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Abstract：
The premutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5\' untranslated region and increased levels of FMR1 mRNA. Molecular mechanisms leading to fragile X-premutation-associated conditions (FXPAC) include cotranscriptional R-loop formations, FMR1 mRNA toxicity through both RNA gelation into nuclear foci and sequestration of various CGG-repeat-binding proteins, and the repeat-associated non-AUG (RAN)-initiated translation of potentially toxic proteins. Such molecular mechanisms contribute to subsequent consequences, including mitochondrial dysfunction and neuronal death. Clinically, premutation carriers may exhibit a wide range of symptoms and phenotypes. Any of the problems associated with the premutation can appropriately be called FXPAC. Fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND) can fall under FXPAC. Understanding the molecular and clinical aspects of the premutation of the FMR1 gene is crucial for the accurate diagnosis, genetic counseling, and appropriate management of affected individuals and families. This paper summarizes all the known problems associated with the premutation and documents the presentations and discussions that occurred at the International Premutation Conference, which took place in New Zealand in 2023.
摘要：
脆性X信使核糖核蛋白1（FMR1）基因的前突变的特征是CGG三核苷酸重复序列（55至200CGG）在5'非翻译区中扩展，并且FMR1mRNA水平升高。导致脆性X-前突变相关条件（FXPAC）的分子机制包括共转录R环形成，FMR1mRNA通过RNA凝胶化到核病灶和各种CGG重复结合蛋白的隔离而产生毒性，和重复相关的非AUG（RAN）启动的潜在毒性蛋白的翻译。这种分子机制会导致随后的后果，包括线粒体功能障碍和神经元死亡。临床上,前突变携带者可能表现出广泛的症状和表型.与前突变相关的任何问题都可以适当地称为FXPAC。脆性X相关震颤/共济失调综合征（FXTAS），脆性X相关原发性卵巢功能不全（FXPOI），和脆性X相关神经精神疾病（FXAND）可以属于FXPAC。了解FMR1基因前突变的分子和临床方面对于准确诊断至关重要。遗传咨询,以及对受影响的个人和家庭的适当管理。本文总结了与预突变相关的所有已知问题，并记录了在国际预突变会议上发生的介绍和讨论，它于2023年在新西兰举行。
