Elevated FMR1-mRNA and lowered FMRP – A double-hit mechanism for psychiatric features in men with FMR1 premutations

Schneider, Andrea; Winarni, Tri Indah; Cabal-Herrera, Ana María; Bacalman, Susan; Gane, Louise W.; Hagerman, Paul J.; Tassone, Flora; Hagerman, Randi J

doi:10.1038/s41398-020-00863-w

Cited by 20 publications

(19 citation statements)

References 47 publications

(47 reference statements)

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“…More specifically, this contribution has been proposed to potentially explain mental traits as we will discuss below, due to the role of FMRP in synapse regulation [63]. Noticeably, PM carriers showing both FMR1 mRNA increase and FMRP decrease may develop psychotic and bipolar disorder features that are extremely rare in FXTAS and FXS patients, probably due to a synergistic effect of the gain-and loss-of-function components of CGG expansion [64].…”

Section: Reduction Of Fmrp Activitymentioning

confidence: 96%

“…Thus, manifestation of specific traits can be largely dependent on unknown genetic interactions, and/or the degree of mosaicism between the gain-and loss-of-function components of the CGG expansion that may differ throughout neural and non-neural tissues. For instance, patients who presented both FMR1 mRNA increase and FMRP decrease manifested a symptomatology resembling combined FXS and FXTAS [64], although the mosaicism of methylated and unmethylated FM alleles can also explain the coexistence of FXS and FXTAS-related diagnosis in the same individuals [64,68]. It has been documented that pediatric PM carriers may develop attention deficit hyperactivity disorder (ADHD), anxiety, autistic features, seizures and other psychiatric symptoms that are reminiscent of FXS but to a much lesser extent and prevalence compared to FXS patients [69].…”

Section: Reduction Of Fmrp Activitymentioning

confidence: 99%

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Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes

Valor

Morales

Hervás-Corpión

et al. 2021

IJMS

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Abnormal trinucleotide expansions cause rare disorders that compromise quality of life and, in some cases, lifespan. In particular, the expansions of the CGG-repeats stretch at the 5’-UTR of the Fragile X Mental Retardation 1 (FMR1) gene have pleiotropic effects that lead to a variety of Fragile X-associated syndromes: the neurodevelopmental Fragile X syndrome (FXS) in children, the late-onset neurodegenerative disorder Fragile X-associated tremor-ataxia syndrome (FXTAS) that mainly affects adult men, the Fragile X-associated primary ovarian insufficiency (FXPOI) in adult women, and a variety of psychiatric and affective disorders that are under the term of Fragile X-associated neuropsychiatric disorders (FXAND). In this review, we will describe the pathological mechanisms of the adult “gain-of-function” syndromes that are mainly caused by the toxic actions of CGG RNA and FMRpolyG peptide. There have been intensive attempts to identify reliable peripheral biomarkers to assess disease progression and onset of specific pathological traits. Mitochondrial dysfunction, altered miRNA expression, endocrine system failure, and impairment of the GABAergic transmission are some of the affectations that are susceptible to be tracked using peripheral blood for monitoring of the motor, cognitive, psychiatric and reproductive impairment of the CGG-expansion carriers. We provided some illustrative examples from our own cohort. Understanding the association between molecular pathogenesis and biomarkers dynamics will improve effective prognosis and clinical management of CGG-expansion carriers.

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Section: Reduction Of Fmrp Activitymentioning

confidence: 96%

Section: Reduction Of Fmrp Activitymentioning

confidence: 99%

Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes

Valor

Morales

Hervás-Corpión

et al. 2021

IJMS

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“…This combination of characteristics in patients with FM, decreased FMRP, PM and increased FMR1 mRNA represents a dual mechanism of clinical significance that may generate characteristics of both FXS and FXTAS. 48 In a clinic-based ascertained group of patients with FXS of both gender, a significant difference was found between FXS with ASD and low levels of FMRP when comparing concentrations of the protein in patients with FXS without ASD. 29 They found that the mean full scale IQ and adaptive skills composite scores were significantly lower in males than in females (p = 0.016 and p = 0.001, respectively, Mann–Whitney).…”

Section: Size and Methylation Mosaicismsmentioning

confidence: 97%

“…Recent investigations explored simultaneously how FMR1 mRNA levels of FMRP are related to phenotypic alterations in males with PM and FM. 48 In a study composed of 14 cases of patients with PM or PM and FM mosaicism and mental illnesses such as bipolar disorder, schizophrenia and psychosis, among others, low levels of FMRP and increased FMR1 mRNA were evident in these patients. This combination of characteristics in patients with FM, decreased FMRP, PM and increased FMR1 mRNA represents a dual mechanism of clinical significance that may generate characteristics of both FXS and FXTAS.…”

Section: Size and Methylation Mosaicismsmentioning

confidence: 99%

“…The quantity of FMRP is directly related with IQ. 34,37,39 While the presence of size mosaicism is related with better intellectual functioning and less maladaptive behavior, 29,42 elevated concentrations of FMR1 mRNA in patients with FM have been associated with a higher risk of developing FXTAS 45,46,48 and with the severity of behavioral symptoms. 47 The search for modifier genes affecting the phenotype has been carried out using the candidate genes strategy.…”

Section: Summary Of the Knowledge Of The Molecular Causes Regarding The Variable Phenotype In Fxsmentioning

confidence: 99%

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Variable Expressivity in Fragile X Syndrome: Towards the Identification of Molecular Characteristics That Modify the Phenotype

Payán‐Gómez¹,

Ramírez-Cheyne²,

Saldarriaga³

2021

TACG

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Fragile X syndrome (FXS), is an X-linked inherited genetic disease. FXS is the leading cause of inherited intellectual disability and autism in the world. Those affected are characterized by intellectual disability, language deficit, typical facies, and macroorchidism. Alterations in the FMR1 gene have been associated with FXS. The majority of people with this condition have an allele with an expansion of more than 200 repeats in a tract of CGGs within the 5ʹ untranslated region, and this expansion is associated with a hypermethylated state of the gene promoter. FXS has incomplete penetrance and variable expressivity. Intellectual disability is present in 100% of males and 60% of females. Autism spectrum disorder symptoms appear in 50% to 60% of males and 20% of females. Other characteristics such as behavioral and physical alterations have significant variations in presentation frequency. The molecular causes of the variable phenotype in FXS patients are becoming clear: these causes are related to the FMR1 gene itself and to secondary, modifying gene effects. In FXS patients, size and methylation mosaicisms are common. Secondary to mosaicism, there is a variation in the quantity of FMR1 mRNA and the protein coded by the gene Fragile Mental Retardation Protein (FMRP). Potential modifier genes have also been proposed, with conflicting results. Characterizing patients according to CGG expansion, methylation status, concentration of mRNA and FMRP, and genotypification for possible modifier genes in a clinical setting offers an opportunity to identify predictors for treatment response evaluation. When intervention strategies become available to modulate the course of the disease they could be crucial for selecting patients and identifying the best therapeutic intervention. The purpose of this review is to present the information available about the molecular causes of the variability of the expression incomplete penetrance and variable expressivity in FXS and their potential clinical applications.

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Fragile X-associated disorders

Hagerman

2023

Neurobiology of Brain Disorders

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Elevated FMR1-mRNA and lowered FMRP – A double-hit mechanism for psychiatric features in men with FMR1 premutations

Cited by 20 publications

References 47 publications

Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes

Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes

Variable Expressivity in Fragile X Syndrome: Towards the Identification of Molecular Characteristics That Modify the Phenotype

Fragile X-associated disorders

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