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AOP: 550

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE.  More help

Increased LMNA gene mutation leading to heart failure

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
LMNA gene mutation
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v2.7

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Sun-Woong Kanga, Myeong Hwa Song,Do-Sun Lim b and Kim Young Jun

aCenter for Biomimetic Research, Korea Institute of Toxicology, Daejeon 34114, Korea

bCardiovascular Center, Department of Cardiology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, South Korea

cEnvironemental Safety Group, KIST Europe, campus E 71 Saarbruecken, Germany 

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Young Jun Kim   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Young Jun Kim

Coaches

This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help

OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on December 03, 2024 09:32

Revision dates for related pages

Page Revision Date/Time
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

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

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

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

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

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

1. Identification of Relevant Data

  • 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.
  • 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.
  • 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

  • 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.
  • 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.
  • 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

  • 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.
  • Experimental Quality:

    • Critically evaluate study design (e.g., controls, replicates, use of human-relevant models) to ensure robust and reliable evidence.
  • 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

  • Causal Network Mapping:

    • Develop a causal map linking chemical exposure to LMNA mutations, subsequent nuclear envelope instability, impaired cardiac signaling, and hypertrophic remodeling.
  • Confidence Assessment:

    • Use confidence scoring (e.g., OECD guidelines) to evaluate the strength of each KE and KER, noting any uncertainties.
  • Documentation:

    • Maintain detailed records of evidence, including data sources, relevance assessments, and quality evaluations, to support transparency and reproducibility.

Summary of the AOP

This section is for information that describes the overall AOP.The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
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)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
Conception to < Fetal Moderate

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
human, mouse, rat human, mouse, rat Moderate NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Mixed High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

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

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help
  • 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.
  • Life Stage:

  1. 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

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

.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

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

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.

  • 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.
  • Fibrotic Pathways:

    • Altered signaling increases the expression of pro-fibrotic factors such as TGF-β, promoting extracellular matrix remodeling and fibrosis.
  • ROS and Oxidative Stress:

    • Persistent oxidative stress from dysfunctional mitochondria and disrupted signaling amplifies cardiac remodeling and fibrosis

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help
Modulating Factor (MF) Influence or Outcome KER(s) involved

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.

  • Severity of Cardiac Hypertrophy:

    • Factors such as age, sex, and comorbidities (e.g., hypertension, diabetes) can exacerbate cardiac remodeling, leading to more severe hypertrophic changes.
  • Rate of Disease Progression:

    • Modulating factors like repeated or chronic chemical exposures can accelerate the progression from early KEs (e.g., LMNA mutation) to late KEs (e.g., hypertrophic remodeling).
  • Threshold for Adverse Outcome:

    • The presence of protective factors (e.g., antioxidants, robust DNA repair mechanisms) can increase the threshold required for the adverse outcome, reducing the likelihood of HCM.
  • Molecular Initiating Event (LMNA Mutation):

    • Genotoxicity modulators, such as antioxidants or DNA repair enhancers, can mitigate the occurrence of LMNA mutations. Conversely, factors like high ROS levels or impaired repair systems increase susceptibility.
  • Nuclear Envelope Instability:

    • Mechanical stress and cell cycle activity in cardiac myocytes can amplify the effects of LMNA dysfunction, worsening nuclear envelope defects.
    • Stabilizing agents (e.g., compounds enhancing lamin A/C function) may attenuate nuclear instability.
  • Altered Signal Transduction:

    • Modulating pathways such as MAPK, NF-κB, or mechanotransduction signals can either amplify or dampen downstream signaling disruptions. Pharmacological inhibitors of pro-hypertrophic pathways (e.g., kinase inhibitors) may reduce the impact of this KE.
  • Hypertrophic Remodeling:

    • Factors influencing cardiac remodeling, such as physical activity, hypertension, or fibrosis-promoting conditions, can modulate the extent and pattern of hypertrophy. Anti-hypertrophic drugs may mitigate this effect.

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

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)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

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

List of the literature that was cited for this AOP. More help
  • 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