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

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 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}",

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 = "Nature Publishing Group",

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

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

VL - 24

SP - 757

EP - 771

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

IS - 5

ER -