Functional Consequences of CHRNA7 Copy-Number Alterations in Induced Pluripotent Stem Cells and Neural Progenitor Cells.,American Journal of Human Genetics

当前位置： X-MOL 学术 › Am. J. Hum. Genet. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Functional Consequences of CHRNA7 Copy-Number Alterations in Induced Pluripotent Stem Cells and Neural Progenitor Cells.
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2017-11-09 00:00:00 , DOI: 10.1016/j.ajhg.2017.09.024
Madelyn A Gillentine ₁ , Jiani Yin ₁ , Aleksandar Bajic ₁ , Ping Zhang ₂ , Steven Cummock ₃ , Jean J Kim ₂ , Christian P Schaaf ₁

Affiliation

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 theCHRNA7-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 ofCHRNA7. For duplications, we found that increased expression ofCHRNA7mRNA 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.

中文翻译：

在诱导的多能干细胞和神经祖细胞中CHRNA7拷贝数变化的功能后果。

染色体15q13.3的拷贝数变异（CNV）在临床上表现为表现力可变的神经精神病.CHRNA7编码α7烟碱乙酰胆碱受体（nAChR），已被建议作为观察到的表型的候选基因。在这里，我们使用了具有杂合的15q13.3缺失和杂合的15q13.3重复的个体衍生的诱导多能干细胞（iPSC）和神经祖细胞（NPC）来研究各个CNV的CHRNA7依赖性分子后果。出乎意料的是，删除和重复均导致与α7nAChR相关的钙通量降低。对于缺失，由于CHRNA7的单倍不足，预期α7nAChR依赖性钙通量的这种降低。对于重复项，我们发现，CHRNA7mRNA的表达增加与nAChR特异性和驻留ER伴侣的更高表达相关，表明ER应激增加。这可能是由于内质网中α7亚基的陪伴和积累效率低下所致，而不是在细胞膜中掺入功能性α7nAChRs中。在这里，我们显示了α7nAChR依赖性钙信号级联在15q13.3缺失和重复NPC中均被下调。虽然相反方向的基因组变化会影响相似方向的下游通路，这似乎令人惊讶，但它与临床数据一致，这表明具有15q13.3缺失和重复的个体均表现出神经精神疾病和认知缺陷。这可能是由于内质网中α7亚基的陪伴和积累效率低下的结果，与在细胞膜中掺入功能性α7nAChRs相反。在这里，我们显示了α7nAChR依赖性钙信号级联在15q13.3缺失和重复NPC中均被下调。尽管相反方向的基因组变化会影响相似方向的下游通路，这似乎令人惊讶，但它与临床数据一致，这表明具有15q13.3缺失和重复的个体均表现出神经精神疾病和认知缺陷。这可能是由于内质网中α7亚基的陪伴和积累效率低下所致，而不是在细胞膜中掺入功能性α7nAChRs中。在这里，我们显示了α7nAChR依赖性钙信号级联在15q13.3缺失和重复NPC中均被下调。虽然相反方向的基因组变化会影响相似方向的下游通路，这似乎令人惊讶，但它与临床数据一致，这表明具有15q13.3缺失和重复的个体均表现出神经精神疾病和认知缺陷。我们发现α7nAChR依赖性钙信号级联在15q13.3缺失和重复NPC中均被下调。虽然相反方向的基因组变化会影响相似方向的下游通路，这似乎令人惊讶，但它与临床数据一致，这表明具有15q13.3缺失和重复的个体均表现出神经精神疾病和认知缺陷。我们发现α7nAChR依赖性钙信号级联在15q13.3缺失和重复NPC中均被下调。虽然相反方向的基因组变化会影响相似方向的下游通路，这似乎令人惊讶，但它与临床数据一致，这表明具有15q13.3缺失和重复的个体均表现出神经精神疾病和认知缺陷。

更新日期：2017-11-10

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南