Size matters: Fighting repeat expansion size in fragile X syndrome using antisense oligonucleotides.
Size matters: Fighting repeat expansion size in fragile X syndrome using antisense oligonucleotides.
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DOI：
10.1073/pnas.2309678120
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发表时间：
2023-07-25
影响因子：
11.1
通讯作者：
Klann, Eric
中科院分区：
文献类型：
--
作者：
Shankar, Vaishnavi G.;Klann, Eric
脆性X综合征（FXS）是一种X连锁的遗传性神经发育障碍，会导致智力残疾和自闭症谱系障碍（ASD）。FXS患者表现出许多神经发育问题，包括异常行为、言语延迟、多动、手拍动，在某些情况下还会出现癫痫发作（1,2）。FXS的分子病理是由X染色体上的FMR1基因的破坏驱动的，导致其蛋白质产物脆性X信使核糖核蛋白（脆性X信使核糖核蛋白，FMRP）的丢失。FMR1基因的5′非翻译区（5′UTR）有CGG三核苷酸的重复扩增，在正常个体中大约有50个核苷酸长。CGG重复数在55到200之间的个体被称为前突变体，具有发生脆性x相关震颤/共济失调（FXTAS）的高风险，而CGG重复数超过200的个体则发生FXS(3)。随着三核苷酸重复数的增加，染色体区域的甲基化程度越来越高，CGG重复数较高的区域（bb0 ~ 200nts）被超甲基化，导致转录物异常错接或不转录FMR1，从而导致FXS。直到最近，人们认为所有FXS的特征都是不表达FMR1 mRNA（随后，FMRP完全丧失），因为DNA聚合酶无法接近基因中这些高甲基化的5′utr(4)。值得注意的是，在本期PNAS中，Shah等人(5)证明，在一些FXS患者中，特别是那些CGG区域部分甲基化的患者，DNA聚合酶可以进入5 ' UTR，从而产生全长fmr1转录物。然而，该转录本仍处于翻译失活状态，在一些FXS患者中导致转录本异常、错接。作者对公开可用的数据集进行了全面的分析，以补充他们自己的发现，并强调了FXS研究领域的一个缺陷——了解FMR1亚型在该疾病中的作用。
Fragile X syndrome (FXS) is an X-linked, inherited neurodevelopmental disorder causing intellectual disability and autism spectrum disorder (ASD). Patients with FXS display numerous neurodevelopmental problems, including aberrant behavior, delayed speech, hyperactivity, hand flapping, and, in some cases, seizures (1, 2). The molecular pathology of FXS is driven by disruption of the FMR1 gene on the X chromosome, resulting in loss of its protein product, Fragile X Messenger Ribonucleoprotein (FMRP). The 5ʹ untranslated region (5ʹUTR) of the FMR1 gene has repeat expansions of CGG trinucleotides that in normal individuals are approximately 50 nucleotides long. Individuals with CGG repeats ranging from 55 to 200 are termed premutants, with a high risk of developing fragile X-associated tremor/ataxia (FXTAS), and individuals with CGG repeats over 200 develop FXS (3). As the trinucleotide repeats increase in number, the chromosomal region becomes increasingly methylated—regions with higher CGG repeats (> 200 nts) are hypermethylated, leading to either aberrant misspliced transcripts or no transcription of FMR1, resulting in FXS. Until recently, it was thought that all instances of FXS were characterized by no expression of FMR1 mRNA (and subsequently, complete loss of FMRP) because of the inaccessibility of the DNA polymerase to these hypermethylated 5ʹUTRs in the gene (4). Remarkably, in this issue of PNAS, Shah et al.(5) demonstrate that in some FXS patients, particularly those with a partially methylated CGG region, the 5ʹUTR can be accessed by DNA polymerase, which gives rise to full-lengthFMR1 transcript. However, this transcript remains translationally inactive and in some FXS patients results in aberrant, misspliced transcripts. The authors performed a comprehensive analysis of publicly available datasets to complement their own findings and highlight a shortcoming in the field of FXS research—understanding the roles of FMR1 isoforms in the disorder.
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DOI：
10.1038/s41583-021-00432-0
发表时间：
2021-04
期刊：
Nature reviews. Neuroscience
影响因子：
--
作者：
Richter JD;Zhao X
通讯作者：
Zhao X
影响因子：
4.6
作者：
Zafarullah, Marwa;Tang, Hiu-Tung;Tassone, Flora
通讯作者：
Tassone, Flora
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DOI：
10.3390/diagnostics11101780
发表时间：
2021-09-28
期刊：
Diagnostics (Basel, Switzerland)
影响因子：
--
作者：
Roth M;Ronco L;Cadavid D;Durbin-Johnson B;Hagerman RJ;Tassone F
通讯作者：
Tassone F
影响因子：
16.6
作者：
Wong JJ;Gao D;Nguyen TV;Kwok CT;van Geldermalsen M;Middleton R;Pinello N;Thoeng A;Nagarajah R;Holst J;Ritchie W;Rasko JEJ
通讯作者：
Rasko JEJ
影响因子：
81.5
作者：
Hagerman, Randi J.;Berry-Kravis, Elizabeth;Hagerman, Paul J.
通讯作者：
Hagerman, Paul J.