Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome.
Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome.
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DOI：
10.1038/ng.2275
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发表时间：
2012-05-27
期刊：
影响因子：
30.8
通讯作者：
Vilain E
中科院分区：
文献类型：
--
作者：
Arboleda VA;Lee H;Parnaik R;Fleming A;Banerjee A;Ferraz-de-Souza B;Délot EC;Rodriguez-Fernandez IA;Braslavsky D;Bergadá I;Dell'Angelica EC;Nelson SF;Martinez-Agosto JA;Achermann JC;Vilain E
影像综合征(胎儿宫内发育受限、干骺端发育不良、肾上腺发育不良、先天性发育不良和生殖器畸形)是一种发育不良的疾病，具有危及生命的后果。在一个患有影像综合征的家庭中进行的血统分析发现，染色体11p15上的一个17.2-Mb基因座在受影响的家庭成员中分离。靶向外显子阵列捕获疾病基因，然后高通量基因组测序和双脱氧测序验证，在两名家族性患者和四名无血缘关系的患者中发现印记基因CDKN1C(也称为P57KIP2)的错义突变。一项家族分析显示了一种印记遗传模式，在这种模式下，只有突变的母体传播才会导致图像综合征。CDKN1C抑制细胞周期进展，我们发现，与野生型CDKN1C相比，图像相关CDKN1C突变在果蝇中的靶向表达导致了严重的眼睛生长缺陷，这表明了一种功能获得机制。所有与图像相关的突变都聚集在CDKN1C的增殖细胞核抗原结合域，并导致增殖细胞核抗原结合的丢失，这与导致Beckwith-Wiedemann综合征(一种过度生长综合征)的CDKN1C突变不同。
IMAGe syndrome (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies) is an undergrowth developmental disorder with life-threatening consequences. An identity-by-descent analysis in a family with IMAGe syndrome identified a 17.2-Mb locus on chromosome 11p15 that segregated in the affected family members. Targeted exon array capture of the disease locus, followed by high-throughput genomic sequencing and validation by dideoxy sequencing, identified missense mutations in the imprinted geneCDKN1C(also known asP57KIP2) in two familial and four unrelated patients. A familial analysis showed an imprinted mode of inheritance in which only maternal transmission of the mutation resulted in IMAGe syndrome.CDKN1Cinhibits cell-cycle progression, and we found that targeted expression of IMAGe-associatedCDKN1Cmutations inDrosophilacaused severe eye growth defects compared to wild-typeCDKN1C, suggesting a gain-of-function mechanism. All IMAGe-associated mutations clustered in the PCNA-binding domain ofCDKN1Cand resulted in loss of PCNA binding, distinguishing them from the mutations ofCDKN1Cthat cause Beckwith-Wiedemann syndrome, an overgrowth syndrome.
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