The large spectrum of eIF2B-related diseases
The large spectrum of eIF2B-related diseases
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DOI：
10.1042/bst0340022
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发表时间：
2006-02-01
影响因子：
3.9
通讯作者：
Boespflug-Tanguy, O
中科院分区：
文献类型：
--
作者：
Fogli, A;Boespflug-Tanguy, O
eIF 2B（真核起始因子2B）是一种鸟嘌呤核苷酸交换因子（GEF），与其底物eIF 2一起在蛋白质合成的翻译起始阶段发挥关键调节作用。最近，编码eIF 2 B亚基的5个基因参与了一种严重的常染色体隐性神经退行性疾病，在幼儿中被描述为CACH（儿童共济失调伴中枢神经系统髓鞘形成不足）/VWM（白质脑病伴白色消失）综合征，这强调了正确控制eIF 2和eIF 2 B对正常生理的重要性。该综合征的特征是在发热性疾病期间或在头部创伤和脑白色物质的对称性脱髓鞘伴空化方面之后快速恶化，导致白色物质逐渐消失，被CSF（脑脊液）取代。然而，在目前报告的148例患者中观察到广泛的临床谱，从快速死亡的先天性形式到缓慢智力下降和进行性运动功能障碍的成人发作形式，有时与先天性眼异常或卵巢发育不全相关。到目前为止，在编码eIF 2B α-亚基的5个EIF 2B基因（EIF 2B 1 -5）中，已经发现了77个不同的突变，其中三分之二影响eIF 2B α-亚基。在突变的白色血细胞中eIF 2 B的GEF活性水平与疾病发作时的年龄之间发现的相关性表明异常翻译控制在疾病的病理生理学中的直接作用。
eIF2B (eukaryotic initiation factor 2B) is a GEF (guanine nucleotide-exchange factor) that plays, with its substrate eIF2, a key regulatory role in the translation initiation phase of protein synthesis. The importance of correct control of eIF2 and eIF2B for normal physiology is underlined by the recent involvement of the five genes that encode the five eIF2B subunits in a severe autosomal recessive neurodegenerative disease, described in young children as CACH (childhood ataxia with central nervous system hypomyelination)/VWM (leukoencephalopathy with vanishing white matter) syndrome. The syndrome is characterized by episodes of rapid deterioration during febrile illnesses or following head trauma and symmetrical demyelination of the brain white matter with cavitation aspects, leading to a progressive vanishing of the white matter replaced by CSF (cerebrospinal fluid). However, a wide clinical spectrum has been observed in the 148 patients presently reported, from congenital forms with rapid death to adult-onset forms with slow mental decline and progressive motor dysfunction, sometimes associated with congenital eye abnormalities or ovariodysgenesis. So far, 77 different mutations in each of the five EIF2B genes (EIF2B1-5), encoding subunits eIF2B alpha-epsilon, have been found, with two-thirds affecting the eIF2B epsilon subunit. The correlation found between the level of GEF activity of eIF2B in the mutated white blood cells and the age at disease onset suggests a direct role of the abnormal translation control in the pathophysiology of the disease.