Candidate CSPG4 Mutations and Induced Pluripotent Stem Cell Modeling Implicate Oligodendrocyte Progenitor Cell Dysfunction in Familial Schizophrenia
Molecular psychiatry(2018)
摘要
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 CSPG4 A131T mutation was absent from the Swedish Schizophrenia Exome Sequencing Study (2536 cases, 2543 controls), while the CSPG4 V901G 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 CSPG4 A131T 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 CSPG4 A131T ( P = 0.006) and CSPG4 V901G ( P = 3.4 × 10 −4 ) mutations. Finally, in vivo diffusion tensor imaging of CSPG4 A131T 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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关键词
Genetics,Schizophrenia,Stem cells,Medicine/Public Health,general,Psychiatry,Neurosciences,Behavioral Sciences,Pharmacotherapy,Biological Psychology
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