A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor
A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor
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DOI：
10.1093/hmg/ddi094
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发表时间：
2005-04-15
影响因子：
3.5
通讯作者：
Nguyen, G
中科院分区：
文献类型：
--
作者：
Ramser, J;Abidi, FE;Nguyen, G
肾素-血管紧张素系统（RAS）对血压控制和水电解质平衡至关重要。在发现肾素受体之前，人们认为肾素主要是一种循环酶，具有独特的功能，即切割血管紧张素原。我们报告了一个独特的突变，在肾素受体基因（ATP 6AP 2）目前在患者与X连锁精神发育迟滞和癫痫（OMIM号300423），但在1200个控制X染色体缺失。一个沉默突变（c.321C > T，p.D107D）驻留在一个假定的外显子剪接增强子位点导致无效的包含在50%的肾素受体mRNA的外显子4，如定量RT-PCR所示。膜相关受体分子形式的分析表明，在病人的全长和截短的蛋白质的存在。功能分析表明，突变的受体可以结合肾素和增加肾素催化活性，类似于野生型受体，但导致ERK 1/2激活的适度和可重复的损害。因此，我们的研究结果证实了RAS在认知过程中的重要性，并表明了肾素受体在认知功能和大脑发育中的新的特定作用。
The renin-angiotensin system (RAS) is essential for blood pressure control and water-electrolyte balance. Until the discovery of the renin receptor, renin was believed to be mainly a circulating enzyme with a unique function, the cleavage of angiotensinogen. We report a unique mutation in the renin receptor gene (ATP6AP2) present in patients with X-linked mental retardation and epilepsy (OMIM no. 300423), but absent in 1200 control X-chromosomes. A silent mutation (c.321C > T, p.D107D) residing in a putative exonic splicing enhancer site resulted in inefficient inclusion of exon 4 in 50% of renin receptor mRNA, as demonstrated by quantitative RT-PCR. Analysis of membrane associated-receptor molecular forms showed the presence of full-length and truncated proteins in the patient. Functional analysis demonstrated that the mutated receptor could bind renin and increase renin catalytic activity, similar to the wild-type receptor, but resulted in a modest and reproducible impairment of ERK1/2 activation. Thus, our findings confirm the importance of the RAS in cognitive processes and indicate a novel specific role for the renin receptor in cognitive functions and brain development.