Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Annu Rev Pathol. 2012;7:219-45. doi: 10.1146/annurev-pathol-011811-132457. Epub 2011 Oct 10.
Fragile X syndrome (FXS) is a common form of inherited intellectual disability and is one of the leading known causes of autism. The mutation responsible for FXS is a large expansion of the trinucleotide CGG repeat in the 5' untranslated region of the X-linked gene FMR1. This expansion leads to DNA methylation of FMR1 and to transcriptional silencing, which results in the absence of the gene product, FMRP, a selective messenger RNA (mRNA)-binding protein that regulates the translation of a subset of dendritic mRNAs. FMRP is critical for mGluR (metabotropic glutamate receptor)-dependent long-term depression, as well as for other forms of synaptic plasticity; its absence causes excessive and persistent protein synthesis in postsynaptic dendrites and dysregulated synaptic function. Studies continue to refine our understanding of FMRP's role in synaptic plasticity and to uncover new functions of this protein, which have illuminated therapeutic approaches for FXS.
脆性 X 综合征（FXS）是一种常见的遗传性智力障碍，也是自闭症的主要已知病因之一。导致 FXS 的突变是 X 连锁基因 FMR1 的 5'非翻译区三核苷酸 CGG 重复的大量扩展。这种扩展导致 FMR1 的 DNA 甲基化和转录沉默，从而导致基因产物 FMRP 的缺失，FMRP 是一种选择性的信使 RNA（mRNA）结合蛋白，可调节树突状 mRNA 的翻译。FMRP 对于 mGluR（代谢型谷氨酸受体）依赖性长时程抑制以及其他形式的突触可塑性至关重要；其缺失导致突触后树突中过度和持续的蛋白质合成以及突触功能失调。研究不断深入了解 FMRP 在突触可塑性中的作用，并揭示该蛋白的新功能，这为 FXS 的治疗方法提供了启示。
