quality:
- Critically evaluate study design (e.g., controls, replicates, use of human-relevant models) to ensure robust and reliable evidence.
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Data Gaps:
- Identify areas where evidence is weak or missing, such as the lack of studies on specific genotoxic chemicals inducing LMNA mutations or detailed molecular pathways connecting LMNA dysfunction to cardiac hypertrophy.
4. Integration of Evidence
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Causal Network Mapping:
- Develop a causal map linking chemical exposure to LMNA mutations, subsequent nuclear envelope instability, impaired cardiac signaling, and hypertrophic remodeling.
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Confidence Assessment:
- Use confidence scoring (e.g., OECD guidelines) to evaluate the strength of each KE and KER, noting any uncertainties.
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Documentation:
- Maintain detailed records of evidence, including data sources, relevance assessments, and quality evaluations, to support transparency and reproducibility.
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
Type | Event ID | Title | Short name |
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MIE | 2278 | Increased LMNA Mutation | LMNA Mutation |
KE | 2279 | Structural changes in lamin A/C | Structural changes in lamin A/C |
KE | 2066 | Altered Signaling Pathways | Altered Signaling |
KE | 1924 | Increased,Cardiac fibrosis | Increased,Cardiac fibrosis |
AO | 1535 | Heart failure | Heart failure |
Relationships Between Two Key Events (Including MIEs and AOs)
Title | Adjacency | Evidence | Quantitative Understanding |
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LMNA Mutation leads to Structural changes in lamin A/C | adjacent | High | High |
Structural changes in lamin A/C leads to Altered Signaling | adjacent | High | Moderate |
Altered Signaling leads to Increased,Cardiac fibrosis | adjacent | Moderate | High |
Increased,Cardiac fibrosis leads to Heart failure | adjacent | High | High |
Network View
Prototypical Stressors
Life Stage Applicability
Life stage | Evidence |
---|---|
Conception to < Fetal | Moderate |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
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human, mouse, rat | human, mouse, rat | Moderate | NCBI |
Sex Applicability
Sex | Evidence |
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Mixed | High |
Overall Assessment of the AOP
The AOP linking chemical-induced LMNA mutations to HCM is supported by strong empirical and mechanistic evidence, particularly for upstream events (LMNA mutation and nuclear envelope instability). Confidence in downstream key events (altered signal transduction, hypertrophic remodeling) is moderate, with some gaps in quantitative understanding and human relevance. Despite these gaps, the overall evidence supports the biological plausibility and applicability of this AOP for research and regulatory purposes. For the AOP linking chemical-induced LMNA gene mutations to hypertrophic cardiomyopathy (HCM), the assessment focuses on the biological and empirical support for the pathway, its applicability across contexts, and confidence in its use for regulatory decision-making.
Domain of Applicability
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Species Applicability:
- Strong evidence supports applicability in humans and mammalian models (e.g., mice, rats).
- Cardiomyocytes from human-derived cell lines provide relevant in vitro systems for studying the pathway.
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Life Stage:
- The AOP is particularly relevant for adult organisms, as hypertrophic cardiomyopathy typically manifests later in life. However, developmental studies might explore early exposures
Essentiality of the Key Events
.Key Event 1: Chemical-Induced LMNA Mutation (Molecular Initiating Event, MIE)
Essentiality:
Mutations in the LMNA gene are the primary driver of nuclear envelope instability. Experimental studies have shown that targeted disruption of LMNA (via CRISPR-Cas9 or other methods) directly results in nuclear structural abnormalities.
Blocking LMNA mutations (e.g., via chemical inhibitors of mutagenesis or DNA repair mechanisms) prevents downstream effects, reinforcing the essentiality of this KE.
Evidence:
Genetic models with induced LMNA mutations exhibit cardiac remodeling and hypertrophy.
Pharmacological interventions targeting upstream genotoxic stress (e.g., antioxidants) mitigate mutation induction and subsequent adverse outcomes.
Key Event 2: Nuclear Envelope Instability
Essentiality:
Lamin A/C dysfunction caused by LMNA mutations leads to loss of nuclear envelope integrity. Experimental restoration of lamin A/C function (via gene therapy or protein supplementation) stabilizes nuclear structure and reduces cellular stress responses.
Prevention of nuclear envelope instability through protective interventions halts the progression to signal transduction defects and cardiac remodeling.
