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.

Molecular psychiatry (2018-01-06)

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 Bakker, Aviva Nijburg, 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 Duijn, M Arfan Ikram, Meike W Vernooij, Henning Tiemeier, André G Uitterlinden, Ype Elgersma, Ben Distel, Joost Gribnau, Tonya White, Vincenzo Bonifati, Steven A Kushner

PMID29302076

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 × 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.