Abstract
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.
Highlights
The identification of novel disease loci through genome-wide characterization of copy number variations (CNVs) has been important in many regards, including the discovery of genotypephenotype relationships and genetic counseling
We first confirmed in lymphoblastoid cell lines from breakpoint deletion region at 15q11.2 (BP1-2) deletion carriers that cytoplasmic FMR1 interacting protein 1 (CYFIP1) mRNA levels were significantly reduced relative to cell lines from BP1-2 copy number neutral individuals (39% reduction; p = 1.4 x 10−3; Fig 1A)
The extent of CYFIP1 reduction in our model system falls within the range of what is observed in neural cells derived from BP1-2 deletion carriers [12,24]. mRNA levels of the closely related CYFIP2 gene were indistinguishable between non-silencing control shRNA (NS) and CYFIP1KD neural progenitor cells (NPCs)
Summary
The identification of novel disease loci through genome-wide characterization of copy number variations (CNVs) has been important in many regards, including the discovery of genotypephenotype relationships and genetic counseling. Personalized treatment, requires a clear understanding of underlying mechanisms, including which genes within disease-associated loci contribute to risk and how effects are mediated across development. Given that penetrance is often incomplete and expressivity is highly variable with CNVs, the ability to model this complexity is likewise critically important. Clinical recruitment efforts were supported by CTSA Grants (UL1RR025750, KL2RR025749, and TL1RR025748; NCRR and 8UL1 TR000086; NCATS). Support to HML was provided by the NIMH (MH097893 and MH087840). Zheng was provided by the NIMH (MH099452)
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