Abstract
Large expansions of a CGG-repeat element (>200 repeats; full mutation) in the fragile X mental retardation 1 (FMR1) gene cause fragile X syndrome (FXS), the leading single-gene form of intellectual disability and of autism spectrum disorder. Smaller expansions (55-200CGGrepeats; premutation) result in theneurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). Whereas FXS is caused by gene silencing and insufficient FMR1 protein (FMRP), FXTAS is thought to be caused by 'toxicity' of expanded-CGG-repeat mRNA. However, as FMRP expression levels decrease with increasing CGG-repeat length, lowered protein may contribute to premutation-associated clinical involvement. To address this issue, we measured brain Fmr1 mRNA and FMRP levels as a function of CGG-repeat length in a congenic (CGG-repeat knock-in) mouse model using 57 wild-type and 97 expanded-CGG-repeat mice carrying up tõ250 CGG repeats. While Fmr1message levels increasedwith repeat length,FMRPlevels trended downward over thesamerange, subject to significant inter-subject variation.Human comparisons of protein levels in the frontal cortex of 7 normal and 17 FXTAS individuals revealed that the mildFMRPdecrease in mice mirrored the more limited data forFMRP expression in thehumansamples. In addition,FMRPexpression levels varied in a subset ofmiceacross the cerebellum, frontal cortex,andhippocampus,aswell asat different ages.Theseresults provide a foundation for understandingboth the CGG-repeat-dependence of FMRP expression and for interpreting clinical phenotypes in premutation carriers in terms of the balance between elevated mRNA and lowered FMRP expression levels.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3228-3238 |
| Number of pages | 11 |
| Journal | Human Molecular Genetics |
| Volume | 23 |
| Issue number | 12 |
| DOIs | |
| State | Published - 2014 |
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ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
- Molecular Biology
- Medicine(all)
Cite this
CNS expression of murine fragile X protein (FMRP) as a function of CGG-repeat size. / Ludwig, Anna Lisa; Espinal, Glenda M.; Pretto, Dalyir I.; Jamal, Amanda L.; Arque, Gloria; Tassone, Flora; Berman, Robert F; Hagerman, Paul J.
In: Human Molecular Genetics, Vol. 23, No. 12, 2014, p. 3228-3238.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - CNS expression of murine fragile X protein (FMRP) as a function of CGG-repeat size
AU - Ludwig, Anna Lisa
AU - Espinal, Glenda M.
AU - Pretto, Dalyir I.
AU - Jamal, Amanda L.
AU - Arque, Gloria
AU - Tassone, Flora
AU - Berman, Robert F
AU - Hagerman, Paul J
PY - 2014
Y1 - 2014
N2 - Large expansions of a CGG-repeat element (>200 repeats; full mutation) in the fragile X mental retardation 1 (FMR1) gene cause fragile X syndrome (FXS), the leading single-gene form of intellectual disability and of autism spectrum disorder. Smaller expansions (55-200CGGrepeats; premutation) result in theneurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). Whereas FXS is caused by gene silencing and insufficient FMR1 protein (FMRP), FXTAS is thought to be caused by 'toxicity' of expanded-CGG-repeat mRNA. However, as FMRP expression levels decrease with increasing CGG-repeat length, lowered protein may contribute to premutation-associated clinical involvement. To address this issue, we measured brain Fmr1 mRNA and FMRP levels as a function of CGG-repeat length in a congenic (CGG-repeat knock-in) mouse model using 57 wild-type and 97 expanded-CGG-repeat mice carrying up tõ250 CGG repeats. While Fmr1message levels increasedwith repeat length,FMRPlevels trended downward over thesamerange, subject to significant inter-subject variation.Human comparisons of protein levels in the frontal cortex of 7 normal and 17 FXTAS individuals revealed that the mildFMRPdecrease in mice mirrored the more limited data forFMRP expression in thehumansamples. In addition,FMRPexpression levels varied in a subset ofmiceacross the cerebellum, frontal cortex,andhippocampus,aswell asat different ages.Theseresults provide a foundation for understandingboth the CGG-repeat-dependence of FMRP expression and for interpreting clinical phenotypes in premutation carriers in terms of the balance between elevated mRNA and lowered FMRP expression levels.
AB - Large expansions of a CGG-repeat element (>200 repeats; full mutation) in the fragile X mental retardation 1 (FMR1) gene cause fragile X syndrome (FXS), the leading single-gene form of intellectual disability and of autism spectrum disorder. Smaller expansions (55-200CGGrepeats; premutation) result in theneurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). Whereas FXS is caused by gene silencing and insufficient FMR1 protein (FMRP), FXTAS is thought to be caused by 'toxicity' of expanded-CGG-repeat mRNA. However, as FMRP expression levels decrease with increasing CGG-repeat length, lowered protein may contribute to premutation-associated clinical involvement. To address this issue, we measured brain Fmr1 mRNA and FMRP levels as a function of CGG-repeat length in a congenic (CGG-repeat knock-in) mouse model using 57 wild-type and 97 expanded-CGG-repeat mice carrying up tõ250 CGG repeats. While Fmr1message levels increasedwith repeat length,FMRPlevels trended downward over thesamerange, subject to significant inter-subject variation.Human comparisons of protein levels in the frontal cortex of 7 normal and 17 FXTAS individuals revealed that the mildFMRPdecrease in mice mirrored the more limited data forFMRP expression in thehumansamples. In addition,FMRPexpression levels varied in a subset ofmiceacross the cerebellum, frontal cortex,andhippocampus,aswell asat different ages.Theseresults provide a foundation for understandingboth the CGG-repeat-dependence of FMRP expression and for interpreting clinical phenotypes in premutation carriers in terms of the balance between elevated mRNA and lowered FMRP expression levels.
UR - http://www.scopus.com/inward/record.url?scp=84897370853&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84897370853&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddu032
DO - 10.1093/hmg/ddu032
M3 - Article
C2 - 24463622
AN - SCOPUS:84897370853
VL - 23
SP - 3228
EP - 3238
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 12
ER -