Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease
Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease
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DOI：
10.1038/83679
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发表时间：
2001-01-01
期刊：
影响因子：
30.8
通讯作者：
Messing, A
中科院分区：
文献类型：
--
作者：
Brenner, M;Johnson, AB;Messing, A
亚历山大病是一种罕见的中枢神经系统疾病，病因不明（1,2）。患有亚历山大病的婴儿会发展为白质脑病，伴有大头畸形、癫痫发作和精神运动迟缓，通常在头十年内导致死亡；青少年或成人形式的患者通常经历共济失调、球体征和痉挛，病程进展较慢。所有形式的亚历山大病的病理标志是罗森塔尔纤维的存在，星形胶质细胞中的细胞质包涵体含有与小热休克蛋白相关的中间丝蛋白GFAP（3,4）。我们之前发现，转基因小鼠星形胶质细胞中人GFAP的过表达是致命的，并伴有与人罗森塔尔纤维难以区分的包涵体的存在(5)。这些结果表明GFAP的原发性改变可能是亚历山大病的原因。对代表不同亚历山大病表型的患者的DNA样本进行序列分析显示，大多数病例与GFAP编码区的非保守突变有关。因此，亚历山大病代表了星形胶质细胞（脊椎动物中枢神经系统的主要细胞类型之一）原发性遗传疾病的第一个例子。
Alexander disease is a rare disorder of the central nervous system of unknown etiology(1,2). Infants with Alexander disease develop a leukoencephalopathy with macrocephaly, seizures and psychomotor retardation, leading to death usually within the first decade; patients with juvenile or adult forms typically experience ataxia, bulbar signs and spasticity, and a more slowly progressive course. The pathological hallmark of all forms of Alexander disease is the presence of Rosenthal fibers, cytoplasmic inclusions in astrocytes that contain the intermediate filament protein GFAP in association with small heat-shock proteins(3,4). We previously found that overexpression of human GFAP in astrocytes of transgenic mice is fatal and accompanied by the presence of inclusion bodies indistinguishable from human Rosenthal fibers(5). These results suggested that a primary alteration in GFAP may be responsible for Alexander disease. Sequence analysis of DNA samples from patients representing different Alexander disease phenotypes revealed that most cases are associated with non-conservative mutations in the coding region of GFAP. Alexander disease therefore represents the first example of a primary genetic disorder of astrocytes, one of the major cell types in the vertebrate CNS.