Reduced CYFIP1 in Human Neural Progenitors Results in Dysregulation of Schizophrenia and Epilepsy Gene Networks

• Published in: PloS one Vol. 11; no. 1; p. e0148039
• Main Authors: Nebel, Rebecca A, Zhao, Dejian, Pedrosa, Erika, Kirschen, Jill, Lachman, Herbert M, Zheng, Deyou, Abrahams, Brett S
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.01.2016; Public Library of Science (PLoS)
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adult; Autism; Base Sequence; Behavioral sciences; Bioinformatics; Biology and Life Sciences; Carriers; Chromosomes, Human, Pair 15; Clonal deletion; Cytoskeleton; Disease; Epilepsy; Epilepsy - genetics; Epilepsy - metabolism; Epilepsy - pathology; Gene expression; Gene Expression Profiling; Gene Expression Regulation; Gene Knockdown Techniques; Gene Regulatory Networks; Genes; Genetic aspects; Genetic counseling; Genetic Loci; Genetics; Genomes; Health risk assessment; Heterozygote; Humans; Male; Medicine; Medicine and Health Sciences; Mental disorders; Middle Aged; Migraine; Molecular Sequence Data; Nerve Tissue Proteins - genetics; Neural stem cells; Neural Stem Cells - metabolism; Neural Stem Cells - pathology; Neurosciences; Physiological aspects; Postsynaptic density; Primary Cell Culture; Proteins; Psychiatry; Ribonucleic acid; Risk; Risk factors; RNA; Schizophrenia; Schizophrenia - genetics; Schizophrenia - metabolism; Schizophrenia - pathology; Sequence Deletion; Stem cells; United States; New York; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0148039

Deletions encompassing the BP1-2 region at 15q11.2 increase schizophrenia and epilepsy risk, but only some carriers have either disorder. To investigate the role of CYFIP1, a gene within the region, we performed knockdown experiments in human neural progenitors derived from donors with 2 copies of each gene at the BP1-2 locus. RNA-seq and cellular assays determined that knockdown of CYFIP1 compromised cytoskeletal remodeling. FMRP targets and postsynaptic density genes, each implicated in schizophrenia, were significantly overrepresented among differentially expressed genes (DEGs). Schizophrenia and/or epilepsy genes, but not those associated with randomly selected disorders, were likewise significantly overrepresented. Mirroring the variable expressivity seen in deletion carriers, marked between-line differences were observed for dysregulation of disease genes. Finally, a subset of DEGs showed a striking similarity to known epilepsy genes and represents novel disease candidates. Results support a role for CYFIP1 in disease and demonstrate that disease-related biological signatures are apparent prior to neuronal differentiation.