High normal CGG repeat number on the fragile x mental retardation 1 (FMR1) gene is not correlated with diminished ovarian reserve

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. FXS is an X-linked, neurodevelopmental disorder caused by a CGG trinucleotide repeat expansion in the 5′ untranslated region (UTR) of the Fragile X Mental Retardation gene, FMR1. Greater than 200 CGG repeats results in epigenetic silencing of the gene leading to the deficiency or absence of Fragile X mental retardation protein (FMRP). The loss of FMRP is considered the root cause of FXS. The relationship between neurological function and FMRP expression in peripheral blood mononuclear cells (PBMCs) has not been well established. Assays to detect and measure FMR1 and FMRP have been described; however, none are sufficiently sensitive, precise, or quantitative to properly characterize the relationships between cognitive ability and CGG repeat number, FMR1 mRNA expression, or FMRP expression measured in PBMCs. To address these limitations, two novel immunoassays were developed and optimized, an electro-chemiluminescence immunoassay and a multiparameter flow cytometry assay. Both assays were performed on PMBCs isolated from 27 study participants with FMR1 CGG repeats ranging from normal to full mutation. After correcting for methylation, a significant positive correlation between CGG repeat number and FMR1 mRNA expression levels and a significant negative correlation between FMRP levels and CGG repeat expansion was observed. Importantly, a high positive correlation was observed between intellectual quotient (IQ) and FMRP expression measured in PBMCs.

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Secondary Structure and Dynamics of the r(CGG) Repeat in the mRNA of the Fragile X Mental Retardation 1(FMR1)Gene

RNA Biology ◽

10.4161/rna.4.2.5039 ◽

2007 ◽

Vol 4 (2) ◽

pp. 93-100 ◽

Cited By ~ 46

Author(s):

Marta Zumwalt ◽

Anna Ludwig ◽

Paul J. Hagerman ◽

Thorsten Dieckmann

Keyword(s):

Mental Retardation ◽

Secondary Structure ◽

Fragile X ◽

Fmr1 Gene ◽

Cgg Repeat ◽

Fragile X Mental Retardation ◽

Structure And Dynamics

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ASFMR1splice variant

Neurology Genetics ◽

10.1212/nxg.0000000000000246 ◽

2018 ◽

Vol 4 (4) ◽

pp. e246 ◽

Cited By ~ 6

Author(s):

Padmaja Vittal ◽

Shrikant Pandya ◽

Kevin Sharp ◽

Elizabeth Berry-Kravis ◽

Lili Zhou ◽

...

Keyword(s):

Mental Retardation ◽

Splice Variant ◽

Messenger Rna ◽

Clinical Symptoms ◽

Fragile X ◽

Cgg Repeat ◽

Men And Women ◽

Fragile X Mental Retardation ◽

Repeat Size ◽

Ataxia Syndrome

ObjectiveTo explore the association of a splice variant of theantisense fragile X mental retardation 1(ASFMR1) gene, loss offragile X mental retardation 1(FMR1) AGG interspersions andFMR1CGG repeat size with manifestation, and severity of clinical symptoms of fragile X-associated tremor/ataxia syndrome (FXTAS).MethodsPremutation carriers (PMCs) with FXTAS, without FXTAS, and normal controls (NCs) had a neurologic evaluation and collection of skin and blood samples. Expression ofASFMR1transcript/splice variant 2 (ASFMR1-TV2), nonsplicedASFMR1, totalASFMR1, andFMR1messenger RNA were quantified and compared using analysis of variance. Least absolute shrinkage and selection operator (LASSO) logistic regression and receiver operating characteristic analyses were performed.ResultsPremutation men and women both with and without FXTAS had higherASFMR1-TV2 levels compared with NC men and women (n = 135,135,p< 0.0001), andASFMR1-TV2 had good discriminating power for FXTAS compared with NCs but not for FXTAS from PMC. After adjusting for age, loss of AGG, larger CGG repeat size (in men), and elevatedASFMR1-TV2 level (in women) were strongly associated with FXTAS compared with NC and PMC (combined).ConclusionsThis study found elevated levels ofASFMR1-TV2and loss of AGG interruptions in both men and women with FXTAS. Future studies will be needed to determine whether these variables can provide useful diagnostic or predictive information.

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