Gillentine Madelyn A, Yin Jiani, Bajic Aleksandar, Zhang Ping, Cummock Steven, Kim Jean J, Schaaf Christian P
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Neurological Research Institute, Houston, TX 77030, USA.
Department of Molecular and Cellular Biology, Stem Cells and Regenerative Medicine Center, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA; Human Stem Cell Core, Advanced Technology Cores, Baylor College of Medicine, Houston, TX 77030, USA.
Am J Hum Genet. 2017 Dec 7;101(6):874-887. doi: 10.1016/j.ajhg.2017.09.024. Epub 2017 Nov 9.
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.
15号染色体15q13.3区域的拷贝数变异（CNV）在临床上表现为具有可变表达性的神经精神疾病。编码α7烟碱型乙酰胆碱受体（nAChR）的CHRNA7基因被认为是观察到的这些表型的候选基因。在此，我们使用了来自15q13.3杂合缺失个体和15q13.3杂合重复个体的诱导多能干细胞（iPSC）和神经祖细胞（NPC），来研究各自CNV的CHRNA7依赖性分子后果。出乎意料的是，缺失和重复均导致α7 nAChR相关的钙通量降低。对于缺失而言，由于CHRNA7的单倍剂量不足，α7 nAChR依赖性钙通量的这种降低是预期的。对于重复，我们发现CHRNA7 mRNA表达增加与nAChR特异性和内质网驻留伴侣蛋白的高表达相关，表明内质网应激增加。这可能是内质网中α7亚基伴侣蛋白功能不足和积累的结果，而不是被整合到细胞膜上的功能性α7 nAChR中。在此，我们表明在15q13.3缺失和重复的NPC中，α7 nAChR依赖性钙信号级联均被下调。虽然相反方向的基因组变化对相似方向的下游通路产生影响可能看起来令人惊讶，但这与临床数据相符，临床数据表明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。
