Fragile X Mental Retardation 1 (FMR1) Intron 1 Methylation in Blood Predicts Verbal Cognitive Impairment in Female Carriers of Expanded FMR1 Alleles: Evidence from a Pilot Study

Abstract BACKGROUND Cognitive status in females with mutations in the FMR1 (fragile X mental retardation 1) gene is highly variable. A biomarker would be of value for predicting which individuals were liable to develop cognitive impairment and could benefit from early intervention. A detailed analysis of CpG sites bridging exon 1 and intron 1 of FMR1, known as fragile X–related epigenetic element 2 (FREE2), suggests that a simple blood test could identify these individuals. METHODS Study participants included 74 control females (<40 CGG repeats), 62 premutation (PM) females (55–200 CGG repeats), and 18 full-mutation (FM) females assessed with Wechsler intelligence quotient (IQ) tests. We used MALDI-TOF mass spectrometry to determine the methylation status of FREE2 CpG sites that best identified low-functioning (IQ <70) FM females (>200 CGG repeats), compared the results with those for Southern blot FMR1 activation ratios, and related these assessments to the level of production of the FMR1 protein product in blood. RESULTS A methylation analysis of intron 1 CpG sites 10–12 showed the highest diagnostic sensitivity (100%) and specificity (98%) of all the molecular measures tested for detecting females with a standardized verbal IQ of <70 among the study participants. In the group consisting of only FM females, methylation of these sites was significantly correlated with full-scale IQ, verbal IQ, and performance IQ. Several verbal subtest scores showed strong correlation with the methylation of these sites (P = 1.2 × 10−5) after adjustment for multiple measures. CONCLUSIONS The data suggest that hypermethylation of the FMR1 intron 1 sites in blood is predictive of cognitive impairment in FM females, with implications for improved fragile X syndrome diagnostics in young children and screening of the newborn population.

Download Full-text

FMRP Levels in Human Peripheral Blood Leukocytes Correlates with Intellectual Disability

Diagnostics ◽

10.3390/diagnostics11101780 ◽

2021 ◽

Vol 11 (10) ◽

pp. 1780

Author(s):

Mark Roth ◽

Lucienne Ronco ◽

Diego Cadavid ◽

Blythe Durbin-Johnson ◽

Randi J. Hagerman ◽

...

Keyword(s):

Mental Retardation ◽

Intellectual Disability ◽

Peripheral Blood ◽

Fragile X ◽

Repeat Expansion ◽

Repeat Number ◽

Cgg Repeat ◽

Fragile X Mental Retardation ◽

Cgg Repeats ◽

Fmr1 Mrna

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.

Download Full-text

Focal areas of a high rate of fragile X in Indonesia: a long term follow up

Journal of Biomedicine and Translational Research ◽

10.14710/jbtr.v5i2.6895 ◽

2019 ◽

Vol 5 (2) ◽

pp. 67-68

Author(s):

Sultana MH Faradz ◽

Tri Indah Winarni

Keyword(s):

Mental Retardation ◽

Behavioral Problems ◽

Fragile X ◽

Autism Spectrum ◽

High Rate ◽

Learning Ability ◽

Fragile X Mental Retardation ◽

Cgg Repeats ◽

Long Term Follow Up

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability (ID) and a leading cause of autism spectrum disorder (ASD). FXS is caused by an expansion of CGG repeats >200 in the 5′ untranslated region of the promotor region fragile X mental retardation 1 gene (FMR1), which is located on Xq27.3. The abnormal CGG expansion leads to methylation and transcriptional silencing of the FMR1 gene, resulting in a reduction or loss of fragile X mental retardation 1 protein (FMRP) and causes long, thin, and immature dendritic spines, which lead to deficits in cognitive function, behavioral problems, and learning ability

Download Full-text

New Targeted Treatments for Fragile X Syndrome

Current Pediatric Reviews ◽

10.2174/1573396315666190625110748 ◽

2019 ◽

Vol 15 (4) ◽

pp. 251-258 ◽

Cited By ~ 1

Author(s):

Dragana Protic ◽

Maria J. Salcedo-Arellano ◽

Jeanne Barbara Dy ◽

Laura A. Potter ◽

Randi J. Hagerman

Keyword(s):

Mental Retardation ◽

Intellectual Disability ◽

Fragile X Syndrome ◽

Behavioral Problems ◽

Rna Binding ◽

Fragile X ◽

Symptomatic Treatment ◽

Fmr1 Gene ◽

Fragile X Mental Retardation ◽

Cgg Repeats

Fragile X Syndrome (FXS) is the most common cause of inherited intellectual disability with prevalence rates estimated to be 1:5,000 in males and 1:8,000 in females. The increase of >200 Cytosine Guanine Guanine (CGG) repeats in the 5’ untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene results in transcriptional silencing on the FMR1 gene with a subsequent reduction or absence of fragile X mental retardation protein (FMRP), an RNA binding protein involved in the maturation and elimination of synapses. In addition to intellectual disability, common features of FXS are behavioral problems, autism, language deficits and atypical physical features. There are still no currently approved curative therapies for FXS, and clinical management continues to focus on symptomatic treatment of comorbid behaviors and psychiatric problems. Here we discuss several treatments that target the neurobiological pathway abnormal in FXS. These medications are clinically available at present and the data suggest that these medications can be helpful for those with FXS.

