Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes
| Autor: | Stepniak, Beata, Kästner, Anne, Poggi, Giulia, Mitjans, Marina, Begemann, Martin, Hartmann, Annette, Van der Auwera, Sandra, Sananbenesi, Farahnaz, Krueger-Burg, Dilja, Matuszko, Gabriela, Brosi, Cornelia, Homuth, Georg, Völzke, Henry, Benseler, Fritz, Bagni, Claudia, Fischer, Utz, Dityatev, Alexander, Grabe, Hans-Jörgen, Rujescu, Dan, Fischer, Andre, Ehrenreich, Hannelore |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
congenital hereditary and neonatal diseases and abnormalities FMR2 PGAS biosynthesis [MicroRNAs] physiopathology [Fragile X Syndrome] FXR2 FXR1 Polymorphism Single Nucleotide genetics [Fragile X Mental Retardation Protein] genetics [Autistic Disorder] Fragile X Mental Retardation Protein ddc:572 Humans genetics [RNA-Binding Proteins] genetics [Schizophrenia] ddc:610 Polymorphism Autistic Disorder FMR1 Research Articles genetics [Fragile X Syndrome] miR-181 Settore BIO/13 RNA-Binding Proteins miR‐181 Fragile X Syndrome MicroRNAs Mutation Schizophrenia Single Nucleotide FMR1 protein human FXR1 protein human physiopathology [Schizophrenia] FXR2 protein human Genetics Gene Therapy & Genetic Disease Research Article Neuroscience MIrn181 microRNA human |
| Zdroj: | EMBO molecular medicine EMBO molecular medicine 7(12), 1565-1579 (2015). doi:10.15252/emmm.201505696 EMBO Molecular Medicine |
| DOI: | 10.15252/emmm.201505696 |
| Popis: | Fragile X syndrome (FXS) is mostly caused by a CGG triplet expansion in the fragile X mental retardation 1 gene (FMR1). Up to 60% of affected males fulfill criteria for autism spectrum disorder (ASD), making FXS the most frequent monogenetic cause of syndromic ASD. It is unknown, however, whether normal variants (independent of mutations) in the fragile X gene family (FMR1, FXR1, FXR2) and in FMR2 modulate autistic features. Here, we report an accumulation model of 8 SNPs in these genes, associated with autistic traits in a discovery sample of male patients with schizophrenia (N = 692) and three independent replicate samples: patients with schizophrenia (N = 626), patients with other psychiatric diagnoses (N = 111) and a general population sample (N = 2005). For first mechanistic insight, we contrasted microRNA expression in peripheral blood mononuclear cells of selected extreme group subjects with high- versus low-risk constellation regarding the accumulation model. Thereby, the brain-expressed miR-181 species emerged as potential "umbrella regulator", with several seed matches across the fragile X gene family and FMR2. To conclude, normal variation in these genes contributes to the continuum of autistic phenotypes. peerReviewed |
| Databáze: | OpenAIRE |
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