Evidence:
In vitro studies using cardiomyocytes with LMNA mutations show that nuclear stability restoration prevents apoptotic and stress responses.
Lamin A/C knockdown models demonstrate severe nuclear abnormalities and altered gene expression, which can be reversed by reintroducing functional lamin A/C.
Key Event 3: Altered Signal Transduction
Essentiality:
Disrupted signal transduction due to nuclear envelope instability affects the expression of cardiac-specific genes. Blocking or modulating key signaling pathways (e.g., MAPK, NF-κB) has been shown to prevent hypertrophic remodeling.
Pharmacological or genetic interventions targeting these pathways reduce the downstream impact on cardiomyocyte hypertrophy and fibrosis.
Evidence:
Signal transduction in LMNA-mutated models result in the normalization of gene expression profiles and reduced cardiac hypertrophy.
Key Event 4: Cardiac Hypertrophic Remodeling
Essentiality:
Hypertrophic remodeling represents the physiological precursor to hypertrophic cardiomyopathy (HCM). Experimental models show that interventions targeting early KEs reduce the extent of cardiac hypertrophy.
Direct inhibition of hypertrophic signaling pathways in cardiomyocytes prevents further progression to heart dysfunction.
Evidence:
Genetic models with suppressed hypertrophic responses (e.g., through silencing of hypertrophic genes) fail to progress to clinically significant HCM.
Cardiac remodeling inhibitors (e.g., angiotensin receptor blockers) demonstrate the ability to reverse or halt hypertrophic changes.
Key Event Relationships (KERs)
Each KE is causally linked to the next through well-established mechanistic pathways. The essentiality of the KERs is supported by:
LMNA Mutation → Nuclear Envelope Instability:
Strong evidence supports this relationship, including consistent findings across multiple experimental models.
Mechanistic studies confirm that LMNA mutations disrupt lamin A/C function, leading to nuclear instability.
Nuclear Envelope Instability → Altered Signal Transduction:
Well-supported by studies showing impaired mechanosensing and disrupted transcription factor regulation in cells with nuclear envelope defects.
Evidence is strong for specific pathways (e.g., MAPK, NF-κB).
Altered Signal Transduction → Hypertrophic Remodeling:
Moderate evidence supports this relationship, with signaling disruptions linked to pro-hypertrophic gene expression.
Direct evidence for causal relationships in human models remains limited.
Hypertrophic Remodeling → HCM:
Strong evidence from clinical studies confirms that hypertrophic remodeling is a precursor to HCM. Genetic and pharmacological models further support this link.
Evidence Assessment
Chemical Exposure and LMNA Mutations (MIE):
Evidence shows that certain genotoxic chemicals (e.g., alkylating agents, ROS inducers) induce LMNA mutations in vitro and in vivo. Mutations are particularly associated with oxidative stress and direct DNA damage.
- DNA Repair Capacity: The efficiency of DNA repair mechanisms (e.g., nucleotide excision repair, base excision repair) in cardiomyocytes determines the extent to which chemical-induced DNA damage leads to mutations.
- Oxidative Stress Susceptibility: High oxidative stress in cells with abundant mitochondria, such as cardiac myocytes, increases vulnerability to DNA damage and LMNA mutations.
- Proliferative vs. Non-Proliferative Cells: Non-dividing cells, like mature cardiomyocytes, rely on robust DNA repair systems, making any defects in repair pathways critical for mutation accumulation.
Studies using chemical mutagens demonstrate dose- and time-dependent increases in LMNA mutations in experimental models.
LMNA Mutations and Nuclear Envelope Instability:
LMNA mutations are consistently linked to nuclear structural abnormalities, including blebbing, chromatin disorganization, and altered nuclear shape in cellular models.
Knockout or knockdown models for LMNA exhibit the same nuclear envelope defects observed in chemical exposure studies.
- Mechanical Stress: Cardiomyocytes experience significant mechanical stress due to continuous contraction and relaxation cycles, exacerbating the consequences of LMNA mutations on nuclear envelope integrity.
- Nuclear-Cytoskeletal Connections: The interaction between the nuclear lamina and the cytoskeleton (via proteins like nesprin and SUN) affects nuclear envelope stability. Disruptions in these connections due to LMNA mutations amplify nuclear instability.
- Chromatin Organization: Lamin A/C interacts with chromatin to maintain nuclear structure. Mutations disrupt chromatin anchoring, exacerbating nuclear defects.
