Journal
MOLECULAR PSYCHIATRY
Volume 24, Issue 5, Pages 757-771Publisher
SPRINGERNATURE
DOI: 10.1038/s41380-017-0004-2
Keywords
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Funding
- Erasmus MC-University Medical Centre Rotterdam
- Netherlands Organization for Scientific Research (NWO)
- Netherlands Organisation for Health Research and Development (ZonMW)
- NeuroBasic-PharmaPhenomics consortium
- Stichting ParkinsonFonds (The Netherlands)
- Netherlands Institute for Regenerative Medicine (NIRM)
- European Research Council
- Lung GO Sequencing Project [HL-102923]
- WHI Sequencing Project [HL-102924]
- Broad GO Sequencing Project [HL-102925]
- Seattle GO Sequencing Project [HL-102926]
- Heart GO Sequencing Project [HL-103010]
- Netherlands Organization for Scientific Research [184021007]
- Netherlands Organisation of Scientific Research Investments [175. 010.2005.011, 911-03-012]
- Netherlands Genomics Initiative (NGI) [050-060-810]
- Erasmus Medical Centre
- Erasmus University, Rotterdam
- Research Institute for Diseases in the Elderly (RIDE)
- Ministry of Education, Culture and Science
- Ministry for Health, Welfare and Sports
- European Commission (DG XII)
- Municipality of Rotterdam
- NIMH [MH60881, MH60875, R01MH077139, RCMH089905]
- Stanley Medical Research Institute
- Swedish Research Council [2009-4959, 2011-4659]
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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 x 10(-5) and c.2702T > G [p.V901G], MAF 2.51 x 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 x 10(-8)), viability (P = 8.9 x 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 x 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 x 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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