Functional Consequences of CHRNA7 Copy-Number Alterations in Induced Pluripotent Stem Cells and Neural Progenitor Cells.

ABSTRACT: Copy-number variants (CNVs) of chromosome 15q13.3 manifest clinically as neuropsychiatric disorders with variable expressivity. CHRNA7, encoding for the ?7 nicotinic acetylcholine receptor (nAChR), has been suggested as a candidate gene for the phenotypes observed. Here, we used induced pluripotent stem cells (iPSCs) and neural progenitor cells (NPCs) derived from individuals with heterozygous 15q13.3 deletions and heterozygous 15q13.3 duplications to investigate the CHRNA7-dependent molecular consequences of the respective CNVs. Unexpectedly, both deletions and duplications lead to decreased ?7 nAChR-associated calcium flux. For deletions, this decrease in ?7 nAChR-dependent calcium flux is expected due to haploinsufficiency of CHRNA7. For duplications, we found that increased expression of CHRNA7 mRNA is associated with higher expression of nAChR-specific and resident ER chaperones, indicating increased ER stress. This is likely a consequence of inefficient chaperoning and accumulation of ?7 subunits in the ER, as opposed to being incorporated into functional ?7 nAChRs at the cell membrane. Here, we showed that ?7 nAChR-dependent calcium signal cascades are downregulated in both 15q13.3 deletion and duplication NPCs. While it may seem surprising that genomic changes in opposite direction have consequences on downstream pathways that are in similar direction, it aligns with clinical data, which suggest that both individuals with deletions and duplications of 15q13.3 manifest neuropsychiatric disease and cognitive deficits.

SUBMITTER: Gillentine MA 

PROVIDER: S-EPMC5812918 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature