Candidate CSPG4 mutations and induced pluripotent stem cell modeling implicate oligodendrocyte progenitor cell dysfunction in familial schizophrenia

Femke M. de Vrij, Christian G. Bouwkamp, Nilhan Gunhanlar, Guy Shpak, Bas Lendemeijer, Maarouf Baghdadi, Shreekara Gopalakrishna, Mehrnaz Ghazvini, Tracy M. Li, Marialuisa Quadri, Simone Olgiati, Guido J. Breedveld, Michiel Coesmans, Edwin Mientjes, Ton de Wit, Frans W. Verheijen, H. Berna Beverloo, Dan Cohen, Rob M. Kok, P. Roberto BakkerAviva Nijbur, Annet T. Spijker, P. M. Judith Haffmans, Erik Hoencamp, Veerle Bergink, Jacob A. Vorstman, Timothy Wu, Loes M. Olde Loohuis, Najaf Amin, Carolyn D. Langen, Albert Hofman, Witte J. Hoogendijk, Cornelia M. van Duijimn, M. Arfan Ikram, Meike W. Vernooij, Henning Tiemeier, Andre G. Uitterlinden, Ype Elgersma, Ben Distel, Joost Gribnau, Tonya White, Vincenzo Bonifati, Steven A. Kushner*, GROUP Study Consortium

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

28 Citations (Web of Science)

Abstract

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.

Original languageEnglish
Pages (from-to)757-771
Number of pages15
JournalMolecular Psychiatry
Volume24
Issue number5
DOIs
Publication statusPublished - May 2019

Keywords

  • ENDOPLASMIC-RETICULUM STRESS
  • WHITE-MATTER
  • NG2 PROTEOGLYCAN
  • CHONDROITIN SULFATE
  • PSYCHIATRIC-DISORDERS
  • PRECURSOR CELLS
  • MYELINATION
  • REVEALS
  • BRAIN
  • GENE

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