Abstract
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 50 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.
| Original language | English (US) |
|---|---|
| Article number | e0226811 |
| Journal | PloS one |
| Volume | 14 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 2019 |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Agricultural and Biological Sciences(all)
- General
Cite this
Association between IQ and FMR1 protein (FMRP) across the spectrum of CGG repeat expansions. / Kim, Kyoungmi; Hessl, David; Randol, Jamie L.; Espinal, Glenda M.; Schneider, Andrea; Protic, Dragana; Aydin, Elber Yuksel; Hagerman, Randi J.; Hagerman, Paul J.
In: PloS one, Vol. 14, No. 12, e0226811, 12.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Association between IQ and FMR1 protein (FMRP) across the spectrum of CGG repeat expansions
AU - Kim, Kyoungmi
AU - Hessl, David
AU - Randol, Jamie L.
AU - Espinal, Glenda M.
AU - Schneider, Andrea
AU - Protic, Dragana
AU - Aydin, Elber Yuksel
AU - Hagerman, Randi J.
AU - Hagerman, Paul J.
PY - 2019/12
Y1 - 2019/12
N2 - 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 50 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.
AB - 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 50 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.
UR - http://www.scopus.com/inward/record.url?scp=85077441666&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85077441666&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0226811
DO - 10.1371/journal.pone.0226811
M3 - Article
C2 - 31891607
AN - SCOPUS:85077441666
VL - 14
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 12
M1 - e0226811
ER -