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

Author

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

Published
2019
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2. Candidate CSPG4 mutations and induced pluripotent stem cell modeling implicate oligodendrocyte progenitor cell dysfunction in familial schizophrenia

Author

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

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.

Published
2018

3. Candidate CSPG4mutations and induced pluripotent stem cell modeling implicate oligodendrocyte progenitor cell dysfunction in familial schizophrenia

Author

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

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 × 10−5and c.2702T > G [p.V901G], MAF 2.51 × 10−3). The CSPG4A131Tmutation was absent from the Swedish Schizophrenia Exome Sequencing Study (2536 cases, 2543 controls), while the CSPG4V901Gmutation 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 CSPG4A131Tmutation 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 vivodiffusion tensor imaging of CSPG4A131Tmutation 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.

Published
2019
Full Text
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