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首页> 外文期刊>American journal of medical genetics, Part A >Whole genome microarray analysis of gene expression in an imprinting center deletion mouse model of Prader-Willi syndrome.
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Whole genome microarray analysis of gene expression in an imprinting center deletion mouse model of Prader-Willi syndrome.

机译：在Prader-Willi综合征的印迹中心缺失小鼠模型中基因表达的全基因组微阵列分析。

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Prader-Willi syndrome (PWS) is caused by loss of paternally expressed genes in the 15q11-q13 region. To further characterize alterations in gene expression in this classical obesity syndrome we used whole genome microarrays to study a PWS mouse model resulting from a paternally derived imprinting center (IC) deletion (PWS IC deletion). These mice die generally within 2-3 days of life (reflective of failure to thrive in infants with PWS) and therefore, the analysis was performed on RNA extracted from the whole brain of PWS IC deletion mice and normal littermates at less than 24 hr after birth. Of more than 45,000 probes examined, 26,471 (59%) were detected for further analysis, and 69 had a significant change in expression of at least 1.5-fold and a false discovery rate (FDR) of 5%. Eight of the genes with differential expression were imprinted and from the PWS critical region (PWSCR). The three genes with the highest expression in the PWS IC mice were pro-opiomelanocortin (Pomc) and two transcripts of unknown function. Pomc knockout mice have been shown to develop obesity. Therefore, elevated Pomc RNA in PWS IC deletion neonatal mice may be an important genetic factor in the survival of these mice as it may affect eating behavior. Interestingly, Mc5r, a melanocortin receptor known to directly respond to Pomc expression changes, was upregulated as well. Mc5r is known to be involved with thermoregulation which is reportedly abnormal in PWS infants. These observations support a role for Pomc and the network of genes involved in regulating energy homeostasis in the early clinical findings of failure to thrive observed in PWS. Other notable patterns include three previously unstudied transcripts that are expressed only from the paternal allele under regulatory control of the IC and include AK013560, BB3144814, and BB182944 (whose genes are located in the mouse PWSCR on chromosome 7B). As expected, all the known paternally expressed genes from the PWSCR had detection signals below the threshold in the PWS IC deletion mice but were clearly detectable in control littermates. Several of the genes in this study were further examined by quantitative reverse transcription-PCR (RT-PCR) to confirm their expression status. Further analysis of gene expression in these mice may lead to novel pathways affected in PWS. These results, along with other recent reports, suggest that the cumulative effect of modest changes in expression of many genes, especially genes involved in energy metabolism, contribute to the failure to thrive of infants with PWS.
机译：Prader-Willi综合征（PWS）是由15q11-q13区域中父本表达的基因缺失引起的。为了进一步表征这种典型的肥胖症候群中基因表达的变化，我们使用了全基因组微阵列来研究由父本衍生的印迹中心（IC）缺失（PWS IC缺失）产生的PWS小鼠模型。这些小鼠通常在生命的2-3天之内死亡（反映出PWS婴儿无法存活），因此，对从PWS IC缺失小鼠和正常同窝仔的全脑中提取的RNA进行了分析，时间少于24小时出生。在检查的45,000多个探针中，检测到26,471（59％）用于进一步分析，其中69的表达变化至少为1.5倍，错误发现率（FDR）为5％。从PWS关键区域（PWSCR）印迹了八个具有差异表达的基因。在PWS IC小鼠中表达最高的三个基因是pro-opiomelanocortin（Pomc）和两个功能未知的转录本。 Pomc基因敲除小鼠已显示出肥胖。因此，PWS IC缺失新生小鼠中Pomc RNA升高可能是这些小鼠存活的重要遗传因素，因为它可能影响进食行为。有趣的是，Mc5r（一种已知直接响应Pomc表达变化的黑皮质素受体）也被上调。已知Mc5r与体温调节有关，据报道在PWS婴儿中体温调节异常。这些观察结果支持Pomc和参与调节能量动态平衡的基因网络在PWS不能存活的早期临床发现中的作用。其他值得注意的模式包括三个以前未被研究的转录本，它们仅在IC的调控下从父本等位基因表达，包括AK013560，BB3144814和BB182944（其基因位于7B号染色体上的小鼠PWSCR中）。如所期望的，来自PWSCR的所有已知的父本表达的基因在PWS IC缺失小鼠中具有低于阈值的检测信号，但是在对照同窝仔中明显可检测到。通过定量逆转录PCR（RT-PCR）进一步检查了本研究中的几个基因，以确认它们的表达状态。这些小鼠中基因表达的进一步分析可能会导致新的途径受PWS影响。这些结果以及其他最近的报道表明，许多基因，特别是参与能量代谢的基因，表达量的适度变化的累积效应导致了PWS婴儿的壮成长。

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