Wolcott-Rallison syndrome -: Clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity
Wolcott-Rallison syndrome -: Clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity
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DOI：
10.2337/diabetes.53.7.1876
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发表时间：
2004-07-01
期刊：
影响因子：
7.7
通讯作者：
Julier, C
中科院分区：
文献类型：
--
作者：
Senée, V;Vattem, KM;Julier, C
Wolcott-Rallison综合征（WRS）是一种罕见的常染色体隐性遗传疾病，其特征是永久性新生儿或婴儿早期胰岛素依赖型糖尿病，多发性骨骺发育不良和生长迟缓，以及其他可变的多系统临床表现。基于对两个近交系家族的遗传学研究，我们先前确定了负责这种疾病的基因为EIF 2AK 3，胰腺真核细胞起始因子2 α（eIF 2alpha）激酶。在这里，我们研究了12个家庭的WRS，共18例。除一例外，所有患者均携带EIF 2AK 3突变，导致蛋白质的截短或错义版本。排除EIF 2AK 3突变在一个病人的情况下，证实了连锁和序列数据。在体内和体外的EIF 2AK 3的错义版本的活动进行了表征，并发现有一个在四个突变体蛋白和残留的激酶活性的活性完全缺乏。值得注意的是，与其他患者相比，表达部分缺陷型EIF 2AK 3突变体的患者和不参与EIF 2AK 3的患者（18个月）的糖尿病发病相对较晚（30个月）。
Wolcott-Rallison syndrome (WRS) is a rare autosomal-recessive disorder characterized by the association of permanent neonatal or early-infancy insulin-dependent diabetes, multiple epiphyseal dysplasia and growth retardation, and other variable multisystemic clinical manifestations. Based on genetic studies of two inbred families, we previously identified the gene responsible for this disorder as EIF2AK3, the pancreatic eukaryotic initiation factor 2alpha (eIF2alpha) kinase. Here, we have studied 12 families with WRS, totalling 18 cases. With the exception of one case, all patients carried EIF2AK3 mutations resulting in truncated or missense versions of the protein. Exclusion of EIF2AK3 mutations in the one patient case was confirmed by both linkage and sequence data. The activities of missense versions of EIF2AK3 were characterized in vivo and in vitro and found to have a complete lack of activity in four mutant proteins and residual kinase activity in one. Remarkably, the onset of diabetes was relatively late (30 months) in the patient expressing the partially defective EIF2AK3 mutant and in the patient with no EIF2AK3 involvement (18 months) compared with other patients (