The fragile X mental retardation 1 gene (<i>FMR1</i>): historical perspective, phenotypes, mechanism, pathology, and epidemiology

Grigsby, Jim

doi:10.1080/13854046.2016.1184652

Cited by 22 publications

(19 citation statements)

References 132 publications

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“…Reduction of functional connectivity was paralleled by structural deficits, with DWI revealing severe fiber coherence reductions in corticocortico and corticostriatal pathways. Our finding of lower FA values, which are also often observed in FXS patients ( Grigsby 2016 ), reflect a reduction in axial diffusivity. Further, with electron microscopy we were able to show that the reduction in axial diffusivity was related to a reduction in the inner diameter of the axons, unveiling the microstructural basis for the aberrant functional connectivity patterns.…”

Section: Discussionsupporting

confidence: 80%

Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories

et al. 2018

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Autism spectrum disorders (ASD) are a set of complex neurodevelopmental disorders for which there is currently no targeted therapeutic approach. It is thought that alterations of genes regulating migration and synapse formation during development affect neural circuit formation and result in aberrant connectivity within distinct circuits that underlie abnormal behaviors. However, it is unknown whether deviant developmental trajectories are circuit-specific for a given autism risk-gene. We used MRI to probe changes in functional and structural connectivity from childhood to adulthood in Fragile-X (Fmr1−/y) and contactin-associated (CNTNAP2−/−) knockout mice. Young Fmr1−/y mice (30 days postnatal) presented with a robust hypoconnectivity phenotype in corticocortico and corticostriatal circuits in areas associated with sensory information processing, which was maintained until adulthood. Conversely, only small differences in hippocampal and striatal areas were present during early postnatal development in CNTNAP2−/− mice, while major connectivity deficits in prefrontal and limbic pathways developed between adolescence and adulthood. These findings are supported by viral tracing and electron micrograph approaches and define 2 clearly distinct connectivity endophenotypes within the autism spectrum. We conclude that the genetic background of ASD strongly influences which circuits are most affected, the nature of the phenotype, and the developmental time course of the associated changes.

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Section: Discussionsupporting

confidence: 80%

Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories

et al. 2018

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“…No tandem repeats were found in the coding region. The expansion of repeats in FMR1 results in a defective protein that is known to be associated with the symptoms of FXS [ 26 ]. Previous studies have shown that under physiological conditions, both the G-rich and C-rich single-stranded d(CGG)·d(CCG) repeats are able to form secondary structures and cause unusual expansions [ 8 , 27 , 28 ].…”

Section: Discussionmentioning

confidence: 99%

CoII(Chromomycin)2 Complex Induces a Conformational Change of CCG Repeats from i-Motif to Base-Extruded DNA Duplex

Chen

Satange

et al. 2018

IJMS

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We have reported the propensity of a DNA sequence containing CCG repeats to form a stable i-motif tetraplex structure in the absence of ligands. Here we show that an i-motif DNA sequence may transition to a base-extruded duplex structure with a GGCC tetranucleotide tract when bound to the (CoII)-mediated dimer of chromomycin A3, CoII(Chro)2. Biophysical experiments reveal that CCG trinucleotide repeats provide favorable binding sites for CoII(Chro)2. In addition, water hydration and divalent metal ion (CoII) interactions also play a crucial role in the stabilization of CCG trinucleotide repeats (TNRs). Our data furnish useful structural information for the design of novel therapeutic strategies to treat neurological diseases caused by repeat expansions.

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“…FXTAS is an age-dependent neurodegenerative disorder with prevalence increasing with age and affecting most commonly males [ 38 ]. It is estimated that approximately over 40% of males with the PM will eventually present FXTAS [ 22 ] in contrast with female carriers in whom it is estimated that approximately 13% to 16% of them will be affected by FXTAS [ 39 ].…”

Section: Epidemiology Of Fxtasmentioning

confidence: 99%

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Pathophysiology and Clinical Implications

Cabal-Herrera

Tassanakijpanich

Salcedo-Arellano

et al. 2020

IJMS

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The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder seen in older premutation (55–200 CGG repeats) carriers of FMR1. The premutation has excessive levels of FMR1 mRNA that lead to toxicity and mitochondrial dysfunction. The clinical features usually begin in the 60 s with an action or intention tremor followed by cerebellar ataxia, although 20% have only ataxia. MRI features include brain atrophy and white matter disease, especially in the middle cerebellar peduncles, periventricular areas, and splenium of the corpus callosum. Neurocognitive problems include memory and executive function deficits, although 50% of males can develop dementia. Females can be less affected by FXTAS because of a second X chromosome that does not carry the premutation. Approximately 40% of males and 16% of female carriers develop FXTAS. Since the premutation can occur in less than 1 in 200 women and 1 in 400 men, the FXTAS diagnosis should be considered in patients that present with tremor, ataxia, parkinsonian symptoms, neuropathy, and psychiatric problems. If a family history of a fragile X mutation is known, then FMR1 DNA testing is essential in patients with these symptoms.

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The fragile X mental retardation 1 gene (FMR1): historical perspective, phenotypes, mechanism, pathology, and epidemiology

Cited by 22 publications

References 132 publications

Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories

Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories

CoII(Chromomycin)2 Complex Induces a Conformational Change of CCG Repeats from i-Motif to Base-Extruded DNA Duplex

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Pathophysiology and Clinical Implications

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