Ablation of the Cardiac-Specific Gene Leucine-Rich Repeat Containing 10 (<em>Lrrc10</em>) Results in Dilated Cardiomyopathy

Leucine-rich repeat containing 10 (LRRC10) is a cardiac-specific protein exclusively expressed in embryonic and adult cardiomyocytes. However, the role of LRRC10 in mammalian cardiac physiology remains unknown. To determine if LRRC10 is critical for cardiac function, Lrrc10-null (Lrrc10−/−) mice were analyzed. Lrrc10−/− mice exhibit prenatal systolic dysfunction and dilated cardiomyopathy in postnatal life. Importantly, Lrrc10−/− mice have diminished cardiac performance in utero, prior to ventricular dilation observed in young adults. We demonstrate that LRRC10 endogenously interacts with α-actinin and α-actin in the heart and all actin isoforms in vitro. Gene expression profiling of embryonic Lrrc10−/− hearts identified pathways and transcripts involved in regulation of the actin cytoskeleton to be significantly upregulated, implicating dysregulation of the actin cytoskeleton as an early defective molecular signal in the absence of LRRC10. In contrast, microarray analyses of adult Lrrc10−/− hearts identified upregulation of oxidative phosphorylation and cardiac muscle contraction pathways during the progression of dilated cardiomyopathy. Analyses of hypertrophic signal transduction pathways indicate increased active forms of Akt and PKCε in adult Lrrc10−/− hearts. Taken together, our data demonstrate that LRRC10 is essential for proper mammalian cardiac function. We identify Lrrc10 as a novel dilated cardiomyopathy candidate gene and the Lrrc10−/− mouse model as a unique system to investigate pediatric cardiomyopathy.富含亮氨酸重复序列蛋白10（Leucine-rich repeat containing 10, LRRC10）是一种心脏特异性蛋白，仅在胚胎期和成年期的心肌细胞中表达。然而，LRRC10在哺乳动物心脏生理过程中的作用仍未明确。为探究LRRC10是否对心脏功能至关重要，本研究对LRRC10基因敲除（Lrrc10−/−）小鼠进行了分析。Lrrc10−/−小鼠在出生后表现出产前收缩功能障碍与扩张型心肌病。值得注意的是，在年轻成年小鼠出现心室扩张之前，Lrrc10−/−小鼠的子宫内心脏功能已出现受损。本研究证实，LRRC10在心脏内可与α-辅肌动蛋白（α-actinin）和α-肌动蛋白（α-actin）发生内源性相互作用，并在体外与所有肌动蛋白同工型结合。对胚胎期Lrrc10−/−小鼠心脏的基因表达谱分析显示，参与调控肌动蛋白细胞骨架的通路与转录本显著上调，这表明在缺乏LRRC10的情况下，肌动蛋白细胞骨架失调是早期缺陷分子信号。与之相反，对成年Lrrc10−/−小鼠心脏的微阵列分析显示，在扩张型心肌病进展过程中，氧化磷酸化与心肌收缩通路出现上调。对肥厚信号转导通路的分析表明，成年Lrrc10−/−小鼠心脏中Akt与PKCε的活化形式水平升高。综上，本研究数据证实LRRC10对维持正常的哺乳动物心脏功能至关重要。本研究确定Lrrc10为新型扩张型心肌病候选基因，并将Lrrc10−/−小鼠模型作为研究儿童心肌病的独特实验体系。