Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
500
result(s) for
"Fragile X syndrome Genetic aspects."
Sort by:
Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease
Noncoding repeat expansions cause various neuromuscular diseases, including myotonic dystrophies, fragile X tremor/ataxia syndrome, some spinocerebellar ataxias, amyotrophic lateral sclerosis and benign adult familial myoclonic epilepsies. Inspired by the striking similarities in the clinical and neuroimaging findings between neuronal intranuclear inclusion disease (NIID) and fragile X tremor/ataxia syndrome caused by noncoding CGG repeat expansions in
FMR1
, we directly searched for repeat expansion mutations and identified noncoding CGG repeat expansions in
NBPF19
(
NOTCH2NLC
) as the causative mutations for NIID. Further prompted by the similarities in the clinical and neuroimaging findings with NIID, we identified similar noncoding CGG repeat expansions in two other diseases: oculopharyngeal myopathy with leukoencephalopathy and oculopharyngodistal myopathy, in
LOC642361
/
NUTM2B-AS1
and
LRP12
, respectively. These findings expand our knowledge of the clinical spectra of diseases caused by expansions of the same repeat motif, and further highlight how directly searching for expanded repeats can help identify mutations underlying diseases.
Whole-genome sequencing identifies noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and oculopharyngeal myopathy with leukoencephalopathy, three disorders with overlapping clinical features and neuroimaging findings.
Journal Article
The translation of translational control by FMRP: therapeutic targets for FXS
In this review, the authors discuss the function of fragile X mental retardation protein (FMRP) in regulating the synthesis of plasticity-related target proteins. The authors review the known mRNA targets of FMRP and discuss the potential therapeutic implications of this research.
De novo
protein synthesis is necessary for long-lasting modifications in synaptic strength and dendritic spine dynamics that underlie cognition. Fragile X syndrome (FXS), characterized by intellectual disability and autistic behaviors, holds promise for revealing the molecular basis for these long-term changes in neuronal function. Loss of function of the fragile X mental retardation protein (FMRP) results in defects in synaptic plasticity and cognition in many models of the disease. FMRP is a polyribosome-associated RNA-binding protein that regulates the synthesis of a set of plasticity-reated proteins by stalling ribosomal translocation on target mRNAs. The recent identification of mRNA targets of FMRP and its upstream regulators, and the use of small molecules to stall ribosomes in the absence of FMRP, have the potential to be translated into new therapeutic avenues for the treatment of FXS.
Journal Article
Dysregulation and restoration of translational homeostasis in fragile X syndrome
Key Points
Fragile X syndrome (FXS) is an X-linked heritable form of intellectual disability with a high incidence of autism spectrum disorder (ASD) characteristics. FXS is recognized as the most commonly inherited form of intellectual disability and ASD.
FXS is a CGG-repeat disease that causes silencing of the fragile X mental retardation 1 (
FMR1
) gene and loss of its protein product, FMR protein (FMRP).
FMRP is an mRNA-binding protein that mainly acts as a translational repressor. Excessive basal protein synthesis has been reported in FXS model mice that lack
Fmr1
as well as in cells from individuals with FXS.
Ten studies have reported genetic rescue of FXS pathophysiologies in
Fmr1
-knockout mice. Eight of these genetic rescues normalize excessive protein synthesis in the FXS model mice, consistent with the hypothesis that resetting translational homeostasis is central to the rescue mechanisms.
If resetting translational homeostasis is central to the rescue of FXS pathophysiologies, it suggests that there are specific mRNAs whose translation is elevated in FXS and normalized in the genetic rescues. These mRNAs are likely to have profound implications for the aetiology of FXS.
Fragile X syndrome (FXS) results from the loss of the RNA-binding protein fragile X mental retardation protein (FMRP). Here, Klann and colleagues discuss the ways in which FMRP loss disrupts mRNA translation in the brain and the outcomes of genetic and pharmacological attempts to reset translational homeostasis in FXS model mice.
