Molecular and cytogenetic analysis of the spreading of X inactivation in a girl with microcephaly, mild dysmorphic features and t(X;5)(q22.1;q31.1)
Molecular and cytogenetic analysis of the spreading of X inactivation in a girl with microcephaly, mild dysmorphic features and t(X;5)(q22.1;q31.1)
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DOI：
10.1038/ejhg.2008.28
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发表时间：
2008-08-01
影响因子：
5.2
通讯作者：
Zuffardi, Orsetta
中科院分区：
文献类型：
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作者：
Giorda, Roberto;Bonaglia, M. Clara;Zuffardi, Orsetta
X染色体失活涉及基因失活的启动、传播和维持。 X 中复制模式和时间的研究；常染色体易位表明 X 失活可能会扩散到常染色体 DNA。为了在分子水平上检查这一现象，我们测试了一名患有小头畸形、轻度畸形特征和 46,X,der(X)t(X;5)(q22.1;q31.1) 核型的女性受试者中多个 5 号染色体位点的转录活性。对跨越 5q31.1-qter 的 20 个转录序列进行 RT-PCR 分析表明，其中 9 个序列在携带易位染色体的体细胞杂交克隆中不表达。然而，有八个基因被表达，因此逃脱了失活。这种直接表达测试表明，失活从 X 染色体到邻近常染色体 DNA 的传播是不完整且“不完整”的。在大多数情况下，失活与含有 CpG 岛的基因中 CpG 序列的甲基化有关，但也存在于无 CpG 岛的基因中。这些结果与其他 X 获得的结果一致；常染色体易位并证明常染色体对 Xist 介导的传播和/或失活的维持具有部分抵抗力。重复分布分析并未表明 5 号染色体上的 L1 和 LINE 重复密度与基因失活之间存在关联。表达数据还可以解释为什么先证者与具有部分 5 号染色体三体性的受试者相比表现出减弱的临床表型。
X chromosome inactivation involves initiation, propagation, and maintenance of gene inactivation. Studies of replication pattern and timing in X; autosome translocations have suggested that X inactivation may spread to autosomal DNA. To examine this phenomenon at the molecular level, we have tested the transcriptional activity of a number of chromosome 5 loci in a female subject with microcephaly, mild dysmorphic features and 46,X,der(X)t(X;5)(q22.1;q31.1) karyotype. RT-PCR analysis of 20 transcribed sequences spanning 5q31.1-qter revealed that nine of them were not expressed in somatic cell hybrid clones carrying the translocated chromosome. However, eight genes were expressed and therefore escaped inactivation. This direct expression test demonstrates that spreading of inactivation from the X chromosome to the adjoining autosomal DNA was incomplete and 'patchy'. Inactivation was associated in most instances to methylation of the CpG sequences in genes containing CpG islands, but was also present in CpG islandless genes. These results agree with those obtained for other X; autosome translocations and demonstrate that autosomes are partially resistant to Xist-mediated spreading and/or maintenance of inactivation. Repeat distribution analysis does not suggest an association between L1 and LINE repeat density on chromosome 5 and gene inactivation. The expression data may also explain why the proband manifests an attenuated clinical phenotype compared to subjects with partial chromosome 5 trisomy.