title: An interaction network of mental disorder proteins in neural stem cells.
abstract: Mental disorders (MDs) such as intellectual disability (ID), autism spectrum disorders (ASD) and schizophrenia have a strong genetic component. Recently, many gene mutations associated with ID, ASD or schizophrenia have been identified by high-throughput sequencing. A substantial fraction of these mutations are in genes encoding transcriptional regulators. Transcriptional regulators associated with different MDs but acting in the same gene regulatory network provide information on the molecular relation between MDs. Physical interaction between transcriptional regulators is a strong predictor for their cooperation in gene regulation. Here, we biochemically purified transcriptional regulators from neural stem cells, identified their interaction partners by mass spectrometry and assembled a protein interaction network containing 206 proteins, including 68 proteins mutated in MD patients and 52 proteins significantly lacking coding variation in humans. Our network shows molecular connections between established MD proteins and provides a discovery tool for novel MD genes. Network proteins preferentially co-localize on the genome and cooperate in disease-relevant gene regulation. Our results suggest that the observed transcriptional regulators associated with ID, ASD or schizophrenia are part of a transcriptional network in neural stem cells. We find that more severe mutations in network proteins are associated with MDs that include lower intelligence quotient (IQ), suggesting that the level of disruption of a shared transcriptional network correlates with cognitive dysfunction.
authors.affiliation: Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: M J
authors.initials: MJ
authors.lastname: Moen
authors.affiliation: Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: H H H
authors.initials: HH
authors.lastname: Adams
authors.affiliation: Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: Brandsma
authors.affiliation: Center for Proteomics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: D H W
authors.initials: DH
authors.lastname: Dekkers
authors.affiliation: Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: U
authors.initials: U
authors.lastname: Akinci
authors.affiliation: Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Karkampouna
authors.affiliation: Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Quevedo
authors.affiliation: Center for Biomics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: C E M
authors.initials: CE
authors.lastname: Kockx
authors.affiliation: Center for Biomics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Z
authors.initials: Z
authors.lastname: Ozgür
authors.affiliation: Center for Biomics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: W F J
authors.initials: WF
authors.lastname: van IJcken
authors.affiliation: Center for Proteomics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Demmers
authors.affiliation: Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: R A
authors.initials: RA
authors.lastname: Poot
mesh_terms: D000067877:Autism Spectrum Disorder / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D053263:Gene Regulatory Networks / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics / Q000523:psychology; D016678:Genome; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D009154:Mutation; D058953:Neural Stem Cells / Q000378:metabolism*; D011618:Psychotic Disorders / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics