Association between IQ and FMR1 protein (FMRP) across the spectrum of CGG repeat expansions

English version

Autoři: Kyoungmi Kim ^aff001; David Hessl ^aff001; Jamie L. Randol ^aff004; Glenda M. Espinal ^aff004; Andrea Schneider ^aff001; Dragana Protic ^aff001; Elber Yuksel Aydin ^aff001; Randi J. Hagerman ^aff001; Paul J. Hagerman ^aff001
Působiště autorů: UC Davis MIND Institute, UC Davis Health, Sacramento, California, United States of America ^aff001; Department of Public Health Sciences, University of California, Davis, School of Medicine, Davis, California, United States of America ^aff002; Department of Psychiatry and Behavioral Sciences, University of California, Davis, School of Medicine, Sacramento, California, United States of America ^aff003; Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, Davis, California, United States of America ^aff004; Department of Pediatrics, University of California, Davis, School of Medicine, Sacramento, California, United States of America ^aff005
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0226811

Souhrn

Fragile X syndrome, the leading heritable form of intellectual disability, is caused by hypermethylation and transcriptional silencing of large (CGG) repeat expansions (> 200 repeats) in the 5′ untranslated region of the fragile X mental retardation 1 (FMR1) gene. As a consequence of FMR1 gene silencing, there is little or no production of FMR1 protein (FMRP), an important element in normal synaptic function. Although the absence of FMRP has long been known to be responsible for the cognitive impairment in fragile X syndrome, the relationship between FMRP level and cognitive ability (IQ) is only imprecisely understood. To address this issue, a high-throughput, fluorescence resonance energy transfer (FRET) assay has been used to quantify FMRP levels in dermal fibroblasts, and the relationship between FMRP and IQ measures was assessed by statistical analysis in a cohort of 184 individuals with CGG-repeat lengths spanning normal (< 45 CGGs) to full mutation (> 200 CGGs) repeat ranges in fibroblasts. The principal findings of the current study are twofold: i) For those with normal CGG repeats, IQ is no longer sensitive to further increases in FMRP above an FMRP threshold of ~70% of the mean FMRP level; below this threshold, IQ decreases steeply with further decreases in FMRP; and ii) For the current cohort, a mean IQ of 85 (lower bound for the normal IQ range) is attained for FMRP levels that are only ~35% of the mean FMRP level among normal CGG-repeat controls. The current results should help guide expectations for efforts to induce FMR1 gene activity and for the levels of cognitive function expected for a given range of FMRP levels.

Klíčová slova:

Methylation – Point mutation – Cognitive impairment – Cognition – Fibroblasts – Regression analysis – Fluorescence resonance energy transfer – Fragile X syndrome

Zdroje

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Association between IQ and FMR1 protein (FMRP) across the spectrum of CGG repeat expansions

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