Candidate CSPG4 mutations and induced pluripotent stem cell modeling implicate oligodendrocyte progenitor cell dysfunction in familial schizophrenia.
Candidate CSPG4 mutations and induced pluripotent stem cell modeling implicate oligodendrocyte progenitor cell dysfunction in familial schizophrenia.
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DOI：
10.1038/s41380-017-0004-2
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发表时间：
2019-05
影响因子：
11
通讯作者：
Kushner SA
中科院分区：
文献类型：
--
作者：
de Vrij FM;Bouwkamp CG;Gunhanlar N;Shpak G;Lendemeijer B;Baghdadi M;Gopalakrishna S;Ghazvini M;Li TM;Quadri M;Olgiati S;Breedveld GJ;Coesmans M;Mientjes E;de Wit T;Verheijen FW;Beverloo HB;Cohen D;Kok RM;Bakker PR;Nijburg A;Spijker AT;Haffmans PMJ;Hoencamp E;Bergink V;GROUP Study Consortium;Vorstman JA;Wu T;Olde Loohuis LM;Amin N;Langen CD;Hofman A;Hoogendijk WJ;van Duijn CM;Ikram MA;Vernooij MW;Tiemeier H;Uitterlinden AG;Elgersma Y;Distel B;Gribnau J;White T;Bonifati V;Kushner SA
精神分裂症具有高度遗传性，但其潜在的病理生理学仍然很大程度上未知。精神分裂症的神经生物学研究中最被重复的发现是髓鞘形成和白质完整性的缺陷。然而，迄今为止还缺乏直接的病因学遗传和细胞证据。在这里，我们实施了一种基于家族的精神分裂症遗传发现方法，并结合使用诱导多能干细胞（iPSC）进行功能分析。我们观察到硫酸软骨素蛋白聚糖 4 (CSPG4) 中两个罕见错义突变的家族分离 (c.391G > A [p.A131T], MAF 7.79 × 10−5 和 c.2702T > G [p.V901G], MAF 2.51 × 10−3)。瑞典精神分裂症外显子组测序研究（2536 例病例，2543 名对照）中不存在 CSPG4A131T 突变，而 CSPG4V901G 突变在病例中名义上富集（11 例病例 vs. 3 名对照，P = 0.026，OR 3.77，95% CI 1.05–13.52）。 CSPG4/NG2 是少突胶质祖细胞 (OPC) 的标志蛋白。来自 CSPG4A131T 突变携带者的 iPSC 衍生 OPC 表现出异常的翻译后加工 (P = 0.029)、突变体 NG2 的亚细胞定位 (P = 0.007) 以及异常的细胞形态 (P = 3.0 × 10−8)、活力(P = 8.9 × 10−7)和髓鞘形成潜能(P = 0.038)。此外，健康非携带者同胞OPC的转染证实了CSPG4A131T (P = 0.006)和CSPG4V901G (P = 3.4 × 10−4)突变对细胞存活的致病作用。最后，CSPG4A131T 突变携带者的体内扩散张量成像表明，与未受影响的兄弟姐妹和匹配的一般人群对照相比，其脑白质完整性降低（P = 2.2 × 10−5）。总之，我们的研究结果提供了遗传和功能证据的融合，表明 OPC 功能障碍是家族性精神分裂症的候选病理生理机制。
Schizophrenia is highly heritable, yet its underlying pathophysiology remains largely unknown. Among the most well-replicated findings in neurobiological studies of schizophrenia are deficits in myelination and white matter integrity; however, direct etiological genetic and cellular evidence has thus far been lacking. Here, we implement a family-based approach for genetic discovery in schizophrenia combined with functional analysis using induced pluripotent stem cells (iPSCs). We observed familial segregation of two rare missense mutations in Chondroitin Sulfate Proteoglycan 4 (CSPG4) (c.391G > A [p.A131T], MAF 7.79 × 10−5 and c.2702T > G [p.V901G], MAF 2.51 × 10−3). The CSPG4A131T mutation was absent from the Swedish Schizophrenia Exome Sequencing Study (2536 cases, 2543 controls), while the CSPG4V901G mutation was nominally enriched in cases (11 cases vs. 3 controls, P = 0.026, OR 3.77, 95% CI 1.05–13.52). CSPG4/NG2 is a hallmark protein of oligodendrocyte progenitor cells (OPCs). iPSC-derived OPCs from CSPG4A131T mutation carriers exhibited abnormal post-translational processing (P = 0.029), subcellular localization of mutant NG2 (P = 0.007), as well as aberrant cellular morphology (P = 3.0 × 10−8), viability (P = 8.9 × 10−7), and myelination potential (P = 0.038). Moreover, transfection of healthy non-carrier sibling OPCs confirmed a pathogenic effect on cell survival of both the CSPG4A131T (P = 0.006) and CSPG4V901G (P = 3.4 × 10−4) mutations. Finally, in vivo diffusion tensor imaging of CSPG4A131T mutation carriers demonstrated a reduction of brain white matter integrity compared to unaffected sibling and matched general population controls (P = 2.2 × 10−5). Together, our findings provide a convergence of genetic and functional evidence to implicate OPC dysfunction as a candidate pathophysiological mechanism of familial schizophrenia.
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影响因子：
2.9
作者：
Clayton, Benjamin L. L.;Popko, Brian
通讯作者：
Popko, Brian
影响因子：
1.8
作者：
Vieland VJ;Walters KA;Azaro M;Brzustowicz LM;Lehner T
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影响因子：
30.8
作者：
Francioli, Laurent C.;Menelaou, Andronild;Wijmenga, Cisca
通讯作者：
Wijmenga, Cisca
影响因子：
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作者：
Burg, MA;Nishiyama, A;Stallcup, WB
通讯作者：
Stallcup, WB
影响因子：
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作者：
Chen, Fang;Venugopal, Vandavasi;Murray, Beverly;Rudenko, Gabby
通讯作者：
Rudenko, Gabby