A study of the distributional characteristics of FMR1 transcript levels in 238 individuals

Allen, Emily G.; He, Weiya; Yadav-Shah, Maneesha; Sherman, Stephanie L.

doi:10.1007/s00439-004-1086-x

Cited by 110 publications

(38 citation statements)

References 19 publications

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“…Although these differ slightly from those proposed for a clinical application (i.e., those based on risk for instability) , they are similar to previous studies used to examine FMR1 mRNA levels (Allen et al 2004;Garcia-Alegria et al 2007). At this point in time, there is no biological underpinning for any of these definitions, particularly with respect to risk for neuropsychological or neurobehavioral phenotypes.…”

Section: Study Populationmentioning

confidence: 57%

“…Premutation alleles remain unmethylated, therefore FMR1 is transcriptionally active and produces FMRP. FMR1 mRNA levels linearly increase across the premutation range due higher rates of transcription as a results of a mechanism that is presently not understood (Tassone et al 2000a, b;Kenneson et al 2001;Tassone and Hagerman 2003;Allen et al 2004;GarciaAlegria et al 2007). However, a negative association has been found between FMRP and repeat size in premutation carriers due to a decreased translation efficiency of the mRNA as the repeat size increases (Feng et al 1995;Tassone et al 2000b;Kenneson et al 2001;Primerano et al 2002;Tassone and Hagerman 2003).…”

Section: Introductionmentioning

confidence: 97%

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Investigation of Phenotypes Associated with Mood and Anxiety Among Male and Female Fragile X Premutation Carriers

et al. 2008

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The fragile X disorder spectrum, due to a CGG expansion in FMR1, includes fragile X syndrome (>200 repeats) and the premutation-associated disorders of ovarian insufficiency and tremor/ataxia syndrome (approximately 55-199 repeats). Altered neurobehavioral profiles including variation of phenotypes associated with mood and anxiety may be expected among younger premutation carriers given this spectrum of disorders. However, previous studies have produced conflicting findings, providing the motivation to examine these phenotypes further. We investigated measures of mood and anxiety in 119 males and 446 females age 18-50 ascertained from families with a history of fragile X syndrome and from the general population. Scores were analyzed using a linear model with repeat length as the main predictor, adjusting for potential confounders. Repeat length was not associated with anxiety, but was marginally associated with depression and negative affect in males and negative affect only in females. These results suggest that premutation carriers may be at risk for emotional morbidity; however, phenotypic differences were subtle and of small effect size.

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Section: Study Populationmentioning

confidence: 57%

Section: Introductionmentioning

confidence: 97%

Investigation of Phenotypes Associated with Mood and Anxiety Among Male and Female Fragile X Premutation Carriers

et al. 2008

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“…We selected this analytic technique based on established precedent, as this is the most common method used to account for two alleles in females in the extant literature (Gleicher et al, 2009a,b; Lledo et al, 2012; Voorhuis et al, 2014; Schufreider et al, 2015). We did not have activation ratio data available (i.e., the percent of cells carrying any given allele on the active X chromosome), which prevented us from employing other techniques that account for the relative influence of each allele (i.e., Allen et al, 2004). In addition to the CGG length on allele-1, covariates included education level, IQ, and age, which have been linked to individual differences in disfluency in prior work (e.g., Bortfeld et al, 2001; Engelhardt et al, 2013; Sterling et al, 2013).…”

Section: Methodsmentioning

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 the underlying molecular mechanism of POI is not clear, consistent features are that the full mutation females, with transcriptional silencing of the FMR1 gene, and absence of FMRP, are not affected with POI, while females with premutation alleles show normal or slightly reduced levels of FMRP and elevated FMR1 mRNA levels [20]. This observation led to the hypothesis that accumulation of FMR1 mRNA is toxic to the ovary and is responsible to POI in a similar mechanism to the FXATS RNA gain-of-function toxicity.…”

Section: Introductionmentioning

confidence: 99%

Elevated Levels of FMR1 mRNA in Granulosa Cells Are Associated with Low Ovarian Reserve in FMR1 Premutation Carriers

et al. 2014

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AimTo assess the role of mRNA accumulation in granulosa cells as the cause of low ovarian response among FMR1 premutation carriers undergoing pre-implantation genetic diagnosis (PGD).DesignCase control study in an academic IVF unit. Twenty-one consecutive FMR1 premutation carriers and 15 control women were included. After oocyte retrieval the granulosa cells mRNA levels of FMR1 was measured using RT-PCR.ResultsIn FMR1 premutation carriers, there was a significant non-linear association between the number of CGG repeats and the number of retrieved oocytes (p<0.0001) and a trend to granulosa cells FMR1 mRNA levels (p = 0.07). The lowest number of retrieved oocytes and the highest level of mRNA were seen in women with mid-size CGG repeats (80–120). A significant negative linear correlation was observed between the granulosa cells FMR1 mRNA levels and the number of retrieved oocytes (R2 linear = 0.231, P = 0.02).ConclusionWe suggest that there is a no-linear association between the number of CGG repeats and ovarian function, resulting from an increased granulosa cells FMR1 mRNA accumulation in FMR1 carriers in the mid-range (80–120 repeats).

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A study of the distributional characteristics of FMR1 transcript levels in 238 individuals

Cited by 110 publications

References 19 publications

Investigation of Phenotypes Associated with Mood and Anxiety Among Male and Female Fragile X Premutation Carriers

Investigation of Phenotypes Associated with Mood and Anxiety Among Male and Female Fragile X Premutation Carriers

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

Elevated Levels of FMR1 mRNA in Granulosa Cells Are Associated with Low Ovarian Reserve in FMR1 Premutation Carriers

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