Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients
Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients
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DOI：
10.1038/sj.ejhg.5201189
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发表时间：
2004-07-01
影响因子：
5.2
通讯作者：
Boespflug-Tanguy, O
中科院分区：
文献类型：
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作者：
Fogli, A;Schiffmann, R;Boespflug-Tanguy, O
在不同严重程度的脑白质营养不良中发现了五种真核起始因子2B（eIF 2B）亚基的突变：Cree白质脑病、儿童共济失调伴中枢性髓鞘形成不足/白质营养不良伴白色物质消失和卵巢脑白质营养不良。从致命的婴儿型到成人型观察到连续性，无神经系统恶化。发现疾病严重程度与发病年龄和特定氨基酸取代相关。为了分析eIF 2B突变的功能后果，我们测量了30例携带eIF 2B突变的受影响患者转化淋巴细胞中eIF 2B的鸟嘌呤核苷酸交换因子（GEF）活性，并与10例未受影响的杂合子和22例无eIF 2B突变的对照进行比较。在所有突变细胞中观察到GEF活性显著降低20 - 70%。GEF活性降低的严重程度与发病时的年龄相关。这些结果表明，GEF活性的缺乏是脑病相关eIF 2B相关疾病的基础。我们的研究表明，转化淋巴细胞中的GEF活性的评价是一个有趣的替代测试的系统筛选的五个EIF 2B基因。这种相关的细胞模型也可用于测试不同分子对GEF活性的功能影响，以用于未来的治疗策略。
Mutations in each of the five eucaryotic initiation factor 2B (eIF2B) subunits have been found in leukodystrophies of various severity: Cree leukoencephalopathy, childhood ataxia with central hypomyelination/leukodystrophy with vanishing white matter and ovarioleukodystrophy. A continuum was observed from fatal infantile forms to adult forms without neurological deterioration. Disease severity was found to correlate with the age at disease onset and the specific amino-acid substitution. In order to analyze the functional consequences of eIF2B mutations, we measured the guanine nucleotide exchange factor (GEF) activity of eIF2B in transformed lymphocytes from 30 affected patients carrying mutations in eIF2B compared to 10 unaffected heterozygotes and 22 controls without eIF2B mutations. A significant decrease of 20 - 70% in GEF activity was observed in all mutated cells. The severity of this decrement of GEF activity correlated with age at onset of the disease. These results suggest that a deficiency in GEF activity underlies the encephalopathy associated eIF2B-related disease. Our study demonstrates that the evaluation of the GEF activity in transformed lymphocytes represents an interesting alternative test to the systematic screening of the five EIF2B genes. This relevant cellular model may also be used to test the functional impact of different molecules on the GEF activity for future therapeutic strategies.