Fragile X syndrome

Fragile X syndrome (FXS) is a monogenetic disorder caused by a mutation in the FMR1 gene and the most common form of inherited intellectual disability and autism spectrum disorder (ASD). Patients with FXS show a range of typical physical features such as macro-orchidism in males, a long and narrow face, large and protruding ears, and hyperextensible joints. Common comorbidities of FXS are neuropsychiatric disorders such as hyperactivity, depression and anxiety. The mutation of FMR1 in FXS disrupts production of the FMR1 gene product, the fragile mental retardation protein (FMRP). The main function of FMRP is to locally act as a translational repressor for target mRNAs and thereby regulate de novo protein synthesis and ultimately synaptic plasticity. FMRP, together with the mTOR pathway and the ERK pathway regulates expression of target mRNAsn mediated by stimulation of Group I metabotropic glutamate receptors (mGluR) and thereby regulate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalisation and thus long term depression (LTD). LTD is a form of synaptic plasticity which is involved in learning and memory. Lack of FMRP leads to exaggerated mGluR dependant LTD, which accounts for most of FXS pathogenesis.

脆性X综合征（FXS）是一种由FMR1基因突变引起的单基因遗传性疾病，也是最常见的遗传性智力障碍和自闭症谱系障碍（ASD）。FXS患者表现出一系列典型的生理特征，如男性巨睾、长而窄的面容、大而突出的耳朵以及过度伸展的关节。FXS的常见合并症包括神经精神疾病，如多动症、抑郁和焦虑。FMR1基因在FXS中的突变扰乱了其产物——脆性智力迟滞蛋白（FMRP）的生成。FMRP的主要功能是在局部作为靶mRNA的翻译抑制因子，从而调节蛋白质的从头合成，并最终影响突触可塑性。FMRP与mTOR通路和ERK通路共同调节由I型代谢型谷氨酸受体（mGluR）刺激引起的靶mRNA表达，进而调节α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）的内化，从而影响长期抑制（LTD）。LTD是一种与学习和记忆相关的突触可塑性形式。FMRP的缺乏导致mGluR依赖性LTD过度表达，这构成了FXS发病机制的大部分。