Examination of FMR1 transcript and protein levels among 74 premutation carriers

Peprah, Emmanuel; He, Weiya; Allen, Emily G.; Oliver, Tiffany; Alex, Boyne; Sherman, Stephanie L.

doi:10.1038/jhg.2009.121

Cited by 60 publications

(60 citation statements)

References 20 publications

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“…Notably, the mRNA expression was higher in PBMCs suggesting that the unmethylated alleles even in the full mutation range are actively transcribed (Tassone et al, 2000). Although an excess in transcription, producing higher than normal levels of mRNA was observed for many of the subjects included in this study, these are long expanded alleles, which are inefficiently translated to FMRP (Primerano et al, 2002; Loesch et al, 2004; Peprah et al, 2010). Thus, it is not surprising that some individuals exhibited elevated FMR1 mRNA but not lower FMRP levels.…”

Section: Discussionmentioning

confidence: 77%

Clinical and molecular implications of mosaicism in FMR1 full mutations

et al. 2014

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Expansions of more than 200 CGG repeats (full mutation) in the FMR1 gene give rise to fragile X syndrome (FXS) through a process that generally involves hypermethylation of the FMR1 promoter region and gene silencing, resulting in absence of expression of the encoded protein, FMRP. However, mosaicism with alleles differing in size and extent of methylation often exist within or between tissues of individuals with FXS. In the current work, CGG-repeat lengths and methylation status were assessed for eighteen individuals with FXS, including 13 mosaics, for which peripheral blood cells (PBMCs) and primary fibroblast cells were available. Our results show that for both PBMCs and fibroblasts, FMR1 mRNA and FMRP expression are directly correlated with the percent of methylation of the FMR1 allele. In addition, Full Scale IQ scores were inversely correlated with the percent methylation and positively correlated with higher FMRP expression. These latter results point toward a positive impact on cognition for full mutation mosaics with lower methylation compared to individuals with fully methylated, full mutation alleles. However, we did not observe a significant reduction in the number of seizures, nor in the severity of hyperactivity or autism spectrum disorder, among individuals with mosaic genotypes in the presentation of FXS. These observations suggest that low, but non-zero expression of FMRP may be sufficient to positively impact cognitive function in individuals with FXS, with methylation mosaicism (lowered methylation fraction) contributing to a more positive clinical outcome.

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Section: Discussionmentioning

confidence: 77%

Clinical and molecular implications of mosaicism in FMR1 full mutations

et al. 2014

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“…FMR1 gene function is directly tied to the length of a trinucleotide (CGG) repeat on the 5’untranslated region (5′UTR) (Chen et al, 2003; Peprah et al, 2010). Historically, investigations of the FMR1 phenotype have focused almost exclusively on two clinical conditions associated with CGG expansion: fragile X syndrome and FMR1 premutation associated disorders.…”

Section: Introductionmentioning

confidence: 99%

Curvilinear Association Between Language Disfluency and FMR1 CGG Repeat Size Across the Normal, Intermediate, and Premutation Range

et al. 2018

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Historically, investigations of FMR1 have focused almost exclusively on the clinical effects of CGG expansion within the categories of the premutation (55–200 CGG repeats) and fragile X syndrome (>200 CGG repeats). However, emerging evidence suggests that CGG-dependent phenotypes may occur across allele sizes traditionally considered within the “normal” range. This study adopted an individual-differences approach to determine the association between language production ability and CGG repeat length across the full range of normal, intermediate, and premutation alleles. Participants included 61 adult women with CGG repeats within the premutation (n = 37), intermediate (i.e., 41–54 repeats; n = 2), or normal (i.e., 6–40 repeats; n = 22) ranges. All participants were the biological mothers of a child with a developmental disorder, to control for the potential effects of parenting stress. Language samples were collected and the frequency of language disfluencies (i.e., interruptions in the flow of speech) served as an index of language production skills. Verbal inhibition skills, measured with the Hayling Sentence Completion Test, were also measured and examined as a correlate of language disfluency, consistent with theoretical work linking language disfluency with inhibitory deficits (i.e., the Inhibition Deficit Hypothesis). Blood samples were collected to determine FMR1 CGG repeat size. A general linear model tested CGG repeat size of the larger allele (allele-2) as the primary predictor of language disfluency, covarying for education level, IQ, age, and CGG repeats on the other allele. A robust curvilinear association between CGG length and language disfluency was detected, where low-normal (∼ <25 repeats) and mid-premutation alleles (∼90–110 repeats) were linked with higher rates of disfluency. Disfluency was not associated with inhibition deficits, which challenges prior theoretical work and suggests that a primary language deficit could account for elevated language disfluency in FMR1-associated conditions. Findings suggest CGG-dependent variation in language production ability, which was evident across individuals with and without CGG expansions on FMR1.

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“…Although elevated FMR1 mRNA levels have been observed for FMR1 mRNA expanded alleles ranging from the premutation to the full mutation range, [17][18][19][20][21] it is currently unknown whether all or only specific FMR1 mRNA isoforms are differentially overexpressed or distributed within cellular compartments as a function of CGG repeat number. As alternative protein isoforms are likely to have differing functions, alteration in their relative abundances could have profound biological consequences.…”

Section: Introductionmentioning

confidence: 99%

Differential increases of specificFMR1mRNA isoforms in premutation carriers

et al. 2014

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Background-Over 40% of males and ~16% of female carriers of a premutation FMR1 allele (55-200 CGG repeats) will develop Fragile X associated Tremor/Ataxia Syndrome (FXTAS), an adult onset neurodegenerative disorder while, about 20% of female carriers will develop Fragile X-associated Primary Ovarian Insufficiency. Marked elevation in FMR1 mRNA transcript levels has been observed with premutation alleles, and RNA toxicity due to increased mRNA levels is the leading molecular mechanism proposed for these disorders. However, although the FMR1 gene undergoes alternative splicing, it is unknown if all or only some of the isoforms are overexpressed in premutation carriers and which isoforms may contribute to the premutation pathology.

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Examination of FMR1 transcript and protein levels among 74 premutation carriers

Cited by 60 publications

References 20 publications

Clinical and molecular implications of mosaicism in FMR1 full mutations

Clinical and molecular implications of mosaicism in FMR1 full mutations

Curvilinear Association Between Language Disfluency and FMR1 CGG Repeat Size Across the Normal, Intermediate, and Premutation Range

Differential increases of specificFMR1mRNA isoforms in premutation carriers

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