A gene expression fingerprint in mental retardation reflects disease causing defects in the histone demethylase KDM5. Homo sapiens

Mutations in KDM5C, (previously named SMCX or JARID1C) a gene that encodes a transcriptional regulator with histone-demethylase activity specific for di- and tri-methylated 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. Here 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 QRT-PCR we identified several genes, including CMKOR1, JARID1B and KIAA0469 that were consistently deregulated in both tissues. These findings shed light on the patho-mechanisms underlying mental retardation and may have implications for future diagnostics of this heterogeneous disorder. Overall design: We compared the mRNA expression of a patient lymphoblastoid cell line deficient for KDM5C with that of three controls to identify genes that are deregulated in the patient cell line.

KDM5C（曾用名SMCX或JARID1C）是一种编码转录调控因子的基因，该因子对二甲基化及三甲基化H3K4具有特异性组蛋白去甲基化酶（histone-demethylase）活性；KDM5C突变是导致非综合征型X连锁智力障碍（non-syndromic X-linked mental retardation, NS-XLMR）的较为常见的病因之一。然而，KDM5C的特异性转录靶点至今仍未明确，KDM5C缺失对基因表达的影响也尚未被研究。本研究对携带KDM5C突变患者的淋巴母细胞系（lymphoblastoid cell lines）及血液样本开展了基因表达谱分析，现将相关结果报道如下。本研究采用全基因组表达芯片（whole genome expression arrays）与实时定量反转录聚合酶链反应（QRT-PCR），在两种组织中均鉴定出多个持续发生表达失调的基因，包括CMKOR1、JARID1B及KIAA0469。上述发现阐明了智力障碍的潜在致病机制，或可为该异质性疾病的未来诊断提供参考依据。实验设计概要：本研究将1株KDM5C缺陷型患者淋巴母细胞系的mRNA表达水平与3株对照细胞系进行对比，以鉴定该患者细胞系中存在表达失调的基因。