Fragile X syndrome (FXS), the most-frequently inherited form of intellectual disability and the most-prevalent single-gene cause of autism, results from a lack of fragile X mental retardation protein (FMRP), an RNA-binding protein that acts, in most cases, to repress translation. Multiple pharmacological and genetic manipulations that target receptors, scaffolding proteins, kinases and translational control proteins can rescue neuronal morphology, synaptic function and behavioural phenotypes in FXS model mice, presumably by reducing excessive neuronal translation to normal levels. Such rescue strategies might also be explored in the future to identify the mRNAs that are critical for FXS pathophysiology.
Journal Article
The molecular biology of FMRP: new insights into fragile X syndrome
Fragile X mental retardation protein (FMRP) is the product of the fragile X mental retardation 1 gene (FMR1), a gene that — when epigenetically inactivated by a triplet nucleotide repeat expansion — causes the neurodevelopmental disorder fragile X syndrome (FXS). FMRP is a widely expressed RNA-binding protein with activity that is essential for proper synaptic plasticity and architecture, aspects of neural function that are known to go awry in FXS. Although the neurophysiology of FXS has been described in remarkable detail, research focusing on the molecular biology of FMRP has only scratched the surface. For more than two decades, FMRP has been well established as a translational repressor; however, recent whole transcriptome and translatome analyses in mouse and human models of FXS have shown that FMRP is involved in the regulation of nearly all aspects of gene expression. The emerging mechanistic details of the mechanisms by which FMRP regulates gene expression may offer ways to design new therapies for FXS.Inactivation of the gene encoding fragile X mental retardation protein (FMRP) drives the impairments in brain development and function that underlie fragile X syndrome. Richter and Zhao illustrate how innovative genetic and molecular biology tools have enhanced our understanding of both FMRP’s function and the causes of fragile X syndrome pathophysiology.
Journal Article
Channelopathies in fragile X syndrome
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and the leading monogenic cause of autism. The condition stems from loss of fragile X mental retardation protein (FMRP), which regulates a wide range of ion channels via translational control, protein–protein interactions and second messenger pathways. Rapidly increasing evidence demonstrates that loss of FMRP leads to numerous ion channel dysfunctions (that is, channelopathies), which in turn contribute significantly to FXS pathophysiology. Consistent with this, pharmacological or genetic interventions that target dysregulated ion channels effectively restore neuronal excitability, synaptic function and behavioural phenotypes in FXS animal models. Recent studies further support a role for direct and rapid FMRP–channel interactions in regulating ion channel function. This Review lays out the current state of knowledge in the field regarding channelopathies and the pathogenesis of FXS, including promising therapeutic implications.Ion channel dysfunctions contribute significantly to fragile X pathophysiology. In this Review, Deng and Klyachko discuss the mechanisms underlying the effects of these channelopathies in fragile X syndrome, and the therapeutic potential of pharmacological interventions that target ion channels.
Journal Article
Tracking the Fragile X Mental Retardation Protein in a Highly Ordered Neuronal RiboNucleoParticles Population: A Link between Stalled Polyribosomes and RNA Granules
Local translation at the synapse plays key roles in neuron development and activity-dependent synaptic plasticity. mRNAs are translocated from the neuronal soma to the distant synapses as compacted ribonucleoparticles referred to as RNA granules. These contain many RNA-binding proteins, including the Fragile X Mental Retardation Protein (FMRP), the absence of which results in Fragile X Syndrome, the most common inherited form of intellectual disability and the leading genetic cause of autism. Using FMRP as a tracer, we purified a specific population of RNA granules from mouse brain homogenates. Protein composition analyses revealed a strong relationship between polyribosomes and RNA granules. However, the latter have distinct architectural and structural properties, since they are detected as close compact structures as observed by electron microscopy, and converging evidence point to the possibility that these structures emerge from stalled polyribosomes. Time-lapse video microscopy indicated that single granules merge to form cargoes that are transported from the soma to distal locations. Transcriptomic analyses showed that a subset of mRNAs involved in cytoskeleton remodelling and neural development is selectively enriched in RNA granules. One third of the putative mRNA targets described for FMRP appear to be transported in granules and FMRP is more abundant in granules than in polyribosomes. This observation supports a primary role for FMRP in granules biology. Our findings open new avenues for the study of RNA granule dysfunctions in animal models of nervous system disorders, such as Fragile X syndrome.
