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The LMNA p.R541C mutation causes dilated cardiomyopathy in human and mice
Luzi Yang1, Jinhuan Sun1, Zhan Chen1
1Peking University Health Science Center, School of Basic Medical Sciences, The Institute of Cardiovascular Sciences, Key Laboratory of Molecular Cardiovascular Science of Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China.
Insights
A specific LMNA gene variant causes dilated cardiomyopathy (DCM) by disrupting mitochondrial function and altering gene expression, leading to heart failure. This study utilized a novel mouse model to investigate the variant's impact.
Area of Science:
- Cardiovascular Biology
- Molecular Genetics
- Epigenetics
Background:
- Dilated cardiomyopathy (DCM) is a primary cause of heart failure, significantly impacting cardiac function.
- Mutations in the LMNA gene are implicated in 6-10% of DCM cases, yet the precise pathogenic mechanisms are not fully elucidated.
Purpose of the Study:
- To investigate the role of the specific LMNA c.1621C > T / p.R541C variant in the pathogenesis of dilated cardiomyopathy.
- To elucidate the molecular mechanisms by which this LMNA variant contributes to cardiac dysfunction.
Main Methods:
- Generation and analysis of a knock-in mouse model (LmnaRC) harboring the human LMNA variant.
- Assessment of cardiac structure and function in LmnaRC/RC mice.
- Transcriptomic and microscopic analyses of cardiomyocytes and mitochondria.
- Evaluation of epigenetic modifications, including heterochromatin and H3K9me2/3 markers.
Main Results:
- LmnaRC/RC mice displayed ventricular dilation and impaired systolic function by 6 months of age.
- Cardiomyocytes showed hypertrophy without nuclear morphological abnormalities.
- Transcriptomic and ultrastructural analyses revealed suppressed gene expression and mitochondrial dysfunction in LmnaRC/RC hearts.
- Increased heterochromatin formation and elevated H3K9me2/3 epigenetic markers were observed.
Conclusions:
- The LMNA c.1621C > T / p.R541C variant promotes DCM by enhancing heterochromatic gene silencing.
- Disruption of mitochondrial function and epigenetic dysregulation are key mechanisms linking this LMNA variant to DCM pathogenesis.
Abstract:
Dilated cardiomyopathy (DCM) is a major cause of heart failure. LMNA variants contribute to 6-10% DCM cases, but the underlying mechanisms remain incompletely understood. Here, we reported two patients carrying the LMNA c.1621C > T/ p.R541C variant and generated a knock-in mouse model (LmnaRC) to study the role of this variant in DCM pathogenesis. We found LmnaRC/RC mice exhibited ventricular dilation and reduced systolic functions at 6 months after birth. The LmnaRC/RC cardiomyocytes increased in size but no nuclear morphology defects were detected. Transcriptomic and microscopic analyses revealed suppressed gene expression and perturbed ultrastructure in LmnaRC/RC mitochondria. These defects were associated with increased heterochromatin structures and epigenetic markers including H3K9me2/3. Together, these data implied that the LMNA c.1621C > T/ p.R541C variant enhanced heterochromatic gene suppression and disrupted mitochondria functions as a cause of DCM.
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