Mutations in the kinase Rsk-2 associated with Coffin-Lowry syndrome
Mutations in the kinase Rsk-2 associated with Coffin-Lowry syndrome
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DOI：
10.1038/384567a0
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发表时间：
1996-12-12
期刊：
影响因子：
64.8
通讯作者：
Hanauer, A
中科院分区：
文献类型：
--
作者：
Trivier, E;DeCesare, D;Hanauer, A
Coffin-Lowry 综合征 (CLS) 是一种 X 连锁疾病，其特征是严重的精神运动迟缓、面部和手指畸形以及进行性骨骼变形 (1)。遗传连锁分析将 CLS 基因座映射到 Xp22.2 处 2-3 兆碱基的区间。编码 Rsk-2（生长因子调节蛋白激酶的成员）的基因位于候选区间内，并作为 CLS 候选基因进行测试。对 76 名不相关的 CLS 患者的 Rsk-2 基因突变进行的初步筛查发现，有一个基因内缺失、一个无义突变、两个剪接位点和两个错义突变。这两个错义影响对 Rsk-2 功能至关重要的位点。在 S6 激酶测定中发现突变的 Rsk-2 蛋白失去活性。这些发现提供了直接证据表明 MAPK/RSK 信号通路异常会导致 Coffin-Lowry 综合征。
THE Coffin-Lowry syndrome (CLS), an X-linked disorder, is characterized by severe psychomotor retardation, facial and digital dysmorphisms, and progressive skeletal deformations(1). Genetic linkage analysis mapped the CLS locus to an interval of 2-3 megabases at Xp22.2. The gene coding for Rsk-2, a member of the growth-factor-regulated protein kinases, maps within the candidate interval, and was tested as a candidate gene for CLS. Initial screening for mutations in the gene for Rsk-2 in 76 unrelated CLS patients revealed one intragenic deletion, a nonsense, two splice site, and two missense mutations. The two missenses affect sites critical for the function of Rsk-2. The mutated Rsk-2 proteins were found to be inactive in a S6 kinase assay. These findings provide direct evidence that abnormalities in the MAPK/RSK signalling pathway cause Coffin-Lowry syndrome.