Conditional gene targeting of an X-linked activator of cytochrome c: modelling of an infantile cardiomyopathy.

心律不齐是导致婴儿猝死和意外死亡的重要原因。在过去的几年里，发现这种异常背后的基因异常的数量急剧增加。特别是，这些异常(称为线粒体疾病)中有相当大一部分被证明是由于线粒体DNA的缺陷或缺陷造成的，线粒体DNA编码了产生细胞能量储存所必需的一些成分。相比之下，令人惊讶的是，这种类型的疾病被证明是由于细胞核DNA的缺陷所致的例子少之又少，尽管它编码了许多成分。我们有强有力的遗传和生化证据表明，一种新的基因(由核DNA编码)是性连锁疾病-嗜酸性心肌病的基础，其主要临床特征是突然和不规则的心率，通常会导致两岁前的女婴死亡。我们将利用一种新的强大的基因技术在实验室小鼠身上复制这种疾病，以便彻底调查疾病是如何表现出来的。希望这一疾病模型能为我们理解其他伴有突发性心律失常的疾病提供有价值的线索。它还可能进一步支持类似的核编码缺陷导致婴儿猝死的流行和/或易感性的可能性。所采取的新方法还将首次直接调查控制女性疾病表现的严重程度的机制。这些研究还将补充我们实验室正在进行的其他生化研究，并可能对许多其他X连锁遗传疾病的临床表现产生影响。

Irregularities in heart rhythms are a significant cause of sudden and unexpected death in infants. The past few years has seen a dramatic increase in the identification of genetic abnormalities underlying such irregularities. In particular, a significant proportion of these abnormalities (known as mitochondriopathies) have been shown to be due to deficiencies or defects in the mitochondrial DNA, which encodes some of the components necessary for the generation of cellular energy stores. In contrast, surprisingly few examples exist where this type of disorder has been shown to be due to a defect in the DNA from the nucleus, despite the numerous components it encodes. We have strong genetic and biochemical evidence to suggest that a new gene (encoded by the nuclear DNA) underlies the sex-linked disorder, oncocytic cardiomyopathy, the major clinical features of which are sudden and irregular heart rhythms usually causing death in female infants before the age of two years. We will utilise a new and powerful genetic technique to reproduce the disorder in laboratory mice to enable a thorough investigation into how the disease manifests itself. It is hoped that this disease model will provide valuable clues towards our understanding of other disorders with sudden heart rhythm abnormalities. It may also give additional support to the likelihood that similar nuclear-encoded defects contribute to the prevalence of, and-or susceptibility to, sudden infant mortality. The novel approach taken will also, for the first time, directly investigate the mechanisms that govern the severity of presentation of the disease in females. These studies will also complement other biochemical studies that are ongoing in our laboratory and will likely have implications for the clinical presentation of numerous other X-linked genetic disorders.