Lee, I. S., Carvalho, C. M., Douvaras, P., Ho, S. M., Hartley, B. J., Zuccherato, L. W., Ladran, I. G., Siegel, A. J., McCarthy, S., Malhotra, D., Sebat, J., Rapoport, J., Fossati, V., Lupski, J. R., Levy, D. L., Brennand, K. J. (June 2015) Characterization of molecular and cellular phenotypes associated with a heterozygous deletion using patient-derived hiPSC neural cells. NPJ Schizophr, 1. ISSN 2334-265X (Print)2334-265X (Linking)
Abstract
Neurodevelopmental disorders, such as autism spectrum disorders (ASD) and schizophrenia (SZ), are complex disorders with a high degree of heritability. Genetic studies have identified several candidate genes associated with these disorders, including contactin-associated protein-like 2 (CNTNAP2). Traditionally, in animal models or in vitro, the function of CNTNAP2 has been studied by genetic deletion or transcriptional knockdown, which reduce the expression of the entire gene; however, it remains unclear whether the mutations identified in clinical settings are sufficient to alter CNTNAP2 expression in human neurons. Here, using human induced pluripotent stem cells (hiPSCs) derived from two individuals with a large (289kb) and heterozygous deletion in CNTNAP2 (affecting exons 14-15) and discordant clinical outcomes, we have characterized CNTNAP2 expression patterns in hiPSC neural progenitor cells (NPCs), two independent populations of hiPSC-derived neurons and hiPSC-derived oligodendrocyte precursor cells (OPCs). First, we observed exon-specific changes in CNTNAP2 expression in both carriers; although the expression of exons 14-15 is significantly decreased, the expression of other exons is upregulated. Second, we observed significant differences in patterns of allele-specific expression in CNTNAP2 carriers that were consistent with clinical outcome. Third, we observed a robust neural migration phenotype that correlated with diagnosis and exon- and allele-specific CNTNAP2 expression patterns, but not with genotype. In all, our data highlight the importance of considering the nature, location and regulation of mutated alleles when attempting to connect GWAS studies to gene function.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > mental disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression Investigative techniques and equipment > assays > genome wide association studies |
| CSHL Authors: | |
| Communities: | CSHL labs > McCombie lab |
| Depositing User: | Matt Covey |
| Date: | 24 June 2015 |
| Date Deposited: | 22 Mar 2016 14:43 |
| Last Modified: | 22 Mar 2016 14:43 |
| PMCID: | PMC4789165 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/32451 |
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