Fragile X and autism: Intertwined at the molecular level leading to targeted treatments.
Fragile X and autism: Intertwined at the molecular level leading to targeted treatments.
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DOI：
10.1186/2040-2392-1-12
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发表时间：
2010-09-21
期刊：
影响因子：
6.2
通讯作者：
Hagerman P
中科院分区：
文献类型：
--
作者：
Hagerman R;Hoem G;Hagerman P
脆性X综合征（FXS）是由脆性智力低下1基因（FMR 1）5'非翻译部分的CGG重复序列扩增（> 200个重复序列）引起的，导致FMR 1蛋白（FMRP）的缺乏或缺失。FMRP是一种RNA载体蛋白，它控制着其他几种调节突触发育和可塑性的基因的翻译。自闭症发生在大约30%的FXS病例中，广泛性发育障碍，未另行说明（PDD-NOS）发生在另外30%的病例中。前突变重复扩增（55至200个CGG重复）也可能导致自闭症谱系障碍（ASD），包括自闭症和PDD-NOS，通过不同的分子机制，涉及扩展的CGG重复FMR 1 mRNA的直接毒性作用。RNA毒性也可导致衰老效应，包括震颤、共济失调和认知下降，称为脆性X相关震颤共济失调综合征（FXTAS），在晚年的前突变携带者中。在对携带前突变扩增的小鼠的研究中，有证据表明出生后早期神经元细胞毒性，表现为细胞寿命缩短、树突分支减少和突触形态改变。也有证据表明前突变携带者的线粒体功能障碍。在突变前和完全突变的神经元中，细胞失调的许多问题也与没有脆性X突变的自闭症中记录的细胞异常平行。关于FXS中神经递质系统的失调的研究，包括代谢型谷氨酸受体（mGluR）1/5途径和γ氨基丁酸（GABA）A途径，已经导致FXS的新靶向治疗。初步证据表明，这些新的靶向治疗也将有利于非脆性X型自闭症。
Fragile X syndrome (FXS) is caused by an expanded CGG repeat (> 200 repeats) in the 5' untranslated portion of the fragile mental retardation 1 gene (FMR1), leading to deficiency or absence of the FMR1 protein (FMRP). FMRP is an RNA carrier protein that controls the translation of several other genes that regulate synaptic development and plasticity. Autism occurs in approximately 30% of FXS cases, and pervasive developmental disorder, not otherwise specified (PDD-NOS) occurs in an additional 30% of cases. Premutation repeat expansions (55 to 200 CGG repeats) may also give rise to autism spectrum disorders (ASD), including both autism and PDD-NOS, through a different molecular mechanism that involves a direct toxic effect of the expanded CGG repeat FMR1 mRNA. RNA toxicity can also lead to aging effects including tremor, ataxia and cognitive decline, termed fragile X-associated tremor ataxia syndrome (FXTAS), in premutation carriers in late life. In studies of mice bearing premutation expansions, there is evidence of early postnatal neuronal cell toxicity, presenting as reduced cell longevity, decreased dendritic arborization and altered synaptic morphology. There is also evidence of mitochondrial dysfunction in premutation carriers. Many of the problems with cellular dysregulation in both premutation and full mutation neurons also parallel the cellular abnormalities that have been documented in autism without fragile X mutations. Research regarding dysregulation of neurotransmitter systems in FXS, including the metabotropic glutamate receptor (mGluR)1/5 pathway and γ aminobutyric acid (GABA)A pathways, have led to new targeted treatments for FXS. Preliminary evidence suggests that these new targeted treatments will also be beneficial in non-fragile X forms of autism.
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DOI：
10.4088/jcp.08m04476
发表时间：
2009-06
期刊：
The Journal of clinical psychiatry
影响因子：
--
作者：
Bourgeois JA;Coffey SM;Rivera SM;Hessl D;Gane LW;Tassone F;Greco C;Finucane B;Nelson L;Berry-Kravis E;Grigsby J;Hagerman PJ;Hagerman RJ
通讯作者：
Hagerman RJ
DOI：
10.2310/jim.0b013e3181af59d6
发表时间：
2009-12
期刊：
Journal of investigative medicine : the official publication of the American Federation for Clinical Research
影响因子：
--
作者：
Berman RF;Willemsen R
通讯作者：
Willemsen R
影响因子：
4.7
作者：
Bilousova, TV;Rusakov, DA;Ethell, IM
通讯作者：
Ethell, IM
DOI：
10.1002/ajmg.b.30910
发表时间：
2009-09-05
影响因子：
2.8
作者：
Brouwer, J. R.;Willemsen, R.;Oostra, B. A.
通讯作者：
Oostra, B. A.
影响因子：
3.5
作者：
Chen, Yucui;Tassone, Flora;Pessah, Isaac N.
通讯作者：
Pessah, Isaac N.