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 Bakker; Aviva 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

doi:10.1038/s41380-017-0004-2

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

MHeNs - Mental Health

Research output: Contribution to journal › Article › Academic › peer-review

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 language	English
Pages (from-to)	757-771
Number of pages	15
Journal	Molecular Psychiatry
Volume	24
Issue number	5
DOIs	https://doi.org/10.1038/s41380-017-0004-2
Publication status	Published - May 2019

Keywords

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

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de Vrij, F. M., Bouwkamp, C. G., Gunhanlar, N., Shpak, G., Lendemeijer, B., Baghdadi, M., Gopalakrishna, S., Ghazvini, M., Li, T. M., Quadri, M., Olgiati, S., Breedveld, G. J., Coesmans, M., Mientjes, E., de Wit, T., Verheijen, F. W., Beverloo, H. B., Cohen, D., Kok, R. M., ... GROUP Study Consortium (2019). Candidate CSPG4 mutations and induced pluripotent stem cell modeling implicate oligodendrocyte progenitor cell dysfunction in familial schizophrenia. Molecular Psychiatry, 24(5), 757-771. https://doi.org/10.1038/s41380-017-0004-2

@article{f32be7b670024ab8b18747aab544cf31,

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

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.",

keywords = "ENDOPLASMIC-RETICULUM STRESS, WHITE-MATTER, NG2 PROTEOGLYCAN, CHONDROITIN SULFATE, PSYCHIATRIC-DISORDERS, PRECURSOR CELLS, MYELINATION, REVEALS, BRAIN, GENE",

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

note = "Funding Information: Rolando Medina. Swedish Schizophrenia Exome Sequencing project: Data obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number (20 September 2015, accession phs000473.v1.p1). Samples used for data analysis were provided by the Swedish Cohort Collection supported by the NIMH grant R01MH077139, the Sylvan C. Herman Foundation, the Stanley Medical Research Institute, and The Swedish Research Council (grants 2009-4959 and 2011-4659). Support for the exome sequencing was provided by the NIMH Grand Opportunity grant RCMH089905, the Sylvan C. Herman Foundation, a grant from the Stanley Medical Research Institute and multiple gifts to the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard. The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at https://exac.broadinstitute. org/about. Funding Information: Acknowledgements We wish to thank Roel Ophoff for facilitating the contribution of the GROUP/Utrecht Study samples and discussions regarding the genetic analyses, Gerard Borst for discussions regarding the electrophysiological analyses, and Siska Verploegh for her assistance in sample collection. This project was partially funded by the Erasmus MC—University Medical Centre Rotterdam, the Netherlands Organization for Scientific Research (NWO) and Netherlands Organisation for Health Research and Development (ZonMW) to SAK, VB, YE, and JG, the NeuroBasic-PharmaPhenomics consortium to SAK and YE, Stichting ParkinsonFonds (The Netherlands) to VB, Netherlands Institute for Regenerative Medicine (NIRM) and European Research Council (Consolidator Grant) to JG. The authors would like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926), and the Heart GO Sequencing Project (HL-103010). This study makes use of data generated by the Genome of the Netherlands Project. A full list of the investigators is available from www.nlgenome.nl. Funding for the project was provided by the Netherlands Organization for Scientific Research under award number 184021007, dated 9 July 2009 and made available as a Rainbow Project of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). The sequencing was carried out in collaboration with the Beijing Institute for Genomics (BGI). The generation and management of genomics data for the Rotterdam Study were supported by the Netherlands Organisation of Scientific Research Investments (nr. 175. 010.2005.011, 911-03-012) and the Netherlands Genomics Initiative (NGI) project nr. 050-060-810 (Netherlands Consortium for Healthy Ageing; NCHA). We thank the members of the Human Genomics Facility (HuGeF) and the ERGO support team for their help in sampling the data and in creating the database. The Rotterdam Study is funded by Erasmus Medical Centre and Erasmus University, Rotterdam, Netherlands Organisation for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. NIMH Study 13—data used in this research report were collected by the International Neuro-Genetics Association of Spanish America and the United States (INGASU), and funded by a collaborative NIMH grant (Genetics of Schizophrenia in Latino Populations) to Dr. Michael Escamilla (University of Texas Health Science Center at San Antonio) (MH60881) and to Dr. Ricardo Mendoza (University of California at Los Angeles-Harbor) (MH60875). Additional principal investigators who participated in these grants were Dr. Henriette Raventos (University of Costa Rica, San Jose, Costa Rica), Dr. Alfonso Ontiveros (Instituto de Informacion de Investigacion en Salud Mental, Monterrey, Mexico), Dr. Humberto Nicolini (Medical and Family Research Group, Carracci S.C., Mexico City, Mexico), Dr. Rodrigo Munoz (Family Health Centers of San Diego, California), and Dr. Alvaro Jerez (Centro Internacional de Trastornos Afectivos y de la Conducta Adictiva-CITACA, Guatemala). Additional investigators from the University of Texas Health Science Center at San Antonio included Dr. Albana Dassori and Dr. Publisher Copyright: {\textcopyright} 2017, The Author(s).",

