Fragile X mental retardation protein interaction with neuronal voltage-gated calcium channels: mechanism and consequences

脆性X综合征是最常见的遗传性严重认知障碍，通常是由于脆性X智力低下蛋白(FMRP)的缺失，有时甚至是功能障碍。它通常是由该基因之前的一段重复DNA引起的，称为CGG重复区域。这段DNA发生突变，因此在脆性X综合征中它的长度要长得多，并干扰该基因的正常功能。该缺陷基因位于X染色体上，在2500-4000名男性和6000-8000名女性中分别有1名和1名。据估计，在130-250名女性中，携带这种延长基因的人比例高达1/250。在携带前突变(55-200个CGG重复)的女性中，重复长度可能会扩大，在她们的孩子中成为完全突变。然而，由于另一条X染色体上有第二个正常基因，具有前突变甚至完全突变的女性通常不会出现症状。正常的大脑发育需要FMRP，缺乏FMRP会导致发育延迟、认知障碍、行为问题和运动不协调。它还会导致外周症状，包括触摸过敏、自我损伤和肠道动力改变。FMRP的缺失不会引起大体的大脑异常，但大脑中神经细胞之间的连接还不成熟，这些细胞的发育也会丧失。脆性X综合征的自闭症特征与其他形式的自闭症有一些相似之处。在我的研究小组中，我们最近发现一种在神经细胞中常见的蛋白质(Cav2.2)似乎与FMRP有关。这可能与脆性X综合征特有的一些行为缺陷有关，特别是在控制触摸和疼痛的通路调节方面，特别是在大脑之外的变化。CaV2.2是一种钙离子通道，存在于神经细胞的质膜上，允许这些细胞之间进行交流。我们将探索FMRP和Cav2.2之间的相互作用，以检查这种相互作用是否影响通道的功能，以及这些通道参与的过程。我们将特别关注痛感神经细胞和脊髓中参与疼痛信号传递的神经细胞之间的通信。这一途径的中断可能是脆性X综合征患者出现一些行为问题的原因，特别是对触摸过敏。在神经损伤性疼痛的动物模型中，Cav2.2功能的调节与触摸过敏高度相关，自我伤害行为也是部分脆性X综合征患者的行为特征之一。总之，新发现的FMRP和Cav2.2之间的相互作用可能在脆性X综合征的行为特征和病理中发挥作用，并可能在未来的某个时候导致新的治疗途径。

Fragile X syndrome is the most common form of inherited severe cognitive impairment, and is usually due to the loss, or sometimes the malfunction, of Fragile X mental retardation protein (FMRP). It is usually caused by a piece of repetitive DNA just before this gene, called the CGG repeat region. This piece of DNA becomes mutated so that it is much longer in Fragile X syndrome, and interferes with the proper function of the gene. The faulty gene is on the X chromosome and is found in 1 in 2500-4000 men and 1 in 6000-8000 women. The prevalence of people carrying this elongation has been estimated to be up to 1 in 130-250 of females. In females carrying pre-mutations (55-200 CGG repeats), the repeat length may expand to become full mutations in their children. However females with a pre-mutation or even a full mutation often do not themselves show symptoms due to a second, normal gene on their other X-chromosome. Normal brain development requires FMRP, and its absence results in developmental delay, cognitive impairment, behavioural problems and motor incoordination. It also results in peripheral symptoms including hypersensitivity to touch, self injury and altered intestinal motility. The loss of FMRP causes no gross brain abnormalities, but connections between nerve cells in the brain are immature and there is a loss of development of these cells. There are some parallels between the autistic features of Fragile X syndrome and other forms of autism. In my research group we have recently found that a protein (CaV2.2) that is commonly found in nerve cells, appears to associate with FMRP. This may relate to some of the behavioural deficits that are characteristic of Fragile X syndrome, particularly the changes that are seen outside the brain, in the regulation of pathways controlling touch and pain.CaV2.2 is a type of calcium ion channel, present in the plasma membrane of nerve cells, which allows these cells to communicate between them. We will probe the interaction between FMRP and CaV2.2 to examine whether how this interaction affects the function of the channels, and the processes in which these channels are involved. We will pay particular attention to communication between pain sensing nerve cells and nerve cells in the spinal cord, which are involved in the transmission of pain signals. It is possible that disruption of this pathway might underlie some of the behavioural problems seen in those with Fragile X syndrome, particularly hypersensitivity to touch. Regulation of CaV2.2 function is highly relevant to touch hypersensitivity in animal models of nerve damage-induced pain, and self-injury behaviour is also one of the behavioural features of in some of those with Fragile X syndrome. In summary, the newly-identified interaction between FMRP and CaV2.2 may play a role in the behavioural features and pathology of Fragile X syndrome, and may at some point in the future lead to novel avenues for treatment.