title: Neural transcriptome of constitutional Pten dysfunction in mice and its relevance to human idiopathic autism spectrum disorder.
abstract: Autism spectrum disorder (ASD) is a neurodevelopmental condition with a clear, but heterogeneous, genetic component. Germline mutations in the tumor suppressor Pten are a well-established risk factor for ASD with macrocephaly, and conditional Pten mouse models have impaired social behavior and brain development. Some mutations observed in patients disrupt the normally balanced nuclear-cytoplasmic localization of the Pten protein, and we developed the Pten(m3m4) model to study the effects of a cytoplasm-predominant Pten. In this model, germline mislocalization of Pten causes inappropriate social behavior with intact learning and memory, a profile reminiscent of high-functioning ASD. These animals also exhibit histological evidence of neuroinflammation and expansion of glial populations by 6 weeks of age. We hypothesized that the neural transcriptome of this model would be altered in a manner that could inform human idiopathic ASD, a constitutional condition. Using total RNA sequencing, we found progressive disruption of neural gene expression in Pten(m3m4) mice from 2-6 weeks of age, involving both immune and synaptic pathways. These alterations include downregulation of many highly coexpressed human ASD-susceptibility genes. Comparison with a human cortical development coexpression network revealed that genes disrupted in Pten(m3m4) mice were enriched in the same areas as those of human ASD. Although Pten-related ASD is relatively uncommon, our observations suggest that the Pten(m3m4) model recapitulates multiple molecular features of human ASD, and that Pten operates far upstream of common pathways within ASD pathogenesis.
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.|Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.|Department of Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Tilot
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.|Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.|Center for Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: G
authors.initials: G
authors.lastname: Bebek
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.|Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: F
authors.initials: F
authors.lastname: Niazi
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.|Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Altemus
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.|Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: T
authors.initials: T
authors.lastname: Romigh
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.|Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.|Department of Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA.|Center for Autism, Pediatric Institute, Cleveland Clinic, Cleveland, OH, USA.|Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: T W
authors.initials: TW
authors.lastname: Frazier
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.|Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.|Department of Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA.|Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.|Stanley Shalom Zielony Institute of Nursing Excellence, Cleveland Clinic, Cleveland, OH, USA.|Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA.|CASE Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: C
authors.identifier: http://orcid.org/0000-0002-3693-5145
authors.initials: C
authors.lastname: Eng
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000378:metabolism*; D002540:Cerebral Cortex / Q000254:growth & development* / Q000378:metabolism*; D015331:Cohort Studies; D004195:Disease Models, Animal; D015870:Gene Expression / Q000502:physiology; D008297:Male; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D059467:Transcriptome
chemical_list: D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse