scholarly journals Alterations of Amino Acids and Monoamine Metabolism in Male Fmr1 Knockout Mice: A Putative Animal Model of the Human Fragile X Mental Retardation Syndrome

2001 ◽  
Vol 8 (4) ◽  
pp. 285-298 ◽  
Author(s):  
Michael Gruss ◽  
Katharina Braun
Keyword(s):  
Amino Acids ◽  
Animal Model ◽  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Knockout Mice ◽  
Fragile X ◽  
Fragile X Mental Retardation ◽  
Behavioral Abnormalities ◽  
Cortical Regions ◽  
Knockout Animals

The Fragile X syndrome, a common form of mental retardation in humans, is caused by silencing the fragile X mental retardation (FMR1) geneleading to the absence of the encoded fragile X mental retardation protein 1 (FMRP). We describe morphological and behavioral abnormalities for both affected humans and Fmr1 knockout mice, a putative animal model for the human Fragile X syndrome. The aim of the present study was to identify possible neurochemical abnormalities in Fmr1 knockout mice, with particular focus on neurotransmission. Significant region-specific differences: of basal neurotransmitter and metabolite levels were found between wildtype and Fmr1 knockout animals, predominantly in juveniles (post-natal days 28 to 31). Adults (postnatal days 209 to 221) showed only few abnormalities as compared with the wildtype. In juvenile knockout mice, aspartate and taurine were especially increased in cortical regions, striatum, hippocampus, cerebellum, and brainstem. In addition, juveniles showed an altered balance between excitatory and inhibitory amino acids in the caudal cortex, hippocampus, and brainstem. We detected very few differences in monoamine turnover in both age stages. The results presented here provide the first evidence that lack of FMRP expression in FMRP knockout mice is accompanied by age-dependent, region-specific alterations in neurotransmission.

scholarly journals Role of microRNA Pathway in Mental Retardation

2007 ◽  
Vol 7 ◽  
pp. 146-154 ◽  
Author(s):  
Abrar Qurashi ◽  
Shuang Chang ◽  
Peng Jin
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Genetic Basis ◽  
Fragile X ◽  
Biological Pathways ◽  
Fragile X Mental Retardation ◽  
Mental Retardation Protein ◽  
Mirna Pathway ◽  
Microrna Pathway

Deficits in cognitive functions lead to mental retardation (MR). Understanding the genetic basis of inherited MR has provided insights into the pathogenesis of MR. Fragile X syndrome is one of the most common forms of inherited MR, caused by the loss of functional Fragile X Mental Retardation Protein (FMRP).MicroRNAs (miRNAs) are endogenous, single-stranded RNAs between 18 and 25 nucleotides in length, which have been implicated in diversified biological pathways. Recent studies have linked the miRNA pathway to fragile X syndrome. Here we review the role of the miRNA pathway in fragile X syndrome and discuss its implication in MR in general.

scholarly journals Comparative Behavioral Phenotypes of Fmr1 KO, Fxr2 Het, and Fmr1 KO/Fxr2 Het Mice

2019 ◽  
Vol 9 (1) ◽  
pp. 13 ◽  
Author(s):  
Rachel Saré ◽  
Christopher Figueroa ◽  
Abigail Lemons ◽  
Inna Loutaev ◽  
Carolyn Beebe Smith
Keyword(s):  
Mental Retardation ◽  
Intellectual Disability ◽  
Fragile X ◽  
Protein Product ◽  
Behavioral Phenotypes ◽  
Memory Impairments ◽  
Fragile X Mental Retardation ◽  
Behavioral Abnormalities ◽  
Mental Retardation Protein ◽  
Functional Consequences

Fragile X syndrome (FXS) is caused by silencing of the FMR1 gene leading to loss of the protein product fragile X mental retardation protein (FMRP). FXS is the most common monogenic cause of intellectual disability. There are two known mammalian paralogs of FMRP, FXR1P, and FXR2P. The functions of FXR1P and FXR2P and their possible roles in producing or modulating the phenotype observed in FXS are yet to be identified. Previous studies have revealed that mice lacking Fxr2 display similar behavioral abnormalities as Fmr1 knockout (KO) mice. In this study, we expand upon the behavioral phenotypes of Fmr1 KO and Fxr2+/− (Het) mice and compare them with Fmr1 KO/Fxr2 Het mice. We find that Fmr1 KO and Fmr1 KO/Fxr2 Het mice are similarly hyperactive compared to WT and Fxr2 Het mice. Fmr1 KO/Fxr2 Het mice have more severe learning and memory impairments than Fmr1 KO mice. Fmr1 KO mice display significantly impaired social behaviors compared to WT mice, which are paradoxically reversed in Fmr1 KO/Fxr2 Het mice. These results highlight the important functional consequences of loss or reduction of FMRP and FXR2P.

scholarly journals Macroorchidism in FMR1 Knockout Mice Is Caused by Increased Sertoli Cell Proliferation during Testicular Development*

Endocrinology ◽  
1998 ◽  
Vol 139 (1) ◽  
pp. 156-162 ◽  
Author(s):  
Karin E. Slegtenhorst-Eegdeman ◽  
Dirk G. de Rooij ◽  
Miriam Verhoef-Post ◽  
Henk J. G. van de Kant ◽  
Cathy E. Bakker ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Cell Proliferation ◽  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Sertoli Cell ◽  
Knockout Mice ◽  
Messenger Rna ◽  
Fragile X ◽  
Fsh Receptor ◽  
Cgg Repeat

Abstract The fragile X syndrome is the most frequent hereditary form of mental retardation. This X-linked disorder is, in most cases, caused by an unstable and expanding trinucleotide CGG repeat located in the 5′-untranslated region of the gene involved, the fragile X mental retardation 1 (FMR1) gene. Expansion of the CGG repeat to a length of more than 200 trinucleotides results in silencing of the FMR1 gene promoter and, thus, in an inactive gene. The clinical features of male fragile X patients include mental retardation, autistiform behavior, and characteristic facial features. In addition, macroorchidism is observed. To study the role of Sertoli cell proliferation and FSH signal transduction in the occurrence of macroorchidism in fragile X males, we made use of an animal model for the fragile X syndrome, an Fmr1 knockout mouse. The results indicate that in male Fmr1 knockout mice, the rate of Sertoli cell proliferation is increased from embryonic day 12 to 15 days postnatally. The onset and length of the period of Sertoli cell proliferation were not changed compared with those in the control males. Serum levels of FSH, FSH receptor messenger RNA expression, and short term effects of FSH on Sertoli cell function, as measured by down-regulation of FSH receptor messenger RNA, were not changed. We conclude that macroorchidism in Fmr1 knockout male mice is caused by an increased rate of Sertoli cell proliferation. This increase does not appear to be the result of a major change in FSH signal transduction in Fmr1 knockout mice.

scholarly journals New Targeted Treatments for Fragile X Syndrome

2019 ◽  
Vol 15 (4) ◽  
pp. 251-258 ◽  
Author(s):  
Dragana Protic ◽  
Maria J. Salcedo-Arellano ◽  
Jeanne Barbara Dy ◽  
Laura A. Potter ◽  
Randi J. Hagerman
Keyword(s):  
Mental Retardation ◽  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Behavioral Problems ◽  
Rna Binding ◽  
Fragile X ◽  
Symptomatic Treatment ◽  
Fmr1 Gene ◽  
Fragile X Mental Retardation ◽  
Cgg Repeats

Fragile X Syndrome (FXS) is the most common cause of inherited intellectual disability with prevalence rates estimated to be 1:5,000 in males and 1:8,000 in females. The increase of >200 Cytosine Guanine Guanine (CGG) repeats in the 5’ untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene results in transcriptional silencing on the FMR1 gene with a subsequent reduction or absence of fragile X mental retardation protein (FMRP), an RNA binding protein involved in the maturation and elimination of synapses. In addition to intellectual disability, common features of FXS are behavioral problems, autism, language deficits and atypical physical features. There are still no currently approved curative therapies for FXS, and clinical management continues to focus on symptomatic treatment of comorbid behaviors and psychiatric problems. Here we discuss several treatments that target the neurobiological pathway abnormal in FXS. These medications are clinically available at present and the data suggest that these medications can be helpful for those with FXS.

scholarly journals The Fragile X Mental Retardation Protein: A Valuable Partner in the Battle against Epileptogenesis

2009 ◽  
Vol 9 (4) ◽  
pp. 116-118 ◽  
Author(s):  
Lisa R. Merlin
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Metabotropic Glutamate Receptor ◽  
Mossy Fiber ◽  
Fragile X ◽  
Critical Role ◽  
Fmr1 Gene ◽  
Metabotropic Glutamate ◽  
Fragile X Mental Retardation ◽  
Mental Retardation Protein

Correction of Fragile X Syndrome in Mice. Dölen G, Osterweil E, Rao BSS, Smith GB, Auerbach BD, Chattarji S, Bear MF. Neuron 2007;56:955–962. Fragile X syndrome (FXS) is the most common form of heritable mental retardation and the leading identified cause of autism. FXS is caused by transcriptional silencing of the FMR1 gene that encodes the fragile X mental retardation protein (FMRP), but the pathogenesis of the disease is unknown. According to one proposal, many psychiatric and neurological symptoms of FXS result from unchecked activation of mGluR5, a metabotropic glutamate receptor. To test this idea we generated Fmr1 mutant mice with a 50% reduction in mGluR5 expression and studied a range of phenotypes with relevance to the human disorder. Our results demonstrate that mGluR5 contributes significantly to the pathogenesis of the disease, a finding that has significant therapeutic implications for fragile X and related developmental disorders. Limbic Epileptogenesis in a Mouse Model of Fragile X Syndrome. Qiu LF, Lu TJ, Hu XL, Yi YH, Liao WP, Xiong ZQ. Cereb Cortex 2009 in press. (doi:10.1093/cercor/bhn163) Fragile X syndrome (FXS), caused by silencing of the Fmr1 gene, is the most common form of inherited mental retardation. Epilepsy is reported to occur in 20–25% of individuals with FXS. However, no overall increased excitability has been reported in Fmr1 knockout (KO) mice, except for increased sensitivity to auditory stimulation. Here, we report that kindling increased the expressions of Fmr1 mRNA and protein in the forebrain of wild-type (WT) mice. Kindling development was dramatically accelerated in Fmr1 KO mice, and Fmr1 KO mice also displayed prolonged electrographic seizures during kindling and more severe mossy fiber sprouting after kindling. The accelerated rate of kindling was partially repressed by inhibiting N-methyl-D-aspartic acid receptor (NMDAR) with MK-801 or mGluR5 receptor with 2-methyl-6-(phenylethynyl)-pyridine (MPEP). The rate of kindling development in WT was not effected by MPEP, however, suggesting that FMRP normally suppresses epileptogenic signaling downstream of metabotropic glutamate receptors. Our findings reveal that FMRP plays a critical role in suppressing limbic epileptogenesis and predict that the enhanced susceptibility of patients with FXS to epilepsy is a direct consequence of the loss of an important homeostatic factor that mitigates vulnerability to excessive neuronal excitation.

Mosaicism in Fragile X syndrome: A family case series

2021 ◽  
pp. 174462952199534
Author(s):  
Wilmar Saldarriaga ◽  
Laura Yuriko González-Teshima ◽  
Jose Vicente Forero-Forero ◽  
Hiu-Tung Tang ◽  
Flora Tassone
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Fmr1 Gene ◽  
Molecular Testing ◽  
Full Mutation ◽  
Mild Phenotype ◽  
Variable Expression ◽  
Fragile X Mental Retardation ◽  
Classic Phenotype

Fragile X syndrome (FXS) has a classic phenotype, however its expression can be variable among full mutation males. This is secondary to variable methylation mosaicisms and the number of CGG triplet repeats in the non-coding region of the Fragile X Mental Retardation 1 ( FMR1) gene, producing a variable expression of the Fragile X Mental Retardation Protein (FMRP). Here we report a family with several individuals affected by FXS: a boy with a hypermethylated FMR1 mutation and a classic phenotype; a man with an FMR1 gene mosaicism in the range of premutation (PM) and full mutation (FM), who has a mild phenotype due to which FXS was initially disregarded; and the cases of four women with a FM and mosaicism. This report highlights the importance of DNA molecular testing for the diagnosis of FXS in patients with developmental delay, intellectual disability and/or autism due to the variable phenotype that occurs in individuals with FMR1 mosaicisms.

scholarly journals An “Omic” Overview of Fragile X Syndrome

Biology ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 433
Author(s):  
Olivier Dionne ◽  
François Corbin
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Medical Problems ◽  
Biochemical Alterations ◽  
Fragile X Mental Retardation ◽  
Wide Range

Fragile X syndrome (FXS) is a neurodevelopmental disorder associated with a wide range of cognitive, behavioral and medical problems. It arises from the silencing of the fragile X mental retardation 1 (FMR1) gene and, consequently, in the absence of its encoded protein, FMRP (fragile X mental retardation protein). FMRP is a ubiquitously expressed and multifunctional RNA-binding protein, primarily considered as a translational regulator. Pre-clinical studies of the past two decades have therefore focused on this function to relate FMRP’s absence to the molecular mechanisms underlying FXS physiopathology. Based on these data, successful pharmacological strategies were developed to rescue fragile X phenotype in animal models. Unfortunately, these results did not translate into humans as clinical trials using same therapeutic approaches did not reach the expected outcomes. These failures highlight the need to put into perspective the different functions of FMRP in order to get a more comprehensive understanding of FXS pathophysiology. This work presents a review of FMRP’s involvement on noteworthy molecular mechanisms that may ultimately contribute to various biochemical alterations composing the fragile X phenotype.

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