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Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling

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Harvard

Johnson, BV, Kumar, R, Oishi, S, Alexander, S, Kasherman, M, Vega, MS, Ivancevic, A, Gardner, A, Domingo, D, Corbett, M, Parnell, E, Yoon, S, Oh, T, Lines, M, Lefroy, H, Kini, U, Van Allen, M, Grønborg, S, Mercier, S, Küry, S, Bézieau, S, Pasquier, L, Raynaud, M, Afenjar, A, Billette de Villemeur, T, Keren, B, Désir, J, Van Maldergem, L, Marangoni, M, Dikow, N, Koolen, DA, VanHasselt, PM, Weiss, M, Zwijnenburg, P, Sa, J, Reis, CF, López-Otín, C, Santiago-Fernández, O, Fernández-Jaén, A, Rauch, A, Steindl, K, Joset, P, Goldstein, A, Madan-Khetarpal, S, Infante, E, Zackai, E, Mcdougall, C, Narayanan, V, Ramsey, K, Mercimek-Andrews, S & Undiagnosed Diseases Network 2020, 'Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling' Biological Psychiatry, bind 87, nr. 2, s. 100-112. https://doi.org/10.1016/j.biopsych.2019.05.028

APA

Johnson, B. V., Kumar, R., Oishi, S., Alexander, S., Kasherman, M., Vega, M. S., ... Undiagnosed Diseases Network (2020). Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling. Biological Psychiatry, 87(2), 100-112. https://doi.org/10.1016/j.biopsych.2019.05.028

CBE

Johnson BV, Kumar R, Oishi S, Alexander S, Kasherman M, Vega MS, Ivancevic A, Gardner A, Domingo D, Corbett M, Parnell E, Yoon S, Oh T, Lines M, Lefroy H, Kini U, Van Allen M, Grønborg S, Mercier S, Küry S, Bézieau S, Pasquier L, Raynaud M, Afenjar A, Billette de Villemeur T, Keren B, Désir J, Van Maldergem L, Marangoni M, Dikow N, Koolen DA, VanHasselt PM, Weiss M, Zwijnenburg P, Sa J, Reis CF, López-Otín C, Santiago-Fernández O, Fernández-Jaén A, Rauch A, Steindl K, Joset P, Goldstein A, Madan-Khetarpal S, Infante E, Zackai E, Mcdougall C, Narayanan V, Ramsey K, Mercimek-Andrews S, Undiagnosed Diseases Network. 2020. Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling. Biological Psychiatry. 87(2):100-112. https://doi.org/10.1016/j.biopsych.2019.05.028

MLA

Vancouver

Author

Johnson, Brett V ; Kumar, Raman ; Oishi, Sabrina ; Alexander, Suzy ; Kasherman, Maria ; Vega, Michelle Sanchez ; Ivancevic, Atma ; Gardner, Alison ; Domingo, Deepti ; Corbett, Mark ; Parnell, Euan ; Yoon, Sehyoun ; Oh, Tracey ; Lines, Matthew ; Lefroy, Henrietta ; Kini, Usha ; Van Allen, Margot ; Grønborg, Sabine ; Mercier, Sandra ; Küry, Sébastien ; Bézieau, Stéphane ; Pasquier, Laurent ; Raynaud, Martine ; Afenjar, Alexandra ; Billette de Villemeur, Thierry ; Keren, Boris ; Désir, Julie ; Van Maldergem, Lionel ; Marangoni, Martina ; Dikow, Nicola ; Koolen, David A ; VanHasselt, Peter M ; Weiss, Marjan ; Zwijnenburg, Petra ; Sa, Joaquim ; Reis, Claudia Falcao ; López-Otín, Carlos ; Santiago-Fernández, Olaya ; Fernández-Jaén, Alberto ; Rauch, Anita ; Steindl, Katharina ; Joset, Pascal ; Goldstein, Amy ; Madan-Khetarpal, Suneeta ; Infante, Elena ; Zackai, Elaine ; Mcdougall, Carey ; Narayanan, Vinodh ; Ramsey, Keri ; Mercimek-Andrews, Saadet ; Undiagnosed Diseases Network. / Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling. I: Biological Psychiatry. 2020 ; Bind 87, Nr. 2. s. 100-112.

