Zwemer Lillian M, Nolin Sarah L, Okamoto Patricia M, Eisenberg Marcia, Wick Heather C, Bianchi Diana W
Mother Infant Research Institute, Tufts Medical Center, Boston, MA, USA.
New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
Prenat Diagn. 2017 Jan;37(1):43-52. doi: 10.1002/pd.4928. Epub 2016 Oct 25.
We tested the hypothesis that FMR1 expansions would result in global gene dysregulation as early as the second trimester of human fetal development.
Using cell-free fetal RNA obtained from amniotic fluid supernatant and expression microarrays, we compared RNA levels in samples from fetuses with premutation or full mutation allele expansions with control samples.
We found clear signals of differential gene expression relating to a variety of cellular functions, including ubiquitination, mitochondrial function, and neuronal/synaptic architecture. Additionally, among the genes showing differential gene expression, we saw links to related diseases of intellectual disability and motor function. Finally, within the unique molecular phenotypes established for each mutation set, we saw clear signatures of mitochondrial dysfunction and disrupted neurological function. Patterns of differential gene expression were very different in male and female fetuses with premutation alleles.
These results support a model for which genetic misregulation during fetal development may set the stage for late clinical manifestations of FMR1-related disorders. © 2016 John Wiley & Sons, Ltd.
我们检验了这样一个假设，即脆性X智力低下基因1（FMR1）的扩增早在人类胎儿发育的中期就会导致整体基因失调。
我们使用从羊水上清液中获取的游离胎儿RNA和表达微阵列，将具有前突变或全突变等位基因扩增的胎儿样本中的RNA水平与对照样本进行了比较。
我们发现了与多种细胞功能相关的基因差异表达的明显信号，这些功能包括泛素化、线粒体功能以及神经元/突触结构。此外，在显示基因差异表达的基因中，我们发现了与智力残疾和运动功能相关疾病的联系。最后，在为每个突变组建立的独特分子表型中，我们看到了线粒体功能障碍和神经功能紊乱的明显特征。具有前突变等位基因的男性和女性胎儿的基因差异表达模式非常不同。
这些结果支持了一种模型，即胎儿发育过程中的基因调控异常可能为FMR1相关疾病的晚期临床表现奠定基础。© 2016约翰威立父子有限公司
