Fmr1-Deficiency Impacts Body Composition, Skeleton, and Bone Microstructure in a Mouse Model of Fragile X Syndrome

Fragile X syndrome (FXS) is a neurodevelopmental disorder associated with intellectual disability, hyperactivity, and autism. FXS is due to the silencing of the X-linked FMR1 gene. Murine models of FXS, knock-out (KO) for the murine homolog Fmr1, have been generated, exhibiting CNS-related behavioral, and neuronal anomalies reminiscent of the human phenotypes. As a reflection of the almost ubiquitous expression of the FMR1 gene, FXS is also accompanied by physical abnormalities. This suggests that the FMR1-deficiency could impact skeletal ontogenesis. In the present study, we highlight that Fmr1-KO mice display changes in body composition with an increase in body weight, likely due to both increase of skeleton length and muscular mass along with reduced visceral adiposity. We also show that, while Fmr1-deficiency has no overt impact on cortical bone mineral density (BMD), cortical thickness was increased, and cortical eccentricity was decreased in the femurs from Fmr1-KO mice as compared to controls. Also, trabecular pore volume was reduced and trabecular thickness distribution was shifted toward higher ranges in Fmr1-KO femurs. Finally, we show that Fmr1-KO mice display increased physical activity. Although the precise molecular signaling mechanism that produces these skeletal and bone microstructure changes remains to be determined, our study warrants further investigation on the impact of FMR1-deficiency on whole-body composition, as well as skeletal and bone architecture.
Source: Frontiers in Endocrinology - Category: Endocrinology Source Type: research

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CONCLUSION: In this concise review, we summarize and analyze the main hypotheses proposed to explain synaptic dysregulation in FXS, by reviewing the scientific evidence that led to pharmaceutical clinical trials and their outcome. PMID: 31682210 [PubMed - as supplied by publisher]
Source: Epilepsy Curr - Category: Neurology Authors: Tags: Curr Pharm Des Source Type: research
Introduction: Fragile X Syndrome (FXS) is the leading form of inherited intellectual disability and autism spectrum disorder, caused by a tri-nucleotide CGG repeat expansion in the promoter region of the FMR1 gene [1]. The cognitive profile in FXS includes deficits in executive control and in visuospatial abilities, as well as in language and severe behavioural alterations with hyperactivity, impulsivity, anxiety: the condition often is associated with medical comorbidities among which epilepsy [1].
Source: Gait and Posture - Category: Orthopaedics Authors: Source Type: research
Publication date: Available online 22 May 2018 Source:Neuroscience Author(s): Christine E. Boone, Heydar Davoudi, Jon B. Harrold, David J. Foster Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and single-gene cause of autism spectrum disorder. The Fmr1 null mouse models much of the human disease including hyperarousal, sensory hypersensitivity, seizure activity, and hippocampus-dependent cognitive impairment. Sleep architecture is disorganized in FXS patients, but has not been examined in Fmr1 knockout (Fmr1-KO) mice. Hippocampal neural activity during sleep, which is implicated in ...
Source: Neuroscience - Category: Neuroscience Source Type: research
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, typically due to CGG‐repeat expansions in the FMR1 gene leading to lack of expression. We identified a rare FMR1 gene mutation (c.413G>A), previously reported in a single patient and reviewed the literature for other rare FMR1 mutations. Our patient at 10 years of age presented with the classical findings of FXS including intellectual disability, autism, craniofacial findings, hyperextensibility, fleshy hands, flat feet, unsteady gait, and seizures but without the typical CGG‐repeat expansion. He had more features of FXS than the ...
Source: American Journal of Medical Genetics Part A - Category: Genetics & Stem Cells Authors: Tags: ORIGINAL ARTICLE Source Type: research
Authors: Pellerin D, Lortie A, Corbin F Abstract Fragile X Syndrome (FXS) is the most common inherited form of intellectual disability and the leading monogenic cause of autism spectrum disorders (ASD). Despite a large number of therapeutics developed in past years, there is currently no targeted treatment approved for FXS. In fact, translation of the positive and very promising preclinical findings from animal models to human subjects has so far fallen short owing in part to the low predictive validity of the Fmr1 ko mouse, an overly simplistic model of the complex human disease. This issue stresses the critical n...
Source: Platelets - Category: Hematology Tags: Platelets Source Type: research
We report that larval locomotion is augmented in a Drosophila FXS model. Genetic or pharmacological intervention on the BMPR2-LIMK pathway ameliorated the synaptic abnormality and locomotion phenotypes of FXS larvae, as well as hyperactivity in an FXS mouse model. Our study demonstrates that (i) the BMPR2-LIMK pathway is a promising therapeutic target for FXS and (ii) the locomotion phenotype of FXS larvae is a quantitative functional readout for the neuromorphological phenotype associated with FXS and is amenable to the screening novel FXS therapeutics. PMID: 28465421 [PubMed - in process]
Source: Science Signaling - Category: Biomedical Science Authors: Tags: Sci Signal Source Type: research
We report that larval locomotion is augmented in a Drosophila FXS model. Genetic or pharmacological intervention on the BMPR2-LIMK pathway ameliorated the synaptic abnormality and locomotion phenotypes of FXS larvae, as well as hyperactivity in an FXS mouse model. Our study demonstrates that (i) the BMPR2-LIMK pathway is a promising therapeutic target for FXS and (ii) the locomotion phenotype of FXS larvae is a quantitative functional readout for the neuromorphological phenotype associated with FXS and is amenable to the screening novel FXS therapeutics.
Source: Signal Transduction Knowledge Environment - Category: Science Authors: Tags: STKE Research Resources Source Type: news
Abstract Many genetic markers are associated with atypical developmental outcomes. In this article, we review evidence from studies on the most common inherited cause of intellectual disability, fragile X syndrome (FXS). We aim to highlight general developmental consequences as well as specific implications for autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), including the complexity of characterizing ASD and ADHD symptoms in FXS. We address three issues: First, links among genes, brain, and cognition need to be situated in a developmental context, even in a monogenic disorder like FXS. S...
Source: Child Development Perspectives - Category: Child Development Authors: Tags: Article Source Type: research
Our bodies are wired for sensory input. Touch, (which includes temperature, texture and pressure), taste, sound, sight and smell are the ways in which we explore the world, from the moment we enter it. When all systems are functioning, we experience a feedback loop. For example, if you were shivering from the cold and wanted to feel warmth, you might put on a cozy sweater or wrap a fleece blanket around your shoulders. Your body would likely respond by relaxing, followed by an emotional relief and perhaps even a sigh. The next time you felt chilly, you would remember what it took to remedy that sensation and follow th...
Source: Psych Central - Category: Psychiatry Authors: Tags: Attention Deficit Disorder Autism / Asperger's Caregivers Children and Teens Genetics Parenting Asperger Syndrome Pervasive Developmental Disorder Sensory integration dysfunction Sensory Processing Disorder Source Type: news
This study demonstrates that FXS mice can be used to study the underlying biological mechanism(s) mediating FXS vocalization abnormalities. PMID: 27142239 [PubMed - as supplied by publisher]
Source: Behavioural Brain Research - Category: Neurology Authors: Tags: Behav Brain Res Source Type: research
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