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Novel mutations of CDKN1C in Japanese patients with Beckwith-Wiedemann syndrome

机译：日本Beckwith-Wiedemann综合征患者的CDKN1C新型突变

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摘要

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 ~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.
机译：Beckwith-Wiedemann综合征（BWS）是一种与印记相关的人类疾病，其特征是巨人症，巨眼症，腹壁缺损和各种次要特征。 BWS是由几种遗传/表观遗传学改变引起的，例如KvDMR1处的甲基化缺失，H19-DMR处的甲基化获得，第11号染色体的父亲单亲二体性和CDKN1C突变以及第11号染色体的结构异常。优先表达，编码细胞周期蛋白依赖性激酶（CDK）抑制剂。在占主导地位的母婴传播的家族性BWS病例中发现CDKN1C突变，在散发性病例中约有5％被发现。在这项研究中，我们搜索了37例BWS病例中没有其他改变证据的CDKN1C突变。我们从总共六名患者中发现了五个突变，其中四个是新突变，另一个是已知的。四个是母系遗传的，一个是从头突变。两个移码突变和一个无意义的突变废除了QT域，其中包含PCNA结合域和核定位信号。在CDK抑制域中发生了两个错义突变，从而减弱了其抑制功能。通过计算机分析预测上述突变会导致功能丧失。因此，我们强烈怀疑这种异常是造成BWS病因的原因。

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  • 来源
    《Genes & Genomics》 |2013年第2期|141-147|共7页
  • 作者

    Hitomi Yatsuki; Ken Higashimoto; Kosuke Jozaki; Kayoko Koide; Junichiro Okada; Yoriko Watanabe; Nobuhiko Okamoto; Yoshinobu Tsuno; Yoko Yoshida; Kazutoshi Ueda; Kenji Shimizu; Hirofumi Ohashi; Tsunehiro Mukai; Hidenobu Soejima;

  • 作者单位

    Division of Molecular Genetics Epigenetics Department of Biomolecular Sciences Faculty of Medicine Saga University">(1);

    Division of Molecular Genetics Epigenetics Department of Biomolecular Sciences Faculty of Medicine Saga University">(1);

    Division of Molecular Genetics Epigenetics Department of Biomolecular Sciences Faculty of Medicine Saga University">(1);

    Division of Molecular Genetics Epigenetics Department of Biomolecular Sciences Faculty of Medicine Saga University">(1);

    Department of Pediatrics and Child Health Kurume University School of Medicine">(2);

    Department of Pediatrics and Child Health Kurume University School of Medicine">(2);

    Department of Medical Genetics Osaka Medical Center and Research Institute for Maternal and Child Health">(3);

    Perinatal Medical Center Wakayama Medical University Hospital">(4);

    Department of Pediatrics Kitano Hospital The Tazuke Kofukai Medical Research Institute">(5);

    Department of Pediatrics Kitano Hospital The Tazuke Kofukai Medical Research Institute">(5);

    Division of Medical Genetics Saitama Children’s Medical Center">(6);

    Division of Medical Genetics Saitama Children’s Medical Center">(6);

    Nishikyushu University">(7);

    Division of Molecular Genetics Epigenetics Department of Biomolecular Sciences Faculty of Medicine Saga University">(1);

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  • 正文语种 eng
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  • 关键词

    Beckwith-Wiedemann syndrome; CDKN1C; Gene mutation; Genomic imprinting;

    机译：Beckwith-Wiedemann综合征;CDKN1C;基因突变;基因组印迹;

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