year = "2019",

month = may,

doi = "10.1038/s41380-017-0004-2",

language = "English",

volume = "24",

pages = "757--771",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Springer",

number = "5",

}

de Vrij, FM, Bouwkamp, CG, Gunhanlar, N, Shpak, G, Lendemeijer, B, Baghdadi, M, Gopalakrishna, S, Ghazvini, M, Li, TM, Quadri, M, Olgiati, S, Breedveld, GJ, Coesmans, M, Mientjes, E, de Wit, T, Verheijen, FW, Beverloo, HB, Cohen, D, Kok, RM, Bakker, PR, Nijbur, A, Spijker, AT, Haffmans, PMJ, Hoencamp, E, Bergink, V, Vorstman, JA, Wu, T, Loohuis, LMO, Amin, N, Langen, CD, Hofman, A, Hoogendijk, WJ, van Duijimn, CM, Ikram, MA, Vernooij, MW, Tiemeier, H, Uitterlinden, AG, Elgersma, Y, Distel, B, Gribnau, J, White, T, Bonifati, V, Kushner, SA & GROUP Study Consortium 2019, 'Candidate CSPG4 mutations and induced pluripotent stem cell modeling implicate oligodendrocyte progenitor cell dysfunction in familial schizophrenia', Molecular Psychiatry, vol. 24, no. 5, pp. 757-771. https://doi.org/10.1038/s41380-017-0004-2

TY - JOUR

T1 - Candidate CSPG4 mutations and induced pluripotent stem cell modeling implicate oligodendrocyte progenitor cell dysfunction in familial schizophrenia

AU - de Vrij, Femke M.

AU - Bouwkamp, Christian G.

AU - Gunhanlar, Nilhan

AU - Shpak, Guy

AU - Lendemeijer, Bas

AU - Baghdadi, Maarouf

AU - Gopalakrishna, Shreekara

AU - Ghazvini, Mehrnaz

AU - Li, Tracy M.

AU - Quadri, Marialuisa

AU - Olgiati, Simone

AU - Breedveld, Guido J.

AU - Coesmans, Michiel

AU - Mientjes, Edwin

AU - de Wit, Ton

AU - Verheijen, Frans W.

AU - Beverloo, H. Berna

AU - Cohen, Dan

AU - Kok, Rob M.

AU - Bakker, P. Roberto

AU - Nijbur, Aviva

AU - Spijker, Annet T.

AU - Haffmans, P. M. Judith

AU - Hoencamp, Erik

AU - Bergink, Veerle

AU - Vorstman, Jacob A.

AU - Wu, Timothy

AU - Loohuis, Loes M. Olde

AU - Amin, Najaf

AU - Langen, Carolyn D.

AU - Hofman, Albert

AU - Hoogendijk, Witte J.

AU - van Duijimn, Cornelia M.

AU - Ikram, M. Arfan

AU - Vernooij, Meike W.

AU - Tiemeier, Henning

AU - Uitterlinden, Andre G.

AU - Elgersma, Ype

AU - Distel, Ben

AU - Gribnau, Joost

AU - White, Tonya

AU - Bonifati, Vincenzo

AU - Kushner, Steven A.

