Cardiac defects contribute to the pathology of spinal muscular atrophy models
Cardiac defects contribute to the pathology of spinal muscular atrophy models
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DOI：
10.1093/hmg/ddq329
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发表时间：
2010-10-15
影响因子：
3.5
通讯作者：
Lorson, Christian L.
中科院分区：
文献类型：
--
作者：
Shababi, Monir;Habibi, Javad;Lorson, Christian L.
脊髓性肌萎缩症（SMA）是一种常染色体隐性遗传疾病，是导致婴儿死亡的主要遗传原因。SMA是最常见的遗传性运动神经元疾病，发生率约为1：6000。SMA的基因被称为运动神经元生存基因1（SMN1）。有趣的是，一个人类特异性拷贝基因存在于染色体5q的同一区域，称为SMN2。运动神经元是SMA中受影响的主要组织。虽然SMA是一种神经退行性疾病，但有临床报告表明其他组织对总体表型有贡献，尤其是在最严重的疾病形式中。在重度SMA病例中，尸检发现越来越多的先天性心脏缺陷。最常见的缺陷是发育缺陷，称为发育不良的左心。本报告的目的是确定SMA模型中的心脏组织是否发生改变，以及这是否有助于SMA发病机制。在这里，我们确定了早期发育缺陷的严重模型SMA。此外，在不太严重的疾病模型中，出生后不久就观察到了包括纤维化和氧化应激标志物在内的病理反应。同样，在野生型和早期SMA动物之间检测到功能差异。总的来说，这项工作证明了心脏发育和功能在这些严重的SMA模型中的重要性。
Spinal muscular atrophy (SMA) is an autosomal recessive disorder, which is the leading genetic cause of infantile death. SMA is the most common inherited motor neuron disease and occurs in approximately 1:6000 live births. The gene responsible for SMA is called Survival Motor Neuron-1 (SMN1). Interestingly, a human-specific copy gene is present on the same region of chromosome 5q, called SMN2. Motor neurons are the primary tissue affected in SMA. Although it is clear that SMA is a neurodegenerative disease, there are clinical reports that suggest that other tissues contribute to the overall phenotype, especially in the most severe forms of the disease. In severe SMA cases, a growing number of congenital heart defects have been identified upon autopsy. The most common defect is a developmental defect referred to as hypoplastic left heart. The purpose of this report is to determine whether cardiac tissue is altered in SMA models and whether this could contribute to SMA pathogenesis. Here we identified early-stage developmental defects in a severe model of SMA. Additionally, pathological responses including fibrosis and oxidative stress markers were observed shortly after birth in a less severe model of disease. Similarly, functional differences were detected between wild-type and early-stage SMA animals. Collectively, this work demonstrates the importance of cardiac development and function in these severe models of SMA.