Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Department of Cellular and Molecular Medicine and Sarver Molecular Cardiovascular Research Program, The University of Arizona, Tucson, AZ 85721, USA.
Cells. 2023 May 23;12(11):1455. doi: 10.3390/cells12111455.
As an essential component of the sarcomere, actin thin filament stems from the Z-disk extend toward the middle of the sarcomere and overlaps with myosin thick filaments. Elongation of the cardiac thin filament is essential for normal sarcomere maturation and heart function. This process is regulated by the actin-binding proteins Leiomodins (LMODs), among which has recently been identified as a key regulator of thin filament elongation to reach a mature length. Few reports have implicated homozygous loss of function variants of in neonatal dilated cardiomyopathy (DCM) associated with thin filament shortening. We present the fifth case of DCM due to biallelic variants in the gene and the second case with the c.1193G>A (p.W398*) nonsense variant identified by whole-exome sequencing. The proband is a 4-month male infant of Hispanic descent with advanced heart failure. Consistent with previous reports, a myocardial biopsy exhibited remarkably short thin filaments. However, compared to other cases of identical or similar biallelic variants, the patient presented here has an unusually late onset of cardiomyopathy during infancy. Herein, we present the phenotypic and histological features of this variant, confirm the pathogenic impact on protein expression and sarcomere structure, and discuss the current knowledge of -related cardiomyopathy.
作为肌节的重要组成部分，肌动蛋白细肌丝源于 Z 盘，向肌节中部延伸，并与肌球蛋白粗肌丝重叠。心肌细肌丝的伸长对于正常肌节成熟和心脏功能至关重要。这个过程受到肌动蛋白结合蛋白雷莫丁（LMODs）的调节，其中 最近被确定为细肌丝伸长以达到成熟长度的关键调节因子。少数报道表明，与细肌丝缩短相关的新生儿扩张型心肌病（DCM）与 基因的纯合失能变异有关。我们报告了第五例由于 基因中双等位基因变异引起的 DCM，这是第二个通过全外显子组测序发现的 c.1193G>A（p.W398*）无义变异病例。该先证者是一名 4 月龄的西班牙裔男性婴儿，患有晚期心力衰竭。与之前的报告一致，心肌活检显示出明显缩短的细肌丝。然而，与其他具有相同或类似双等位基因变异的病例相比，本例患者在婴儿期出现了异常晚发性心肌病。在此，我们介绍了该变异的表型和组织学特征，证实了其对蛋白表达和肌节结构的致病影响，并讨论了与 -相关心肌病的现有知识。
