Novel mutations of CDKN1C in Japanese patients with Beckwith-Wiedemann syndrome
Novel mutations of CDKN1C in Japanese patients with Beckwith-Wiedemann syndrome
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DOI：
10.1007/s13258-013-0079-3
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发表时间：
2013-04-01
期刊：
影响因子：
2.1
通讯作者：
Soejima, Hidenobu
中科院分区：
文献类型：
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作者：
Yatsuki, Hitomi;Higashimoto, Ken;Soejima, Hidenobu
Beckwith-Wiedemann综合征（BWS）是一种与印记相关的人类疾病，其特征在于巨大儿、巨舌症、腹壁缺陷和可变的次要特征。BWS是由几种遗传/表观遗传改变引起的，如KvDMR 1甲基化缺失、H19-DMR甲基化获得、11号染色体父系单亲二体、CDKN 1C突变和11号染色体结构异常。CDKN 1C是一种具有母体优先表达的印迹基因，编码细胞周期蛋白依赖性激酶（CDK）抑制剂。40%的以母体传播为主的家族性BWS病例中发现了CDKN 1C突变，而散发病例的这一比例与5%相似。在这项研究中，我们在37例没有其他改变证据的BWS病例中寻找CDKN 1C突变。我们从总共6名患者中发现了5种突变，4种是新的，1种是已知的。四个是母系遗传，一个是新生突变。两个移码突变和一个无义突变取消了QT结构域，包含一个PCNA结合结构域和一个核定位信号。CDK抑制结构域发生两个错义突变，降低了其抑制功能。通过计算机模拟分析预测上述突变会导致功能丧失;因此，我们强烈怀疑这些异常是BWS病因的原因。
Beckwith-Wiedemann syndrome (BWS) is an imprinting-related human disease that is characterized by macrosomia, macroglossia, abdominal wall defects, and variable minor features. BWS is caused by several genetic/epigenetic alterations, such as loss of methylation at KvDMR1, gain of methylation at H19-DMR, paternal uniparental disomy of chromosome 11, CDKN1C mutations, and structural abnormalities of chromosome 11. CDKN1C is an imprinted gene with maternal preferential expression, encoding for a cyclin-dependent kinase (CDK) inhibitor. Mutations in CDKN1C are found in 40 % of familial BWS cases with dominant maternal transmission and in similar to 5 % of sporadic cases. In this study, we searched for CDKN1C mutations in 37 BWS cases that had no evidence for other alterations. We found five mutations-four novel and one known-from a total of six patients. Four were maternally inherited and one was a de novo mutation. Two frame-shift mutations and one nonsense mutation abolished the QT domain, containing a PCNA-binding domain and a nuclear localization signal. Two missense mutations occurred in the CDK inhibitory domain, diminishing its inhibitory function. The above-mentioned mutations were predicted by in silico analysis to lead to loss of function; therefore, we strongly suspect that such anomalies are causative in the etiology of BWS.