Pugin A, Faundes V, Santa María L, Curotto B, Aliaga S, Salas I, Soto P, Bravo P, Peña M I, Alliende M A
Laboratorio de Genética y Enfermedades Metabólicas, Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile.
Laboratorio de Genética y Enfermedades Metabólicas, Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile.
Neurologia. 2017 May;32(4):241-252. doi: 10.1016/j.nrl.2014.10.009. Epub 2014 Dec 17.
Fragile X syndrome, the most common inherited cause of intellectual disability, is associated with a broad spectrum of disorders across different generations of a single family. This study reviews the clinical manifestations of fragile X-associated disorders as well as the spectrum of mutations of the fragile X mental retardation 1 gene (FMR1) and the neurobiology of the fragile X mental retardation protein (FMRP), and also provides an overview of the potential therapeutic targets and genetic counselling.
This disorder is caused by expansion of the CGG repeat (>200 repeats) in the 5 prime untranslated region of FMR1, resulting in a deficit or absence of FMRP. FMRP is an RNA-binding protein that regulates the translation of several genes that are important in synaptic plasticity and dendritic maturation. It is believed that CGG repeat expansions in the premutation range (55 to 200 repeats) elicit an increase in mRNA levels of FMR1, which may cause neuronal toxicity. These changes manifest clinically as developmental problems such as autism and learning disabilities as well as neurodegenerative diseases including fragile X-associated tremor/ataxia syndrome (FXTAS).
Advances in identifying the molecular basis of fragile X syndrome may help us understand the causes of neuropsychiatric disorders, and they will probably contribute to development of new and specific treatments.
脆性X综合征是智力障碍最常见的遗传性病因，与单个家族不同代际的广泛疾病谱相关。本研究回顾了脆性X相关疾病的临床表现、脆性X智力低下1基因（FMR1）的突变谱以及脆性X智力低下蛋白（FMRP）的神经生物学，并概述了潜在的治疗靶点和遗传咨询。
该疾病由FMR1基因5'非翻译区的CGG重复序列扩增（>200次重复）引起，导致FMRP缺乏或缺失。FMRP是一种RNA结合蛋白，可调节在突触可塑性和树突成熟中起重要作用的几个基因的翻译。据信，前突变范围内（55至200次重复）的CGG重复序列扩增会导致FMR1的mRNA水平升高，这可能会引起神经元毒性。这些变化在临床上表现为发育问题，如自闭症和学习障碍，以及神经退行性疾病，包括脆性X相关震颤/共济失调综合征（FXTAS）。
在确定脆性X综合征分子基础方面的进展可能有助于我们理解神经精神疾病的病因，并且可能会有助于开发新的特异性治疗方法。
