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FRA2A Is a CGG Repeat Expansion Associated with Silencing of AFF3
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نویسنده
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metsu s. ,rooms l. ,rainger j. ,taylor m.s. ,bengani h. ,wilson d.i. ,chilamakuri c.s.r. ,morrison h. ,vandeweyer g. ,reyniers e. ,douglas e. ,thompson g. ,haan e. ,gecz j. ,fitzpatrick d.r. ,kooy r.f.
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منبع
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plos genetics - 2014 - دوره : 10 - شماره : 4
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چکیده
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Folate-sensitive fragile sites (fsfs) are a rare cytogenetically visible subset of dynamic mutations. of the eight molecularly characterized fsfs,four are associated with intellectual disability (id). cytogenetic expression results from cgg tri-nucleotide-repeat expansion mutation associated with local cpg hypermethylation and transcriptional silencing. the best studied is the fraxa site in the fmr1 gene,where large expansions cause fragile x syndrome,the most common inherited id syndrome. here we studied three families with fra2a expression at 2q11 associated with a wide spectrum of neurodevelopmental phenotypes. we identified a polymorphic cgg repeat in a conserved,brain-active alternative promoter of the aff3 gene,an autosomal homolog of the x-linked aff2/fmr2 gene: expansion of the aff2 cgg repeat causes fraxe id. we found that fra2a-expressing individuals have mosaic expansions of the aff3 cgg repeat in the range of several hundred repeat units. moreover,bisulfite sequencing and pyrosequencing both suggest aff3 promoter hypermethylation. csnp-analysis demonstrates monoallelic expression of the aff3 gene in fra2a carriers thus predicting that fra2a expression results in functional haploinsufficiency for aff3 at least in a subset of tissues. by whole-mount in situ hybridization the mouse aff3 ortholog shows strong regional expression in the developing brain,somites and limb buds in 9.5-12.5dpc mouse embryos. our data suggest that there may be an association between fra2a and a delay in the acquisition of motor and language skills in the families studied here. however,additional cases are required to firmly establish a causal relationship. © 2014 metsu et al.
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آدرس
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department of medical genetics,university of antwerp,antwerp, Belgium, department of medical genetics,university of antwerp,antwerp, Belgium, medical and developmental genetics section,mrc human genetics unit,igmm,university of edinburgh,edinburgh, United Kingdom, medical and developmental genetics section,mrc human genetics unit,igmm,university of edinburgh,edinburgh, United Kingdom, medical and developmental genetics section,mrc human genetics unit,igmm,university of edinburgh,edinburgh, United Kingdom, university of southampton,centre for human development,stem cells and regeneration,human genetics,southampton, United Kingdom, department of tumor biology,institute for cancer research,oslo university hospital,oslo, Norway, medical and developmental genetics section,mrc human genetics unit,igmm,university of edinburgh,edinburgh, United Kingdom, department of medical genetics,university of antwerp,antwerp, Belgium, department of medical genetics,university of antwerp,antwerp, Belgium, genetics and molecular pathology,sa pathology,adelaide,sa, Australia, department of paediatrics,the university of adelaide,adelaide,sa,australia,department of paediatrics and child health,flinders university,adelaide,sa, Australia, genetics and molecular pathology,sa pathology,adelaide,sa,australia,south australian clinical genetic service,sa pathology (at women's and children's hospital),adelaide,sa, Australia, genetics and molecular pathology,sa pathology,adelaide,sa,australia,department of paediatrics,the university of adelaide,adelaide,sa, Australia, medical and developmental genetics section,mrc human genetics unit,igmm,university of edinburgh,edinburgh, United Kingdom, department of medical genetics,university of antwerp,antwerp, Belgium
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Authors
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