AU - GROUP Study Consortium

N1 - Funding Information: Rolando Medina. Swedish Schizophrenia Exome Sequencing project: Data obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number (20 September 2015, accession phs000473.v1.p1). Samples used for data analysis were provided by the Swedish Cohort Collection supported by the NIMH grant R01MH077139, the Sylvan C. Herman Foundation, the Stanley Medical Research Institute, and The Swedish Research Council (grants 2009-4959 and 2011-4659). Support for the exome sequencing was provided by the NIMH Grand Opportunity grant RCMH089905, the Sylvan C. Herman Foundation, a grant from the Stanley Medical Research Institute and multiple gifts to the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard. The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at https://exac.broadinstitute. org/about. Funding Information: Acknowledgements We wish to thank Roel Ophoff for facilitating the contribution of the GROUP/Utrecht Study samples and discussions regarding the genetic analyses, Gerard Borst for discussions regarding the electrophysiological analyses, and Siska Verploegh for her assistance in sample collection. This project was partially funded by the Erasmus MC—University Medical Centre Rotterdam, the Netherlands Organization for Scientific Research (NWO) and Netherlands Organisation for Health Research and Development (ZonMW) to SAK, VB, YE, and JG, the NeuroBasic-PharmaPhenomics consortium to SAK and YE, Stichting ParkinsonFonds (The Netherlands) to VB, Netherlands Institute for Regenerative Medicine (NIRM) and European Research Council (Consolidator Grant) to JG. The authors would like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926), and the Heart GO Sequencing Project (HL-103010). This study makes use of data generated by the Genome of the Netherlands Project. A full list of the investigators is available from www.nlgenome.nl. Funding for the project was provided by the Netherlands Organization for Scientific Research under award number 184021007, dated 9 July 2009 and made available as a Rainbow Project of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). The sequencing was carried out in collaboration with the Beijing Institute for Genomics (BGI). The generation and management of genomics data for the Rotterdam Study were supported by the Netherlands Organisation of Scientific Research Investments (nr. 175. 010.2005.011, 911-03-012) and the Netherlands Genomics Initiative (NGI) project nr. 050-060-810 (Netherlands Consortium for Healthy Ageing; NCHA). We thank the members of the Human Genomics Facility (HuGeF) and the ERGO support team for their help in sampling the data and in creating the database. The Rotterdam Study is funded by Erasmus Medical Centre and Erasmus University, Rotterdam, Netherlands Organisation for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. NIMH Study 13—data used in this research report were collected by the International Neuro-Genetics Association of Spanish America and the United States (INGASU), and funded by a collaborative NIMH grant (Genetics of Schizophrenia in Latino Populations) to Dr. Michael Escamilla (University of Texas Health Science Center at San Antonio) (MH60881) and to Dr. Ricardo Mendoza (University of California at Los Angeles-Harbor) (MH60875). Additional principal investigators who participated in these grants were Dr. Henriette Raventos (University of Costa Rica, San Jose, Costa Rica), Dr. Alfonso Ontiveros (Instituto de Informacion de Investigacion en Salud Mental, Monterrey, Mexico), Dr. Humberto Nicolini (Medical and Family Research Group, Carracci S.C., Mexico City, Mexico), Dr. Rodrigo Munoz (Family Health Centers of San Diego, California), and Dr. Alvaro Jerez (Centro Internacional de Trastornos Afectivos y de la Conducta Adictiva-CITACA, Guatemala). Additional investigators from the University of Texas Health Science Center at San Antonio included Dr. Albana Dassori and Dr. Publisher Copyright: © 2017, The Author(s).

PY - 2019/5

Y1 - 2019/5

N2 - 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.

AB - 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.

KW - ENDOPLASMIC-RETICULUM STRESS

KW - WHITE-MATTER

KW - NG2 PROTEOGLYCAN

KW - CHONDROITIN SULFATE

KW - PSYCHIATRIC-DISORDERS

KW - PRECURSOR CELLS

KW - MYELINATION

KW - REVEALS

KW - BRAIN

KW - GENE

U2 - 10.1038/s41380-017-0004-2

DO - 10.1038/s41380-017-0004-2

M3 - Article

C2 - 29302076

SN - 1359-4184

VL - 24

SP - 757

EP - 771

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 5

ER -

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

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