Yousuf Aadil, Ahmed Nadeem, Qurashi Abrar
Department of Biotechnology, University of Kashmir, Srinagar, Jammu and Kashmir, India.
Front Genet. 2022 Aug 30;13:866021. doi: 10.3389/fgene.2022.866021. eCollection 2022.
Fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X syndrome (FXS) are primary examples of fragile X-related disorders (FXDs) caused by abnormal expansion of CGG repeats above a certain threshold in the 5'-untranslated region of the fragile X mental retardation (FMR1) gene. Both diseases have distinct clinical manifestations and molecular pathogenesis. FXTAS is a late-adult-onset neurodegenerative disorder caused by a premutation (PM) allele (CGG expansion of 55-200 repeats), resulting in FMR1 gene hyperexpression. On the other hand, FXS is a neurodevelopmental disorder that results from a full mutation (FM) allele (CGG expansions of ≥200 repeats) leading to heterochromatization and transcriptional silencing of the FMR1 gene. The main challenge is to determine how CGG repeat expansion affects the fundamentally distinct nature of FMR1 expression in FM and PM ranges. Abnormal CGG repeat expansions form a variety of non-canonical DNA and RNA structures that can disrupt various cellular processes and cause distinct effects in PM and FM alleles. Here, we review these structures and how they are related to underlying mutations and disease pathology in FXS and FXTAS. Finally, as new CGG expansions within the genome have been identified, it will be interesting to determine their implications in disease pathology and treatment.
脆性X相关震颤/共济失调综合征（FXTAS）和脆性X综合征（FXS）是脆性X相关疾病（FXD）的主要例子，这些疾病由脆性X智力低下（FMR1）基因5'-非翻译区中CGG重复序列在特定阈值以上的异常扩增引起。这两种疾病具有不同的临床表现和分子发病机制。FXTAS是一种成年晚期发病的神经退行性疾病，由前突变（PM）等位基因（CGG重复55 - 200次）引起，导致FMR1基因过度表达。另一方面，FXS是一种神经发育障碍，由完全突变（FM）等位基因（CGG重复≥200次）导致FMR1基因异染色质化和转录沉默引起。主要挑战在于确定CGG重复扩增如何影响FM和PM范围内FMR1表达的根本不同性质。异常的CGG重复扩增形成多种非规范的DNA和RNA结构，这些结构可破坏各种细胞过程，并在PM和FM等位基因中产生不同影响。在这里，我们综述这些结构以及它们与FXS和FXTAS中潜在突变和疾病病理的关系。最后，由于基因组内已鉴定出新的CGG扩增，确定它们在疾病病理和治疗中的意义将很有趣。
