A distinctive gene expression fingerprint in mentally retarded male patients reflects disease-causing defects in the histone demethylase KDM5C.
A distinctive gene expression fingerprint in mentally retarded male patients reflects disease-causing defects in the histone demethylase KDM5C.
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DOI：
10.1186/1755-8417-3-2
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发表时间：
2010-02-02
期刊：
影响因子：
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通讯作者：
Kuss, Andreas W
中科院分区：
文献类型：
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作者：
Jensen, Lars R;Bartenschlager, Heinz;Kuss, Andreas W
背景技术背景：精神发育迟滞是一种遗传异质性疾病，因为仅在X染色体上就发现了90多个这种疾病的基因。此外，大多数患者为非综合征型，因为他们不存在临床可识别的特征。这使得很难确定这种疾病的分子原因的基础上的表型。KDM 5C（以前命名为SMCX或JARID 1C）是一种编码具有组蛋白去甲基化酶活性的转录调节因子的基因，对二甲基化和三甲基化H3 K4具有特异性，KDM 5C突变是非综合征性X连锁精神发育迟滞（NS-XLMR）的相对常见原因。然而，KDM 5C的特定转录靶点仍然是未知的，KDM 5C缺陷对基因表达的影响尚未被调查。结果：通过整体原位杂交，我们发现，小鼠同源KDM 5C在小鼠发育过程中在多个组织中表达。我们目前的结果进行基因表达谱的淋巴母细胞系，以及血液中的KDM 5C突变的患者。使用全基因组表达阵列和定量逆转录酶聚合酶链反应（QRT-PCR）实验，我们确定了几个基因，包括CMKOR 1，KDM 5 B和KIAA 0469，一致解除管制，在这两个tissues.Conclusions：我们的研究结果揭示了精神发育迟滞的病理机制，并为未来诊断这种异质性疾病的影响。
BACKGROUND: Mental retardation is a genetically heterogeneous disorder, as more than 90 genes for this disorder has been found on the X chromosome alone. In addition the majority of patients are non-syndromic in that they do not present with clinically recognisable features. This makes it difficult to determine the molecular cause of this disorder on the basis of the phenotype alone. Mutations in KDM5C (previously named SMCX or JARID1C), a gene that encodes a transcriptional regulator with histone demethylase activity specific for dimethylated and trimethylated H3K4, are a comparatively frequent cause of non-syndromic X-linked mental retardation (NS-XLMR). Specific transcriptional targets of KDM5C, however, are still unknown and the effects of KDM5C deficiency on gene expression have not yet been investigated.RESULTS: By whole-mount in situ hybridisation we showed that the mouse homologue of KDM5C is expressed in multiple tissues during mouse development.We present the results of gene expression profiling performed on lymphoblastoid cell lines as well as blood from patients with mutations in KDM5C. Using whole genome expression arrays and quantitative reverse transcriptase polymerase chain reaction (QRT-PCR) experiments, we identified several genes, including CMKOR1, KDM5B and KIAA0469 that were consistently deregulated in both tissues.CONCLUSIONS: Our findings shed light on the pathological mechanisms underlying mental retardation and have implications for future diagnostics of this heterogeneous disorder.