Nuclear Envelope Instability and Altered Signal Transduction:
Studies show that nuclear envelope disruption impairs mechanosensing and transcription factor regulation (e.g., MAPK, NF-κB pathways), leading to dysregulated cardiac gene expression.
- Mechanosensitive Pathways: Cardiomyocytes rely on mechanotransduction pathways to sense and respond to mechanical stimuli. Nuclear envelope instability caused by LMNA dysfunction disrupts these pathways, altering signal transduction.
- Transcription Factor Dysregulation: Lamin A/C interacts with transcription factors such as p53, NF-κB, and MAPK regulators. Nuclear instability affects their localization and activity, disrupting downstream signaling.
- Calcium Signaling: LMNA mutations can indirectly impair calcium signaling in cardiomyocytes, further contributing to signaling disruptions critical for cardiac function.
Altered Signal Transduction and Hypertrophic Remodeling:
Dysregulated signaling is strongly correlated with upregulation of pro-hypertrophic genes, which drive structural and functional remodeling of the heart in experimental models.
Reversal of these signaling disruptions (e.g., via pharmacological inhibition) prevents hypertrophic changes.
Hypertrophic Remodeling and HCM:
Extensive clinical and preclinical data and cardiac Organoid confirm that hypertrophic remodeling progresses to HCM, with fibrosis, inflammation, and compromised cardiac function as hallmark features.
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Pro-Hypertrophic Gene Expression:
- Dysregulated signaling leads to the upregulation of genes involved in hypertrophy, such as:
- ANP/BNP (Natriuretic Peptides): Markers of cardiac stress.
- Myosin Heavy Chain Beta (β-MHC): Associated with pathological hypertrophy.
- Dysregulated signaling leads to the upregulation of genes involved in hypertrophy, such as:
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Fibrotic Pathways:
- Altered signaling increases the expression of pro-fibrotic factors such as TGF-β, promoting extracellular matrix remodeling and fibrosis.
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ROS and Oxidative Stress:
- Persistent oxidative stress from dysfunctional mitochondria and disrupted signaling amplifies cardiac remodeling and fibrosis
Known Modulating Factors
Modulating Factor (MF) | Influence or Outcome | KER(s) involved |
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Polymorphisms in LMNA: Variations in the LMNA gene may predispose individuals to higher sensitivity to chemical-induced mutations. Chemical-Specific Properties: Genotoxic Potency: Chemicals with high mutagenic or oxidative stress potential (e.g., alkylating agents, ROS inducers) are more likely to trigger the molecular initiating event (MIE). Bioavailability and Metabolism: The extent to which a chemical is absorbed, distributed, metabolized, and excreted affects its ability to induce LMNA mutations. Biological Factors: Age: Older individuals may be more susceptible due to accumulated DNA damage and reduced repair efficiency. Sex: Hormonal differences may modulate cardiac remodeling, potentially affecting the severity of hypertrophy. Cell Type and Tissue Sensitivity: Cardiac myocytes have high mechanical demands and are particularly vulnerable to nuclear envelope instability caused by LMNA dysfunction. Environmental Factors: Oxidative Stress: Environmental exposures to ROS-generating agents (e.g., air pollutants, radiation, oxidants) can synergize with genotoxic chemicals to amplify LMNA mutations. Lifestyle Factors: Diet, smoking, and other behaviors that influence oxidative stress and DNA repair capacity can modulate pathway progression. |
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Quantitative Understanding
Dose-Response Relationships:
Empirical data demonstrate dose-response relationships for key upstream events, such as chemical exposure leading to LMNA mutations and subsequent nuclear envelope instability. Quantitative relationships between altered signaling and cardiac hypertrophy are less well-defined and may require further experimental validation.
Molecular Initiating Event (MIE): Chemical-Induced LMNA Mutation
DNA Damage Mechanisms:
Oxidative DNA Damage: Reactive oxygen species (ROS) generated by chemical exposure cause oxidative lesions in the DNA, including single- and double-strand breaks, which can lead to mutations in the LMNA gene.
Adduct Formation: Chemicals like alkylating agents form covalent adducts with DNA bases, increasing the likelihood of mutagenesis in the LMNA locus.
Mismatch Repair Defects: Mutations in mismatch repair enzymes exacerbate errors during replication, promoting mutations in critical regions of the LMNA gene.