Download Full-text

Diminished ovarian reserve is not observed in infertility patients with high normal CGG repeats on the fragile X mental retardation 1 (FMR1) gene

Human Reproduction ◽

10.1093/humrep/dev220 ◽

2015 ◽

Vol 30 (11) ◽

pp. 2686-2692 ◽

Cited By ~ 19

Author(s):

Ann Schufreider ◽

Dana B. McQueen ◽

Sang Mee Lee ◽

Rachel Allon ◽

Meike L. Uhler ◽

...

Keyword(s):

Mental Retardation ◽

Ovarian Reserve ◽

Fragile X ◽

Diminished Ovarian Reserve ◽

Fmr1 Gene ◽

Fragile X Mental Retardation ◽

Cgg Repeats ◽

Infertility Patients

Download Full-text

Fragile X Syndrome

Colombia Medica ◽

10.25100/cm.v45i4.1810 ◽

2014 ◽

pp. 190-198 ◽

Cited By ~ 45

Author(s):

Wilmar Saldarriaga ◽

Flora Tassone ◽

Laura Yuriko González-Teshima ◽

Jose Vicente Forero-Forero ◽

Sebastián Ayala-Zapata ◽

...

Keyword(s):

Mental Retardation ◽

Intellectual Disability ◽

Fragile X Syndrome ◽

Fragile X ◽

Gene Promoter ◽

Molecular Techniques ◽

Pharmaceutical Management ◽

Developmental Problems ◽

Fragile X Mental Retardation ◽

Cgg Repeats

Fragile X Syndrome (FXS) is a genetic disease due to a CGG trinucleotide expansion, named full mutation (greater than 200 CGG repeats), in the fragile X mental retardation 1 gene locus Xq27.3; which leads to an hypermethylated region in the gene promoter therefore silencing it and lowering the expression levels of the fragile X mental retardation 1, a protein involved in synaptic plasticity and maturation. Individuals with FXS present with intellectual disability, autism, hyperactivity, long face, large or prominent ears and macroorchidism at puberty and thereafter. Most of the young children with FXS will present with language delay, sensory hyper arousal and anxiety. Girls are less affected than boys, only 25% have intellectual disability. Given the genomic features of the syndrome, there are patients with a number of triplet repeats between 55 and 200, known as premutation carriers. Most carriers have a normal IQ but some have developmental problems. The diagnosis of FXS has evolved from karyotype with special culture medium, to molecular techniques that are more sensitive and specific including PCR and Southern Blot. During the last decade, the advances in the knowledge of FXS, has led to the development of investigations on pharmaceutical management or targeted treatments for FXS. Minocycline and sertraline have shown efficacy in children.

Download Full-text

An Origin of DNA Replication in the Promoter Region of the Human Fragile X Mental Retardation (FMR1) Gene

Molecular and Cellular Biology ◽

10.1128/mcb.01382-06 ◽

2006 ◽

Vol 27 (2) ◽

pp. 426-437 ◽

Cited By ~ 35

Author(s):

Steven J. Gray ◽

Jeannine Gerhardt ◽

Walter Doerfler ◽

Lawrence E. Small ◽

Ellen Fanning

Keyword(s):

Mental Retardation ◽

Dna Replication ◽

Fragile X Syndrome ◽

Fragile X ◽

Model Systems ◽

Fmr1 Gene ◽

Fragile X Mental Retardation ◽

Cgg Repeats ◽

Origin Of Dna Replication ◽

Transformed Cell Lines

ABSTRACT Fragile X syndrome, the most common form of inherited mental retardation in males, arises when the normally stable 5 to 50 CGG repeats in the 5′ untranslated region of the fragile X mental retardation protein 1 (FMR1) gene expand to over 200, leading to DNA methylation and silencing of the FMR1 promoter. Although the events that trigger local CGG expansion remain unknown, the stability of trinucleotide repeat tracts is affected by their position relative to an origin of DNA replication in model systems. Origins of DNA replication in the FMR1 locus have not yet been described. Here, we report an origin of replication adjacent to the FMR1 promoter and CGG repeats that was identified by scanning a 35-kb region. Prereplication proteins Orc3p and Mcm4p bind to chromatin in the FMR1 initiation region in vivo. The position of the FMR1 origin relative to the CGG repeats is consistent with a role in repeat maintenance. The FMR1 origin is active in transformed cell lines, fibroblasts from healthy individuals, fibroblasts from patients with fragile X syndrome, and fetal cells as early as 8 weeks old. The potential role of the FMR1 origin in CGG tract instability is discussed.

Download Full-text