A Genotype-Phenotype Study of High-Resolution FMR1 Nucleic Acid and Protein Analyses in Fragile X Patients with Neurobehavioral Assessments.
A Genotype-Phenotype Study of High-Resolution FMR1 Nucleic Acid and Protein Analyses in Fragile X Patients with Neurobehavioral Assessments.
复制标题
脆性X患者神经行为评估的高分辨率FMR 1核酸和蛋白质分析的基因型-表型研究。
DOI：
10.3390/brainsci10100694
复制
发表时间：
2020-09-30
期刊：
影响因子：
3.3
通讯作者：
Latham GJ
中科院分区：
文献类型：
--
作者：
Budimirovic DB;Schlageter A;Filipovic-Sadic S;Protic DD;Bram E;Mahone EM;Nicholson K;Culp K;Javanmardi K;Kemppainen J;Hadd A;Sharp K;Adayev T;LaFauci G;Dobkin C;Zhou L;Brown WT;Berry-Kravis E;Kaufmann WE;Latham GJ
脆性X综合征（FXS）是由FMR1基因沉默引起的，该基因编码一种在突触可塑性中起关键作用的蛋白质。FMR1沉默背后的分子异常，即CGG重复扩增，已被很好地表征；然而，利用来自特征良好的FXS患者的生物样本来描绘从DNA到RNA到蛋白质的途径是有限的。由于FXS是一种与智力残疾（ID）和自闭症谱系障碍（ASD）相关的常见的典型遗传疾病，因此全面评估FMR1 dna - rna -蛋白通路及其与神经行为表型的相关性是一个优先考虑的问题。我们对代表FMR1扩增范围的一组细胞系应用了9种敏感和定量的方法来评估FMR1 DNA、RNA和FMRP参数。然后，我们对来自不同FMR1扩增患者队列的血液和口腔标本进行了最具信息量的检测，重点是FXS患者（N = 42, N = 31， FMRP测量）。具有FMRP数据的组也根据其神经行为特征进行了全面评估，这允许分子-神经行为的相关性。在细胞系和血液样本中，FMR1 CGG重复扩增、甲基化水平和FMRP水平与之前的FMR1基因组和蛋白质研究结果一致。他们还证明了血液和口腔标本之间的高度一致。这些分析进一步证实了先前关于甲基化镶嵌现象相对较高患病率（略高于50%的样本）的报告。分子-神经行为相关性证实了FXS表型总体严重程度与FMRP水平下降之间的负相关关系（N = 26名男性，平均4.2±3.3 pg FMRP/ng基因组DNA）。其他有趣的发现包括FXS合并ASD的诊断与两倍低的FMRP水平之间的显著关系（平均2.8±1.3 pg FMRP/ng基因组DNA， p = 0.04），特别是在年龄较小和智商调整的男性中（平均年龄6.9±0.9岁，平均3.2±1.2 pg FMRP/ng基因组DNA， 57%为严重ASD），与没有ASD的FXS相比。在只有男性的亚群中，那些严重的ID患者的FMRP水平更低，与ASD状态无关。结果强调了FMR1扩增、基因甲基化和FMRP缺陷之间的联系。FMRP缺乏与神经行为表型总体严重程度之间的关联需要在更大的患者队列中进行随访研究。它们将有价值地证实并潜在地扩展我们关于ASD和其他神经行为特征以及FMRP缺陷程度之间关系的初步发现。FXS个体的分子谱分析可能在研究和临床实践中具有重要意义。
Fragile X syndrome (FXS) is caused by silencing of the FMR1 gene, which encodes a protein with a critical role in synaptic plasticity. The molecular abnormality underlying FMR1 silencing, CGG repeat expansion, is well characterized; however, delineation of the pathway from DNA to RNA to protein using biosamples from well characterized patients with FXS is limited. Since FXS is a common and prototypical genetic disorder associated with intellectual disability (ID) and autism spectrum disorder (ASD), a comprehensive assessment of the FMR1 DNA-RNA-protein pathway and its correlations with the neurobehavioral phenotype is a priority. We applied nine sensitive and quantitative assays evaluating FMR1 DNA, RNA, and FMRP parameters to a reference set of cell lines representing the range of FMR1 expansions. We then used the most informative of these assays on blood and buccal specimens from cohorts of patients with different FMR1 expansions, with emphasis on those with FXS (N = 42 total, N = 31 with FMRP measurements). The group with FMRP data was also evaluated comprehensively in terms of its neurobehavioral profile, which allowed molecular–neurobehavioral correlations. FMR1 CGG repeat expansions, methylation levels, and FMRP levels, in both cell lines and blood samples, were consistent with findings of previous FMR1 genomic and protein studies. They also demonstrated a high level of agreement between blood and buccal specimens. These assays further corroborated previous reports of the relatively high prevalence of methylation mosaicism (slightly over 50% of the samples). Molecular-neurobehavioral correlations confirmed the inverse relationship between overall severity of the FXS phenotype and decrease in FMRP levels (N = 26 males, mean 4.2 ± 3.3 pg FMRP/ng genomic DNA). Other intriguing findings included a significant relationship between the diagnosis of FXS with ASD and two-fold lower levels of FMRP (mean 2.8 ± 1.3 pg FMRP/ng genomic DNA, p = 0.04), in particular observed in younger age- and IQ-adjusted males (mean age 6.9 ± 0.9 years with mean 3.2 ± 1.2 pg FMRP/ng genomic DNA, 57% with severe ASD), compared to FXS without ASD. Those with severe ID had even lower FMRP levels independent of ASD status in the male-only subset. The results underscore the link between FMR1 expansion, gene methylation, and FMRP deficit. The association between FMRP deficiency and overall severity of the neurobehavioral phenotype invites follow up studies in larger patient cohorts. They would be valuable to confirm and potentially extend our initial findings of the relationship between ASD and other neurobehavioral features and the magnitude of FMRP deficit. Molecular profiling of individuals with FXS may have important implications in research and clinical practice.
登录
查看更多内容
影响因子：
4.7
作者：
Fatemi, S. Hossein;Folsom, Timothy D.
通讯作者：
Folsom, Timothy D.
影响因子：
2.1
作者：
Berry-Kravis E;Sumis A;Hervey C;Mathur S
通讯作者：
Mathur S
影响因子：
3.4
作者：
Erickson, Craig A.;Stigler, Kimberly A.;McDougle, Christopher J.
通讯作者：
McDougle, Christopher J.
影响因子：
4.9
作者：
Baker, Emma K.;Arpone, Marta;Godler, David E.
通讯作者：
Godler, David E.
影响因子：
14.9
作者：
Genç, B;Müller-Hartmann, H;Doerfler, W
通讯作者：
Doerfler, W