Epigenetic Modifications:
DNA Methylation: Aberrant methylation patterns at LMNA promoter regions can suppress or dysregulate lamin A/C expression.
Histone Modifications: Changes in histone acetylation or methylation can alter chromatin structure near the LMNA locus, influencing its susceptibility to damage and transcriptional regulation.
Temporal Concordance:
Studies consistently show that upstream events (e.g., LMNA mutations, nuclear envelope disruption) occur before downstream effects (e.g., altered signaling, hypertrophic remodeling).
The time required for each step in the pathway is supported by experimental evidence, particularly in cardiac organoid models.
Considerations for Potential Applications of the AOP (optional)
The Adverse Outcome Pathway (AOP) for chemical-induced LMNA gene mutation leading to hypertrophic cardiomyopathy (HCM) has significant applications in regulatory toxicology and risk assessment. In regulatory toxicology, the AOP provides a framework for screening chemicals with the potential to induce LMNA mutations and subsequent adverse effects, facilitating prioritization for further testing or regulatory focus. High-throughput platforms such as ToxCast and Tox21 can be employed to evaluate the likelihood of triggering molecular initiating events (MIEs) or key events (KEs). This AOP also aids in hazard identification by establishing a mechanistic link between chemical exposures and cardiac risks, particularly for genotoxic agents affecting the cardiovascular system. Additionally, it supports read-across approaches, leveraging data from chemicals with known LMNA-related effects to predict outcomes for structurally similar compounds.
In risk assessment, the AOP enables quantitative risk evaluations by incorporating dose-response data for key event relationships (KERs), supporting the development of predictive models to estimate adverse outcomes under various exposure conditions. Furthermore, the framework facilitates cumulative risk assessment by accounting for the combined effects of multiple genotoxic agents that contribute to LMNA mutations and HCM. This integrative approach enhances chemical risk management and underscores the utility of the AOP for regualtory purpose.
References
- Lamin A/C deficiency-mediated ROS elevation contributes to pathogenic phenotypes of dilated cardiomyopathy in iPSC model Nature Communications | (2024) 15:7000
- Epigenetics in LMNA-Related Cardiomyopathy Cells 2023, 12(5), 783
- When lamins go bad: Nuclear structure and disease. Cell 2013, 152, 1365–1375.
- The nuclear lamins: Flexibility in function. Nat. Rev. Mol. Cell Biol. 2013, 14, 13–24.
- Mutations in the Lamin A/C gene mimic arrhythmogenic right ventricular cardiomyopathy. Eur. Heart J. 2012, 33, 1128–1136
- Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N. Engl. J. Med. 1999, 341, 1715–1724.
- Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy. Eur. J. Hum. Genet. 2013, 21, 1105–1111
- Modeling treatment response for lamin A/C related dilated cardiomyopathy in human induced pluripotent stem cells. J. Am. Heart Assoc. 2017, 6, e005677
- Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy. Nature 2019, 572, 335–340.
- Expanding the phenotype of LMNA mutations in dilated cardiomyopathy and functional consequences of these mutations. J. Med. Genet. 2003, 40, 560–567.
- Pathogenic LMNA variants disrupt cardiac lamina-chromatin interactions and de-repress alternative fate genes. Cell Stem Cell 2021, 28, 938–954.e939
- Phenotypic Variability in iPSC-Induced Cardiomyocytes and Cardiac Fibroblasts Carrying Diverse LMNA Mutations. Front. Physiol. 2021, 12, 2162.
- The LMNA p. R541C mutation causes dilated cardiomyopathy in human and mice. Int. J. Cardiol. 2022, 363, 149–158
- Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C–deficient mice. J. Clin. Investig. 2004, 113, 357–369.
- The significant arrhythmia and cardiomyopathy burden of lamin A/C mutations. J. Am. Coll. Cardiol. 68, 2308–2310 (2016).
- From gene to mechanics: a comprehensive insight into the mechanobiology of LMNA mutations in cardiomyopathy Cell Communication and Signaling volume 22, Article number: 197 2024
- N-acetyl cysteine alleviates oxidative stress and protects mice from dilated cardiomyopathy caused by mutations in nuclear A-type lamins gene Human Molecular Genetics, Volume 27, Issue 19, 1 October 2018, Pages 3353–3360.
- Epigenetics in LMNA-Related Cardiomyopathy Cells 2023, 12(5), 783