Global transcriptome dysregulation in second trimester fetuses with FMR1 expansions

Abstract

Objective We tested the hypothesis that FMR1 expansions would result in global gene dysregulation as early as the second trimester of human fetal development. Method 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 to control samples. Results We found clear signals of differential gene expression relating to a variety of cellular functions, including ubiquitination, mitochondrial function and neuronal/synaptic architecture, among others. 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. Conclusion These results support a model for which genetic misregulation during fetal development may set the stage for late clinical manifestations of FMR1-related disorders.

Amniotic fluid cell-free transcriptome: a glimpse into fetal development and placental cellular dynamics during normal pregnancy

“…Among the omics platforms used to study AF (see Kamath-Rayne et al [88] for a review), the analysis of cell-free mRNA (cfRNA) has the advantage of being easier to profile than its proteomics [45,89,90] and metabolomics [91][92][93][94][95][96] counterparts. The AF cfRNAs are thought to be contributed directly by the fetus and by apoptotic amniocytes [97] and have been shown to be altered by physiologic and pathologic factors such as gestational age [83,85,98], fetal sex [83], maternal obesity [99], genetic syndromes [100][101][102], and neonatal comorbidities [85] (see Zwemer and Bianchi for a review [97]). Of all the factors previously reported to be reflected in the AF transcriptome, advancing gestation seems to have the most dramatic effect on the AF transcriptome considering the number of genes differentially expressed.…”

Amniotic fluid transcriptomics reflects novel disease mechanisms in fetuses with myelomeningocele

“…Gene expression can be assessed from various organs including brain and spinal cord. 6–9 Previous reports of the AF cfRNA transcriptome analysis using microarrays identified specific and molecular mechanisms in fetal diseases such as aneuploidies 10,11 , twin-twin transfusion syndrome 12 , maternal obesity 9 and fragile X syndrome 13 . We hypothesized that analysis of the AF transcriptome using cfRNA will provide novel insights into myelomeningocele pathophysiology that will lead to the identification of novel therapeutic targets.…”

Cortical gyrification and its relationships with molecular measures and cognition in children with the FMR1 premutation

“…Loss of FMRP expression in fragile X syndrome (FXS) can lead to periventricular nodular heterotopia, the presence of nodules of gray matter along the lateral ventricles due to migration failure in some of the neurons during embryonic development 44 . Additional evidence supporting a potential link between FMR1 gene and aberrant gyrification include the FMRP regulation of microtubule network formation and transport of mitochondria in flies 48 , disoriented neuronal migration in embryonic knock-in mouse models of the FMR1 premutation 26 , and dysregulated global transcriptome in the second trimester of human PM fetuses using cell-free fetal RNA obtained from amniotic fluid supernatant 49 .…”