Bibtex

@article{976469cbe8634c0bb1fefd6300e27a12,
title = "Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling",
abstract = "BACKGROUND: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative.METHODS: We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology.RESULTS: Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor β signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory.CONCLUSIONS: Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor β signaling and hippocampal function.",
keywords = "Brain malformation, Deubiquitylating enzyme, Hippocampus, Neurodevelopmental disorder, TGFβ, USP9X",
author = "Johnson, {Brett V} and Raman Kumar and Sabrina Oishi and Suzy Alexander and Maria Kasherman and Vega, {Michelle Sanchez} and Atma Ivancevic and Alison Gardner and Deepti Domingo and Mark Corbett and Euan Parnell and Sehyoun Yoon and Tracey Oh and Matthew Lines and Henrietta Lefroy and Usha Kini and {Van Allen}, Margot and Sabine Gr{\o}nborg and Sandra Mercier and S{\'e}bastien K{\"u}ry and St{\'e}phane B{\'e}zieau and Laurent Pasquier and Martine Raynaud and Alexandra Afenjar and {Billette de Villemeur}, Thierry and Boris Keren and Julie D{\'e}sir and {Van Maldergem}, Lionel and Martina Marangoni and Nicola Dikow and Koolen, {David A} and VanHasselt, {Peter M} and Marjan Weiss and Petra Zwijnenburg and Joaquim Sa and Reis, {Claudia Falcao} and Carlos L{\'o}pez-Ot{\'i}n and Olaya Santiago-Fern{\'a}ndez and Alberto Fern{\'a}ndez-Ja{\'e}n and Anita Rauch and Katharina Steindl and Pascal Joset and Amy Goldstein and Suneeta Madan-Khetarpal and Elena Infante and Elaine Zackai and Carey Mcdougall and Vinodh Narayanan and Keri Ramsey and Saadet Mercimek-Andrews and {Undiagnosed Diseases Network}",
note = "Copyright {\circledC} 2019 Society of Biological Psychiatry. All rights reserved.",
year = "2020",
month = "1",
day = "15",
doi = "10.1016/j.biopsych.2019.05.028",
language = "English",
volume = "87",
pages = "100--112",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier Inc",
number = "2",

}

RIS

TY - JOUR

T1 - Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling

AU - Johnson, Brett V

AU - Kumar, Raman

AU - Oishi, Sabrina

AU - Alexander, Suzy

AU - Kasherman, Maria

AU - Vega, Michelle Sanchez

AU - Ivancevic, Atma

AU - Gardner, Alison

AU - Domingo, Deepti

AU - Corbett, Mark

AU - Parnell, Euan

AU - Yoon, Sehyoun

AU - Oh, Tracey

AU - Lines, Matthew

AU - Lefroy, Henrietta

AU - Kini, Usha

AU - Van Allen, Margot

AU - Grønborg, Sabine

AU - Mercier, Sandra

AU - Küry, Sébastien

AU - Bézieau, Stéphane

AU - Pasquier, Laurent

AU - Raynaud, Martine

AU - Afenjar, Alexandra

AU - Billette de Villemeur, Thierry

AU - Keren, Boris

AU - Désir, Julie

AU - Van Maldergem, Lionel

AU - Marangoni, Martina

AU - Dikow, Nicola

AU - Koolen, David A

AU - VanHasselt, Peter M

AU - Weiss, Marjan

AU - Zwijnenburg, Petra

AU - Sa, Joaquim

AU - Reis, Claudia Falcao

AU - López-Otín, Carlos

AU - Santiago-Fernández, Olaya

AU - Fernández-Jaén, Alberto

AU - Rauch, Anita

AU - Steindl, Katharina

AU - Joset, Pascal

AU - Goldstein, Amy

AU - Madan-Khetarpal, Suneeta

AU - Infante, Elena

AU - Zackai, Elaine

AU - Mcdougall, Carey

AU - Narayanan, Vinodh

AU - Ramsey, Keri

AU - Mercimek-Andrews, Saadet

AU - Undiagnosed Diseases Network

N1 - Copyright © 2019 Society of Biological Psychiatry. All rights reserved.

PY - 2020/1/15

Y1 - 2020/1/15

N2 - BACKGROUND: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative.METHODS: We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology.RESULTS: Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor β signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory.CONCLUSIONS: Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor β signaling and hippocampal function.

AB - BACKGROUND: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative.METHODS: We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology.RESULTS: Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor β signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory.CONCLUSIONS: Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor β signaling and hippocampal function.

KW - Brain malformation

KW - Deubiquitylating enzyme

KW - Hippocampus

KW - Neurodevelopmental disorder

KW - TGFβ

KW - USP9X

U2 - 10.1016/j.biopsych.2019.05.028

DO - 10.1016/j.biopsych.2019.05.028

M3 - Journal article

VL - 87

SP - 100

EP - 112

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

IS - 2

ER -

ID: 58998327