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

• Published in: PloS one Vol. 14; no. 12; p. e0226811
• Main Authors: Kim, Kyoungmi, Hessl, David, Randol, Jamie L, Espinal, Glenda M, Schneider, Andrea, Protic, Dragana, Aydin, Elber Yuksel, Hagerman, Randi J, Hagerman, Paul J
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 31-12-2019; Public Library of Science (PLoS)
• Subjects: 5' Untranslated Regions; Adolescent; Adult; Aged; Analysis; Autism; Biochemistry; Biology and Life Sciences; Child; Cognition; Cognitive ability; Cohort Studies; Disabilities; Energy transfer; Female; Fibroblasts; Fluorescence; Fluorescence resonance energy transfer; FMR1 protein; Fragile X mental retardation protein; Fragile X Mental Retardation Protein - genetics; Fragile X syndrome; Fragile X Syndrome - genetics; Gene Silencing; Genes; Genetic aspects; Genetic engineering; Humans; Intellectual disabilities; Intelligence; Intelligence - genetics; Level (quantity); Levels; Lower bounds; Male; Males; Medicine; Medicine and Health Sciences; Mental disorders; Mental retardation; Methods; Middle Aged; Mutation; Neurophysiology; Pediatrics; Physical Sciences; Proteins; Research and Analysis Methods; Statistical analysis; Trinucleotide Repeat Expansion - genetics; Wechsler Scales; Young Adult; Sacramento California; Istanbul Turkey; Turkey; California; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0226811

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.