Constitutive knockout of Surf1 is associated with high embryonic lethality, mitochondrial disease and cytochrome c oxidase deficiency in mice
Constitutive knockout of Surf1 is associated with high embryonic lethality, mitochondrial disease and cytochrome c oxidase deficiency in mice
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DOI：
10.1093/hmg/ddg038
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发表时间：
2003-02-15
影响因子：
3.5
通讯作者：
Zeviani, M
中科院分区：
文献类型：
--
作者：
Agostino, A;Invernizzi, F;Zeviani, M
我们在这里报告创建一个组成性敲除小鼠SURF 1，一个基因编码的组装蛋白参与细胞色素c氧化酶（考克斯）的形成。SURF 1的功能缺失突变导致Leigh综合征，与人类孤立和广泛的考克斯缺乏症相关。小鼠表型的特征是：（1）高植入后胚胎致死率，影响到90%的Surf 1（-/-）个体;（2）出生后个体的早发性死亡率;（3）肌肉力量和运动能力的高度显著缺陷;（4）骨骼肌和肝脏中考克斯活性的严重和孤立缺陷，以及在较小程度上心脏和大脑中的缺陷;（5）骨骼肌形态学异常，表现为考克斯组织化学反应减弱和线粒体增生;（6）脑形态无明显异常，反映神经系统症状基本消失。这些结果表明，鼠Surf 1蛋白（Surf 1 p）的功能与考克斯特异性相关，并至少部分地概括了人类表型。这是：第一个哺乳动物模型的核疾病基因的人类线粒体疾病。我们的模型构成了一个有用的工具，调查的功能，Surf 1 p，帮助了解的发病机制Surf 1 p缺乏症在体内，并评估治疗的疗效。
We report here the creation of a constitutive knockout mouse for SURF1, a gene encoding one of the assembly proteins involved in the formation of cytochrome c oxidase (COX). Loss-of-function mutations of SURF1 cause Leigh syndrome associated with an isolated and generalized COX deficiency in humans. The murine phenotype is characterized by the following hallmarks: (1) high post-implantation embryonic lethality, affecting similar to90% of the Surf1(-/-) individuals; (2) early-onset mortality of post-natal individuals; (3) highly significant deficit in muscle strength and motor performance; (4) profound and isolated defect of COX activity in skeletal muscle and liver, and, to a lesser extent, heart and brain; (5) morphological abnormalities of skeletal muscle, characterized by reduced histochemical reaction to COX and mitochondrial proliferation; (6) no obvious abnormalities in brain morphology, reflecting the virtual absence of overt neurological symptoms. These results indicate a function for murine Surf1 protein (Surf1p) specifically related to COX and recapitulate, at least in part, the human phenotype. This is:the first mammalian model for a nuclear disease gene of a human mitochondrial disorder. Our model constitutes a useful tool to investigate the function of Surf1p, help understand the pathogenesis of Surf1p deficiency in vivo, and evaluate the efficacy of treatment.