PDF(Pubmed)
Abstract：
Williams-Beuren syndrome (WBS) is a rare neurodevelopmental disorder that, together with a rather characteristic neurocognitive profile, presents a strong cardiovascular phenotype. The cardiovascular features of WBS are mainly related to a gene dosage effect due to hemizygosity of the elastin (ELN) gene; however, the phenotypic variability between WBS patients indicates the presence of important modulators of the clinical impact of elastin deficiency. Recently, two genes within the WBS region have been linked to mitochondrial dysfunction. Numerous cardiovascular diseases are related to mitochondrial dysfunction; therefore, it could be a modulator of the phenotype present in WBS. Here, we analyze mitochondrial function and dynamics in cardiac tissue from a WBS complete deletion (CD) model. Our research reveals that cardiac fiber mitochondria from CD animals have altered mitochondrial dynamics, accompanied by respiratory chain dysfunction with decreased ATP production, reproducing alterations observed in fibroblasts from WBS patients. Our results highlight two major factors: on the one hand, that mitochondrial dysfunction is probably a relevant mechanism underlying several risk factors associated with WBS disease; on the other, the CD murine model mimics the mitochondrial phenotype of WBS and could be a great model for carrying out preclinical tests on drugs targeting the mitochondria.
摘要：
Williams-Beuren综合征(WBS)是一种罕见的神经发育障碍,加上相当独特的神经认知特征，表现出强烈的心血管表型。由于弹性蛋白（ELN）基因的半合子，WBS的心血管特征主要与基因剂量效应有关；然而，WBS患者之间的表型差异表明存在弹性蛋白缺乏的临床影响的重要调节剂。最近,WBS区域内的两个基因与线粒体功能障碍有关。许多心血管疾病与线粒体功能障碍有关；因此，它可能是WBS中存在的表型的调节剂。这里,我们从WBS完全缺失(CD)模型分析了心肌组织中的线粒体功能和动力学.我们的研究表明，来自CD动物的心脏纤维线粒体改变了线粒体动力学，伴有呼吸链功能障碍，ATP产生减少，在WBS患者的成纤维细胞中观察到的复制改变。我们的结果突出了两个主要因素：一方面，线粒体功能障碍可能是与WBS疾病相关的几个危险因素的相关机制；另一方面，CD鼠模型模拟WBS的线粒体表型,可作为针对线粒体的药物进行临床前试验的良好模型.
