Functional Consequences of CHRNA7 Copy-Number Alterations in Induced Pluripotent Stem Cells and Neural Progenitor Cells.
Am J Hum Genet
; 101(6): 874-887, 2017 Dec 07.
Article
em En
| MEDLINE
| ID: mdl-29129316
ABSTRACT
Copy-number variants (CNVs) of chromosome 15q13.3 manifest clinically as neuropsychiatric disorders with variable expressivity. CHRNA7, encoding for the α7 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 α7 nAChR-associated calcium flux. For deletions, this decrease in α7 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 α7 subunits in the ER, as opposed to being incorporated into functional α7 nAChRs at the cell membrane. Here, we showed that α7 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.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Convulsões
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Dosagem de Genes
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Sinalização do Cálcio
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Transtornos Cromossômicos
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Células-Tronco Pluripotentes Induzidas
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Variações do Número de Cópias de DNA
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Células-Tronco Neurais
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Estresse do Retículo Endoplasmático
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Receptor Nicotínico de Acetilcolina alfa7
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Deficiência Intelectual
Limite:
Adolescent
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Child
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Child, preschool
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Female
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Humans
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Male
Idioma:
En
Revista:
Am J Hum Genet
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Estados Unidos