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

被引:1
作者
Randol, Jamie L. [1 ]
Kim, Kyoungmi [2 ,3 ]
Ponzini, Matthew D. [2 ,3 ]
Tassone, Flora [1 ,2 ]
Falcon, Alexandria K. [1 ]
Hagerman, Randi J. [2 ,4 ]
Hagerman, Paul J. [1 ,2 ]
机构
[1] Univ Calif Davis, Sch Med, Dept Biochem & Mol Med, Davis, CA 95616 USA
[2] UC Davis Hlth, Med Invest Neurodev Disorders MIND Inst, Sacramento, CA 95817 USA
[3] Univ Calif Davis, Sch Med, Dept Publ Hlth Sci, Davis, CA 95616 USA
[4] Univ Calif Davis, Sch Med, Dept Pediat, Sacramento, CA 95817 USA
基金
美国国家卫生研究院;
关键词
FMR1; fragile X syndrome; autism; full mutation; TR-FRET; mosaicism; intellectual disability; EXPANDED ALLELES; ELEVATED LEVELS; PROTEIN-LEVELS; MESSENGER-RNA; GENE; METHYLATION; PREMUTATION; MOSAICISM; MALES; IDENTIFICATION;
D O I
10.3390/genes15030356
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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 fragile X messenger ribonucleoprotein 1 (FMR1) gene due to expansion of a 5 '-non-coding trinucleotide (CGG) element beyond 200 repeats (full mutation). To better understand the complex relationships among FMR1 allelotype, methylation status, mRNA expression, and FMR1 protein (FMRP) levels, FMRP was quantified in peripheral blood mononuclear cells for a large cohort of FXS (n = 154) and control (n = 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 FMR1 mRNA and FMRP levels in FXS samples, predominantly driven by those with the lowest FMRP values. This study underscores the complexity of FMR1 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.
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