GluD1 is a common altered player in neuronal differentiation from both MECP2-mutated and CDKL5-mutated iPS cells.
GluD1 is a common altered player in neuronal differentiation from both MECP2-mutated and CDKL5-mutated iPS cells.
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DOI：
10.1038/ejhg.2014.81
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发表时间：
2015-02
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Rett综合征是由MECP2或CDKL 5基因的新生突变引起的单基因疾病。尽管它们参与同一种疾病，但这两个基因之间的功能相互作用尚未得到证实。MeCP 2是一种转录调节因子; CDKL 5编码一种激酶蛋白，可能参与基因表达的调节。因此，我们假设影响这两个基因的突变可能通过共同基因表达的失调导致相似的表型。为了验证这一假设，我们使用了诱导多能干细胞（iPS），这些细胞来源于一名具有MECP2突变（p.Arg306C）的Rett患者和2名具有CDKL5突变（p.Gln347Ter和p.Thr288Ile）的患者的成纤维细胞。在CDKL 5突变的细胞中进行表达谱分析，并通过实时RT-PCR在CDKL 5和MECP 2突变的细胞中确认感兴趣的基因。MECP 2和CDKL 5突变细胞共同的基因表达的唯一主要变化是GRID 1，编码谷氨酸D1受体（GluD 1），离子型谷氨酸受体δ家族的成员。GluD1不形成AMPA或NMDA-谷氨酸受体。它像一个粘附分子一样连接突触后和突触前区室，优先诱导皮层神经元的抑制性突触前分化。我们的研究结果表明，GRID1的表达在MECP2和CDKL5突变的iPS细胞中下调，在神经元前体和成熟神经元中上调。这些数据为疾病病理生理学提供了新的见解，并确定了Rett综合征治疗的可能新靶点。
Rett syndrome is a monogenic disease due to de novo mutations in either MECP2 or CDKL5 genes. In spite of their involvement in the same disease, a functional interaction between the two genes has not been proven. MeCP2 is a transcriptional regulator; CDKL5 encodes for a kinase protein that might be involved in the regulation of gene expression. Therefore, we hypothesized that mutations affecting the two genes may lead to similar phenotypes by dys-regulating the expression of common genes. To test this hypothesis we used induced pluripotent stem (iPS) cells derived from fibroblasts of one Rett patient with a MECP2 mutation (p.Arg306C) and 2 patients with mutations in CDKL5 (p.Gln347Ter and p.Thr288Ile). Expression profiling was performed in CDKL5-mutated cells and genes of interest were confirmed by real-time RT-PCR in both CDKL5 and MECP2 mutated cells. The only major change in gene expression common to MECP2-and CDKL5-mutated cells was for GRID1, encoding for glutamate D1 receptor (GluD1), a member of the delta family of ionotropic glutamate receptors. GluD1 does not form AMPA or NMDA - glutamate receptors. It acts like an adhesion molecule by linking the postsynaptic and presynaptic compartments, preferentially inducing the inhibitory presynaptic differentiation of cortical neurons. Our results demonstrate that GRID1 expression is down-regulated in both MECP2 and CDKL5-mutated iPS cells and up-regulated in neuronal precursors and mature neurons. These data provide novel insights into disease pathophysiology and identify possible new targets for therapeutic treatment of Rett syndrome.
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