Low frequency of p57(KIP2) mutation in Beckwith-Wiedemann syndrome
Low frequency of p57(KIP2) mutation in Beckwith-Wiedemann syndrome
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DOI：
10.1086/514858
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发表时间：
1997-08-01
影响因子：
9.8
通讯作者：
Feinberg, AP
中科院分区：
文献类型：
--
作者：
Lee, MP;DeBaun, M;Feinberg, AP
Beckwith-Wiedemann综合征(BWS)是一种常染色体显性遗传性疾病，产前生长发育增加，易患胚胎癌，如肾母细胞瘤。BWS被认为涉及一个或多个印记基因，因为一些患者表现出父亲的单亲二体，而另一些患者则表现出涉及母体染色体的平衡生殖系染色体重排。我们先前通过遗传连锁分析将BW定位到11p15.5，这些基因和其他也被发现含有几个印记基因；其中包括胰岛素样生长因子II(IGF2)和H19的基因，它们表现出异常的印记特异性表达和/？或甲基化在20%的BWS患者中，以及p57(KIP2)，一种周期蛋白依赖的激酶抑制物，我们发现在所研究的9例BWS患者中有1例显示出双等位基因的表达。此外，最近报道p57(KIP2)显示9例BWS患者中有2例发生突变。我们现在已经分析了40名无关的BWS患者的p57(KIP2)的整个编码序列和内含子边界。在这些患者中，只有两例(5%)显示出突变，均涉及第二外显子的移码，在一例中，突变从先证者的母亲传递给了先证者的母亲，母亲也受到了影响，这表明p57(KIP2)没有：在发育的关键阶段至少在一些受影响的组织中印迹，父母中任何一个等位基因的突变导致的单倍体不足可能导致BWS的至少一些特征。P57(KIP2)突变的低频率，以及我们最近在染色体重排患者中发现的K(V)LQT1基因的中断，表明BWS可能涉及多个独立的11p15.5基因的中断。
Beckwith-Wiedemann syndrome (BWS) is an autosomal dominant disorder of increased prenatal growth and predisposition to embryonal cancers such as Wilms tumor. BWS is thought to involve One or more imprinted genes, since some patients show paternal uniparental disomy, and others show balanced germ-line chromosomal rearrangements involving the maternal chromosome. We previously mapped BWS, by genetic linkage analysis, to 11p15.5, which are and others also found to contain several imprinted genes; these include the gene for insulin-like growth factor II (IGF2) and H19, which show abnormal imprint-specific expression and/???? or methylation in 20% of BWS patients, and p57(KIP2), a cyclin-dependent Kinase inhibitor, which we found showed biallelic expression in one of nine BWS patients studied. In addition, p57(KIP2) was recently reported to show mutations ire two of nine BWS patients. We have now analyzed the entire coding sequence and intronexon boundaries of p57(KIP2) in 40 unrelated BWS patients. Of these patients, only two (5%) showed mutations, both involving frameshifts in the second exon, In one case, the mutation was transmitted to the proband's mother, who was also affected, from the maternal grandfather, suggesting that p57(KIP2) is not: imprinted in at least some affected tissues at a critical stage of development and that haploinsufficiency due to mutation of either parental allele may cause at least some features of BWS. The low frequency of p57(KIP2) mutations, as well as our recent discovery of disruption of the K(v)LQT1 gene in patients with chromosomal rearrangements, suggest that BWS can involve disruption of multiple independent 11p15.5 genes.