The LMNA p.R541C mutation causes dilated cardiomyopathy in human and mice
Summary
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. Copyright © 2022 Elsevier B.V. All rights reserved.
| Authors | Yang L, Sun J, Chen Z, Liu L, Sun Y, Lin J, Hu X, Zhao M, Ma Y, Lu D, Li Y, Guo Y, Dong E |
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| Journal | International journal of cardiology |
| Publication Date | 2022 Sep 15;363:149-158 |
| PubMed | 35714719 |
| DOI | 10.1016/j.ijcard.2022.06.038 |