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Lamin and the heart
Gabriella Captur1,2,3, Eloisa Arbustini4, Gisèle Bonne5
1UCL Biological Mass Spectrometry Laboratory, Institute of Child Health and Great Ormond Street Hospital, London, UK.
Insights
Mutations in the LMNA gene cause severe heart disease, a form of dilated cardiomyopathy (DCM). Early recognition and integrated genetic, functional, and pathological data are key for managing this under-recognized condition.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Nuclear Envelope Biology
Background:
- Mutations in the LMNA gene, encoding lamins A and C, are a significant cause of inherited dilated cardiomyopathy (DCM), accounting for 10% of cases.
- Lamin A/C heart disease presents with progressive conduction system disease, arrhythmia, and systolic impairment, often with a more severe clinical course than other DCM types.
- This condition is potentially under-recognized due to phenotypic mimics, despite a high probability of LMNA mutations in familial DCM with early conduction disease.
Purpose of the Study:
- To review the biology, clinical presentation, screening, and management of lamin A/C heart disease.
- To highlight the importance of recognizing LMNA-related cardiomyopathy for early intervention with devices and novel therapies.
- To discuss the integration of genetic, functional, and pathological data in advancing the understanding of LMNA variants.
Main Methods:
- Review of current literature on LMNA gene mutations and associated cardiomyopathies.
- Analysis of clinical presentations, diagnostic pointers, and imaging features.
- Discussion of genotype-phenotype correlations and emerging therapeutic strategies.
Main Results:
- LMNA mutations lead to a distinct and aggressive form of DCM requiring early intervention.
- Integrated approaches combining genetic, in vivo cardiomyocyte mechanics, and nuclear envelope pathology are crucial for understanding LMNA variants.
- Research into MAPK pathways suggests promising oral drug therapies and personalized treatment approaches.
Conclusions:
- Early identification of lamin A/C heart disease is critical for timely implantation of cardioverter defibrillators.
- Personalized risk stratification and heart failure therapy are becoming feasible for LMNA-related cardiomyopathies.
- Continued research integrating diverse data types is essential for advancing knowledge and improving patient outcomes.
Abstract:
Lamins A and C are intermediate filament nuclear envelope proteins encoded by the LMNA gene. Mutations in LMNA cause autosomal dominant severe heart disease, accounting for 10% of dilated cardiomyopathy (DCM). Characterised by progressive conduction system disease, arrhythmia and systolic impairment, lamin A/C heart disease is more malignant than other common DCMs due to high event rates even when the left ventricular impairment is mild. It has several phenotypic mimics, but overall it is likely to be an under-recognised cause of DCM. In certain clinical scenarios, particularly familial DCM with early conduction disease, the pretest probability of finding an LMNA mutation may be quite high.Recognising lamin A/C heart disease is important because implantable cardioverter defibrillators need to be implanted early. Promising oral drug therapies are within reach thanks to research into the mitogen-activated protein kinase (MAPK) and affiliated pathways. Personalised heart failure therapy may soon become feasible for LMNA, alongside personalised risk stratification, as variant-related differences in phenotype severity and clinical course are being steadily elucidated.Genotyping and family screening are clinically important both to confirm and to exclude LMNA mutations, but it is the three-pronged integration of such genetic information with functional data from in vivo cardiomyocyte mechanics, and pathological data from microscopy of the nuclear envelope, that is properly reshaping our LMNA knowledge base, one variant at a time. This review explains the biology of lamin A/C heart disease (genetics, structure and function of lamins), clinical presentation (diagnostic pointers, electrocardiographic and imaging features), aspects of screening and management, including current uncertainties, and future directions.
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