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

Undiagnosed Diseases Network

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
JournalBiological psychiatry
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Transforming Growth Factors
Virulence
Phenotype
Joint Instability
Haploinsufficiency
Cell Line
X Chromosome Inactivation
X-Linked Genes
Muscle Hypotonia
Corpus Callosum
Brain
Knockout Mice
Intellectual Disability
Computer Simulation
Language
Central Nervous System
Learning
Guidelines
Pathology
Mutation

Keywords

  • Brain malformation
  • Deubiquitylating enzyme
  • Hippocampus
  • Neurodevelopmental disorder
  • TGFβ
  • USP9X

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

@article{5bdae37377ce4d3ab8b1f7d822d253b5,
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 = "{Undiagnosed Diseases Network} and 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 {Pinto e Vairo}, Filippo",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.biopsych.2019.05.028",
language = "English (US)",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier USA",

}

TY - JOUR

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

AU - Undiagnosed Diseases Network

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 - Pinto e Vairo, Filippo

PY - 2019/1/1

Y1 - 2019/1/1

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

UR - http://www.scopus.com/inward/record.url?scp=85070835300&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85070835300&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2019.05.028

DO - 10.1016/j.biopsych.2019.05.028

M3 - Article

AN - SCOPUS:85070835300

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

ER -