Variation of FMRP Expression in Peripheral Blood Mononuclear Cells from Individuals with Fragile X Syndrome

Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and autism spectrum disorder. The syndrome is often caused by greatly reduced or absent protein expression from the ( ) gene due to expansion of a 5'-non-coding trinucleotide (CGG) element beyond 200 repeats...

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Bibliographic Details
Published in:Genes 2024-03, Vol.15 (3), p.356
Main Authors: Randol, Jamie L, Kim, Kyoungmi, Ponzini, Matthew D, Tassone, Flora, Falcon, Alexandria K, Hagerman, Randi J, Hagerman, Paul J
Format: Article
Language:English
Subjects:
Alleles
Ataxia
Autism
Autism Spectrum Disorder - genetics
Cognitive ability
Fluorescence resonance energy transfer
FMR1 protein
Fragile X Mental Retardation Protein - genetics
Fragile X Mental Retardation Protein - metabolism
Fragile X syndrome
Fragile X Syndrome - genetics
Gene expression
Genetic aspects
Humans
Intellectual disabilities
Leukocytes (mononuclear)
Leukocytes, Mononuclear - metabolism
Males
Messenger RNA
Methylation
Mosaicism
Mutation
Peripheral blood mononuclear cells
Pervasive developmental disorders
Proteins
RNA, Messenger - genetics
RNA, Messenger - metabolism
Trinucleotide Repeat Expansion - genetics
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Summary:Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and autism spectrum disorder. The syndrome is often caused by greatly reduced or absent protein expression from the ( ) gene due to expansion of a 5'-non-coding trinucleotide (CGG) element beyond 200 repeats (full mutation). To better understand the complex relationships among allelotype, methylation status, mRNA expression, and protein (FMRP) levels, FMRP was quantified in peripheral blood mononuclear cells for a large cohort of FXS ( = 154) and control ( = 139) individuals using time-resolved fluorescence resonance energy transfer. Considerable size and methylation mosaicism were observed among individuals with FXS, with FMRP detected only in the presence of such mosaicism. No sample with a minimum allele size greater than 273 CGG repeats had significant levels of FMRP. Additionally, an association was observed between mRNA and FMRP levels in FXS samples, predominantly driven by those with the lowest FMRP values. This study underscores the complexity of allelotypes and FMRP expression and prompts a reevaluation of FXS therapies aimed at reactivating large full mutation alleles that are likely not capable of producing sufficient FMRP to improve cognitive function.
ISSN:2073-4425
2073-4425
DOI:10.3390/genes15030356