Gene disruption of Mfsd8 in mice provides the first animal model for CLN7 disease
Gene disruption of Mfsd8 in mice provides the first animal model for CLN7 disease
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DOI：
10.1016/j.nbd.2014.01.003
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发表时间：
2014-05-01
影响因子：
6.1
通讯作者：
Storch, Stephan
中科院分区：
文献类型：
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作者：
Damme, Markus;Brandenstein, Laura;Storch, Stephan
编码溶酶体CLN 7膜蛋白的主要易化剂超家族结构域8（MFSD 8）基因的突变导致CLN 7病，一种儿童期溶酶体贮积病。CLN 7疾病属于一组遗传性疾病，称为神经元蜡样脂褐质病（NCL），其特征在于自发荧光蜡样脂色素的积累、神经炎症、光感受器和神经变性。我们通过在小鼠外显子1和2之间插入lacZ基因陷阱盒破坏了Mfsd 8基因，并分析了Cln 7耗竭对神经元和内脏组织的影响。在杂合子Mfsd 8（（wt/tm 1a））小鼠中lacZ报告基因活性的分析显示在大脑皮层、海马和肾脏中强烈的Mfsd 8 mRNA表达。纯合子Mfsd 8（（tm 1a/tm 1a））小鼠是可行的和可生育的，并且在生物化学上类似于人类CLN 7患者的NCL表型，包括脑和外周组织中自发荧光物质的积累以及小脑和不同脑区域的细胞核中线粒体ATP合酶c亚基的积累，以及视网膜中感光细胞的变性。在突变小鼠的延髓、海马和小脑浦肯野细胞的大神经元中发现溶酶体储存。超微结构显示小脑和海马神经元内有致密的板层体，形状不规则。在10个月龄时，Cln 7的脑损失分别伴有轻度反应性小胶质细胞增生和轻微星形胶质细胞增生。总之，我们已经产生了一种小鼠模型，其部分有价值，因为人类CLN 7疾病的一些但不是所有神经病理学特征被概括，因此代表了研究CLN 7特异性疾病机制的动物模型。(C)2014爱思唯尔公司All rights reserved.
Mutations in the major facilitator superfamily domain containing 8 (MFSD8) gene coding for the lysosomal CLN7 membrane protein result in CLN7 disease, a lysosomal storage disease of childhood. CLN7 disease belongs to a group of inherited disorders, called neuronal ceroid lipofuscinoses (NCL), which are characterized by the accumulation of autofluorescent ceroid lipopigments, neuroinflammation, photoreceptor- and neurodegeneration. We have disrupted the Mfsd8 gene by insertion of a lacZ gene-trap cassette between exons 1 and 2 in mice and have analyzed the impact of Cln7 depletion on neuronal and visceral tissues. Analysis of lacZ reporter gene activity in heterozygous Mfsd8((wt/tm1a)) mice showed strong Mfsd8 mRNA expression in the cerebral cortex, in the hippocampus and in the kidney. Homozygous Mfsd8((tm1a/tm1a)) mice were viable and fertile and resembled biochemically the NCL-phenotype of human CLN7 patients including the accumulation of autofluorescent material in the brain and peripheral tissues and of subunit c of mitochondrial ATP synthase in the cerebellum and nuclei of distinct brain regions, and the degeneration of photoreceptor cells in the retina. Lysosomal storage was found in large neurons of the medulla, the hippocampus and in Purkinje cells of the cerebellum in mutant mice. The ultrastructure of the storage material revealed dense lamellar bodies with irregular forms within cerebellar and hippocampal neurons. In the brain loss of Cln7 was accompanied by mild reactive microgliosis and subtle astrogliosis by 10 months of age, respectively. In summary we have generated a mouse model which is partly valuable as some but not all neuropathological features of human CLN7 disease are recapitulated thus representing an animal model to study CLN7-specific disease mechanisms. (C) 2014 Elsevier Inc. All rights reserved.