Journal Article
Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome
This study shows that the interaction between metabotropic glutamate receptor 5 (mGluR5) and a specific form of the scaffolding protein Homer contributes to the behavioral and physiological defects in the mouse model of fragile X syndrome.
Enhanced metabotropic glutamate receptor subunit 5 (mGluR5) function is causally associated with the pathophysiology of fragile X syndrome, a leading inherited cause of intellectual disability and autism. Here we provide evidence that altered mGluR5-Homer scaffolds contribute to mGluR5 dysfunction and phenotypes in the fragile X syndrome mouse model,
Fmr1
knockout (
Fmr1
−/
y
). In
Fmr1
−/
y
mice, mGluR5 was less associated with long Homer isoforms but more associated with the short Homer1a. Genetic deletion of Homer1a restored mGluR5–long Homer scaffolds and corrected several phenotypes in
Fmr1
−/
y
mice, including altered mGluR5 signaling, neocortical circuit dysfunction and behavior. Acute, peptide-mediated disruption of mGluR5-Homer scaffolds in wild-type mice mimicked many
Fmr1
−/
y
phenotypes. In contrast, Homer1a deletion did not rescue altered mGluR-dependent long-term synaptic depression or translational control of target mRNAs of fragile X mental retardation protein, the gene product of
Fmr1
. Our findings reveal new functions for mGluR5-Homer interactions in the brain and delineate distinct mechanisms of mGluR5 dysfunction in a mouse model of cognitive dysfunction and autism.
Journal Article
A randomized, controlled trial of ZYN002 cannabidiol transdermal gel in children and adolescents with fragile X syndrome (CONNECT-FX)
Background
Fragile X syndrome (FXS) is associated with dysregulated endocannabinoid signaling and may therefore respond to cannabidiol therapy.
Design
CONNECT-FX was a double-blind, randomized phase 3 trial assessing efficacy and safety of ZYN002, transdermal cannabidiol gel, for the treatment of behavioral symptoms in children and adolescents with FXS.
Methods
Patients were randomized to 12 weeks of ZYN002 (250 mg or 500 mg daily [weight-based]) or placebo, as add-on to standard of care. The primary endpoint assessed change in social avoidance (SA) measured by the Aberrant Behavior Checklist–Community Edition FXS (ABC-C
FXS
) SA subscale in a full cohort of patients with a FXS full mutation, regardless of the
FMR1
methylation status. Ad hoc analyses assessed efficacy in patients with ≥ 90% and 100% methylation of the promoter region of the
FMR1
gene, in whom
FMR1
gene silencing is most likely.
Results
A total of 212 patients, mean age 9.7 years, 75% males, were enrolled. A total of 169 (79.7%) patients presented with ≥ 90% methylation of the
FMR1
promoter and full mutation of
FMR1
. Although statistical significance for the primary endpoint was not achieved in the full cohort, significant improvement was demonstrated in patients with ≥ 90% methylation of
FMR1
(nominal
P
= 0.020). This group also achieved statistically significant improvements in Caregiver Global Impression‐Change in SA and isolation, irritable and disruptive behaviors, and social interactions (nominal
P
-values:
P
= 0.038,
P
= 0.028, and
P
= 0.002). Similar results were seen in patients with 100% methylation of
FMR1
. ZYN002 was safe and well tolerated. All treatment-emergent adverse events (TEAEs) were mild or moderate. The most common treatment-related TEAE was application site pain (ZYN002: 6.4%; placebo: 1.0%).
Conclusions
In CONNECT-FX, ZYN002 was well tolerated in patients with FXS and demonstrated evidence of efficacy with a favorable benefit risk relationship in patients with ≥ 90% methylation of the
FMR1
gene, in whom gene silencing is most likely, and the impact of FXS is typically most severe.
Trial registration
The CONNECT-FX trial is registered on Clinicaltrials.gov (NCT03614663).
Journal Article