Cohesin complex-associated holoprosencephaly

Paul Kruszka; Seth I. Berger; Valentina Casa; Mike R. Dekker; Jenna Gaesser; Karin Weiss; Ariel F. Martinez; David R. Murdock; Raymond J. Louie; Eloise J. Prijoles; Angie W. Lichty; Oebele F. Brouwer; Evelien Zonneveld-Huijssoon; Mark J. Stephan; Jacob Hogue; Ping Hu; Momoko Tanima-Nagai; Joshua L. Everson; Chitra Prasad; Anna Cereda; Maria Iascone; Allison Schreiber; Vickie Zurcher; Nicole Corsten-Janssen; Luis Escobar; Nancy J. Clegg; Mauricio R. Delgado; Omkar Hajirnis; Meena Balasubramanian; Hülya Kayserili; Matthew Deardorff; Raymond A. Poot; Kerstin S. Wendt; Robert J. Lipinski; Maximilian Muenke

doi:10.1093/brain/awz210

Cohesin complex-associated holoprosencephaly

Paul Kruszka, Seth I. Berger, Valentina Casa, Mike R. Dekker, Jenna Gaesser, Karin Weiss, Ariel F. Martinez, David R. Murdock, Raymond J. Louie, Eloise J. Prijoles, Angie W. Lichty, Oebele F. Brouwer, Evelien Zonneveld-Huijssoon, Mark J. Stephan, Jacob Hogue, Ping Hu, Momoko Tanima-Nagai, Joshua L. Everson, Chitra Prasad, Anna CeredaMaria Iascone, Allison Schreiber, Vickie Zurcher, Nicole Corsten-Janssen, Luis Escobar, Nancy J. Clegg, Mauricio R. Delgado, Omkar Hajirnis, Meena Balasubramanian, Hülya Kayserili, Matthew Deardorff, Raymond A. Poot, Kerstin S. Wendt, Robert J. Lipinski, Maximilian Muenke

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

41 Scopus citations

Abstract

Marked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80–90% of aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly.

Original language	English (US)
Pages (from-to)	2631-2643
Number of pages	13
Journal	Brain
Volume	142
Issue number	9
DOIs	https://doi.org/10.1093/brain/awz210
State	Published - Sep 1 2019

Keywords

Cohesin complex
Forebrain division
Holoprosencephaly
X-linked inheritance

ASJC Scopus subject areas

Clinical Neurology

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10.1093/brain/awz210

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Kruszka, P., Berger, S. I., Casa, V., Dekker, M. R., Gaesser, J., Weiss, K., Martinez, A. F., Murdock, D. R., Louie, R. J., Prijoles, E. J., Lichty, A. W., Brouwer, O. F., Zonneveld-Huijssoon, E., Stephan, M. J., Hogue, J., Hu, P., Tanima-Nagai, M., Everson, J. L., Prasad, C., ... Muenke, M. (2019). Cohesin complex-associated holoprosencephaly. Brain, 142(9), 2631-2643. https://doi.org/10.1093/brain/awz210

Kruszka, P, Berger, SI, Casa, V, Dekker, MR, Gaesser, J, Weiss, K, Martinez, AF, Murdock, DR, Louie, RJ, Prijoles, EJ, Lichty, AW, Brouwer, OF, Zonneveld-Huijssoon, E, Stephan, MJ, Hogue, J, Hu, P, Tanima-Nagai, M, Everson, JL, Prasad, C, Cereda, A, Iascone, M, Schreiber, A, Zurcher, V, Corsten-Janssen, N, Escobar, L, Clegg, NJ, Delgado, MR, Hajirnis, O, Balasubramanian, M, Kayserili, H, Deardorff, M, Poot, RA, Wendt, KS, Lipinski, RJ & Muenke, M 2019, 'Cohesin complex-associated holoprosencephaly', Brain, vol. 142, no. 9, pp. 2631-2643. https://doi.org/10.1093/brain/awz210

@article{20461fdcc5c94bef805930f069d36985,

title = "Cohesin complex-associated holoprosencephaly",

abstract = "Marked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80–90% of aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly.",

keywords = "Cohesin complex, Forebrain division, Holoprosencephaly, X-linked inheritance",

author = "Paul Kruszka and Berger, {Seth I.} and Valentina Casa and Dekker, {Mike R.} and Jenna Gaesser and Karin Weiss and Martinez, {Ariel F.} and Murdock, {David R.} and Louie, {Raymond J.} and Prijoles, {Eloise J.} and Lichty, {Angie W.} and Brouwer, {Oebele F.} and Evelien Zonneveld-Huijssoon and Stephan, {Mark J.} and Jacob Hogue and Ping Hu and Momoko Tanima-Nagai and Everson, {Joshua L.} and Chitra Prasad and Anna Cereda and Maria Iascone and Allison Schreiber and Vickie Zurcher and Nicole Corsten-Janssen and Luis Escobar and Clegg, {Nancy J.} and Delgado, {Mauricio R.} and Omkar Hajirnis and Meena Balasubramanian and H{\"u}lya Kayserili and Matthew Deardorff and Poot, {Raymond A.} and Wendt, {Kerstin S.} and Lipinski, {Robert J.} and Maximilian Muenke",

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doi = "10.1093/brain/awz210",

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T1 - Cohesin complex-associated holoprosencephaly

AU - Kruszka, Paul

AU - Berger, Seth I.

AU - Casa, Valentina

AU - Dekker, Mike R.

AU - Gaesser, Jenna

AU - Weiss, Karin

AU - Martinez, Ariel F.

AU - Murdock, David R.

AU - Louie, Raymond J.

AU - Prijoles, Eloise J.

AU - Lichty, Angie W.

AU - Brouwer, Oebele F.

AU - Zonneveld-Huijssoon, Evelien

AU - Stephan, Mark J.

AU - Hogue, Jacob

AU - Hu, Ping

AU - Tanima-Nagai, Momoko

AU - Everson, Joshua L.

AU - Prasad, Chitra

AU - Cereda, Anna

AU - Iascone, Maria

AU - Schreiber, Allison

AU - Zurcher, Vickie

AU - Corsten-Janssen, Nicole

AU - Escobar, Luis

AU - Clegg, Nancy J.

AU - Delgado, Mauricio R.

AU - Hajirnis, Omkar

AU - Balasubramanian, Meena

AU - Kayserili, Hülya

AU - Deardorff, Matthew

AU - Poot, Raymond A.

AU - Wendt, Kerstin S.

AU - Lipinski, Robert J.

AU - Muenke, Maximilian

PY - 2019/9/1

Y1 - 2019/9/1

N2 - Marked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80–90% of aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly.

AB - Marked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80–90% of aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly.

KW - Cohesin complex

KW - Forebrain division

KW - Holoprosencephaly

KW - X-linked inheritance

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SP - 2631

EP - 2643

JO - Brain

JF - Brain

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ER -

Cohesin complex-associated holoprosencephaly

Abstract

Keywords

ASJC Scopus subject areas

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