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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\u2032-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.<\/jats:p>","DOI":"10.3390\/genes15030356","type":"journal-article","created":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T13:23:11Z","timestamp":1710336191000},"page":"356","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Variation of FMRP Expression in Peripheral Blood Mononuclear Cells from Individuals with Fragile X Syndrome"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9936-7528","authenticated-orcid":false,"given":"Jamie L.","family":"Randol","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoungmi","family":"Kim","sequence":"additional","affiliation":[{"name":"Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, UC Davis Health, Sacramento, CA 95817, USA"},{"name":"Department of Public Health Sciences, School of Medicine, University of California, Davis, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7758-8688","authenticated-orcid":false,"given":"Matthew D.","family":"Ponzini","sequence":"additional","affiliation":[{"name":"Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, UC Davis Health, Sacramento, CA 95817, USA"},{"name":"Department of Public Health Sciences, School of Medicine, University of California, Davis, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6388-9180","authenticated-orcid":false,"given":"Flora","family":"Tassone","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Davis, CA 95616, USA"},{"name":"Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, UC Davis Health, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandria K.","family":"Falcon","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5029-8448","authenticated-orcid":false,"given":"Randi J.","family":"Hagerman","sequence":"additional","affiliation":[{"name":"Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, UC Davis Health, Sacramento, CA 95817, USA"},{"name":"Department of Pediatrics, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1142-5680","authenticated-orcid":false,"given":"Paul J.","family":"Hagerman","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Davis, CA 95616, USA"},{"name":"Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, UC Davis Health, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.neuron.2008.10.004","article-title":"Fragile X syndrome: Loss of local mRNA regulation alters synaptic development and function","volume":"60","author":"Bassell","year":"2008","journal-title":"Neuron"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1007\/s11689-011-9087-2","article-title":"Regulation of molecular pathways in the Fragile X Syndrome: Insights into Autism Spectrum Disorders","volume":"3","author":"Bagni","year":"2011","journal-title":"J. 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