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Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes

Please always quote using this URN: urn:nbn:de:bvb:20-opus-136893
  • 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 ofFragile 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.show moreshow less

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Metadaten
Author: Beata Stepniak, Anne Kästner, Giulia Poggi, Marina Mitjans, Martin Begemann, Annette Hartmann, Sandra Van der Auwera, Farahnaz Sananbenesi, Dilja Krüger-Burg, Gabriela Matuszko, Cornelia Brosi, Georg Homuth, Henry Völzke, Fritz Benseler, Claudia Bagni, Utz Fischer, Alexander Dityatev, Hans-Jörgen Grabe, Dan Rujescu, Andre Fischer, Hannelore Ehrenreich
URN:urn:nbn:de:bvb:20-opus-136893
Document Type:Journal article
Faculties:Fakultät für Chemie und Pharmazie / Lehrstuhl für Biochemie
Language:English
Parent Title (English):EMBO Molecular Medicine
Year of Completion:2015
Volume:7
Issue:12
Pagenumber:1565-1579
Source:EMBO Molecular Medicine, 7(12), 2015, p. 1565-1579. DOI 10.15252/emmm.201505696
DOI:https://doi.org/10.15252/emmm.201505696
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=PMC4693501
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 572 Biochemie
Tag:CGG repeat; CPG Island; FMR1; FMR2; FXR1; FXR2; PGAS; expression; fraxe mental retardation; identification; males; miR-181; permutation; protein; schizophrenia
Release Date:2016/09/02
EU-Project number / Contract (GA) number:606950
OpenAIRE:OpenAIRE
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung