scholarly journals The Contribution of Pluripotent Stem Cell (PSC)-Based Models to the Study of Fragile X Syndrome (FXS)

2019 ◽  
Vol 9 (2) ◽  
pp. 42 ◽  
Author(s):  
Manar Abu Diab ◽  
Rachel Eiges
Keyword(s):  
Stem Cells ◽  
Gene Silencing ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Embryonic Stem ◽  
Cgg Repeat ◽  
Molecular Features ◽  
Epigenetic Gene Silencing ◽  
Mental Retardation Protein ◽  
Induced Pluripotent

Fragile X syndrome (FXS) is the most common heritable form of cognitive impairment. It results from a deficiency in the fragile X mental retardation protein (FMRP) due to a CGG repeat expansion in the 5′-UTR of the X-linked FMR1 gene. When CGGs expand beyond 200 copies, they lead to epigenetic gene silencing of the gene. In addition, the greater the allele size, the more likely it will become unstable and exhibit mosaicism for expansion size between and within tissues in affected individuals. The timing and mechanisms of FMR1 epigenetic gene silencing and repeat instability are far from being understood given the lack of appropriate cellular and animal models that can fully recapitulate the molecular features characteristic of the disease pathogenesis in humans. This review summarizes the data collected to date from mutant human embryonic stem cells, induced pluripotent stem cells, and hybrid fusions, and discusses their contribution to the investigation of FXS, their key limitations, and future prospects.

scholarly journals Autism Profiles of Males With Fragile X Syndrome

2008 ◽  
Vol 113 (6) ◽  
pp. 427-438 ◽  
Author(s):  
Susan W. Harris ◽  
David Hessl ◽  
Beth Goodlin-Jones ◽  
Jessica Ferranti ◽  
Susan Bacalman ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Autism Diagnosis ◽  
Cgg Repeat ◽  
Molecular Features ◽  
Fmr1 Mrna ◽  
Two Measures ◽  
Dsm Iv ◽  
Relationship Of ◽  
The Relationship

Abstract Autism, which is common in individuals with fragile X syndrome, is often difficult to diagnose. We compared the diagnostic classifications of two measures for autism diagnosis, the ADOS and the ADI-R, in addition to the DSM-IV-TR in 63 males with this syndrome. Overall, 30% of the subjects met criteria for autistic disorder and 30% met criteria for PDD-NOS. The classifications on the ADOS and DSM-IV-TR were most similar, whereas the ADI-R classified subjects as autistic much more frequently. We further investigated the relationship of both FMRP and FMR1 mRNA to symptoms of autism in this cohort and found no significant relationship between the measures of autism and molecular features, including FMRP, FMR1 mRNA, and CGG repeat number.

scholarly journals Developmental Study of Fragile X Syndrome Using Human Embryonic Stem Cells Derived from Preimplantation Genetically Diagnosed Embryos

2007 ◽  
Vol 1 (5) ◽  
pp. 568-577 ◽  
Author(s):  
Rachel Eiges ◽  
Achia Urbach ◽  
Mira Malcov ◽  
Tsvia Frumkin ◽  
Tamar Schwartz ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Fragile X Syndrome ◽  
Human Embryonic Stem Cells ◽  
Fragile X ◽  
Embryonic Stem ◽  
Developmental Study

scholarly journals Targeted Reactivation of FMR1 Transcription in Fragile X Syndrome Embryonic Stem Cells

2018 ◽  
Author(s):  
Jill M. Haenfler ◽  
Geena Skariah ◽  
Caitlin M. Rodriguez ◽  
Andre Monteiro da Rocha ◽  
Jack M. Parent ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Embryonic Stem ◽  
Transcriptional Silencing ◽  
Hesc Line ◽  
Human Patient ◽  
Cgg Repeat ◽  
Heterochromatin Formation ◽  
Fmr1 Mrna

ABSTRACTFragile X Syndrome (FXS) is the most common inherited cause of intellectual disability and autism. It results from expansion of a CGG nucleotide repeat in the 5’ untranslated region of FMR1. Large expansions elicit repeat and promoter hyper-methylation, heterochromatin formation, FMR1 transcriptional silencing, and loss of the Fragile X protein, FMRP. Efforts aimed at correcting the sequelae resultant from FMRP loss have thus far proven insufficient, perhaps because of FMRP’s pleiotropic functions. As the repeats do not disrupt the FMRP coding sequence, reactivation of endogenous FMR1 gene expression could correct the proximal event in FXS pathogenesis. Here we utilize the CRISPR/dCAS9 system to selectively re-activate transcription from the silenced FMR1 locus. Fusion of the transcriptional activator VP192 to dCAS9 robustly enhances FMR1 transcription and increases FMRP levels when targeted directly to the CGG repeat in human cells. Using a previously uncharacterized FXS human embryonic stem cell (hESC) line which acquires transcriptional silencing with serial passaging, we achieved locus-specific transcriptional re-activation of FMR1 mRNA expression despite promoter and repeat methylation. These studies demonstrate that FMR1 mRNA expression can be selectively reactivated in human patient cells, creating a pathway forward for therapeutic development in Fragile X Syndrome.

Depletion of the Fragile X Mental Retardation Protein in Embryonic Stem Cells Alters the Kinetics of Neurogenesis

Stem Cells ◽  
2016 ◽  
Vol 35 (2) ◽  
pp. 374-385 ◽  
Author(s):  
Olfa Khalfallah ◽  
Marielle Jarjat ◽  
Laetitia Davidovic ◽  
Nicolas Nottet ◽  
Sandrine Cestèle ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mental Retardation ◽  
Embryonic Stem Cells ◽  
Fragile X ◽  
Embryonic Stem ◽  
Fragile X Mental Retardation ◽  
Mental Retardation Protein ◽  
Kinetics Of

scholarly journals Targeted Reactivation of FMR1 Transcription in Fragile X Syndrome Embryonic Stem Cells

2018 ◽  
Vol 11 ◽  
Author(s):  
Jill M. Haenfler ◽  
Geena Skariah ◽  
Caitlin M. Rodriguez ◽  
Andre Monteiro da Rocha ◽  
Jack M. Parent ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Embryonic Stem
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