Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling.
Brain malformation
Deubiquitylating enzyme
Hippocampus
Neurodevelopmental disorder
TGFβ
USP9X
Journal
Biological psychiatry
ISSN: 1873-2402
Titre abrégé: Biol Psychiatry
Pays: United States
ID NLM: 0213264
Informations de publication
Date de publication:
15 01 2020
15 01 2020
Historique:
received:
27
03
2019
revised:
23
05
2019
accepted:
30
05
2019
pubmed:
25
8
2019
medline:
7
1
2021
entrez:
25
8
2019
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 31443933
pii: S0006-3223(19)31479-9
doi: 10.1016/j.biopsych.2019.05.028
pmc: PMC6925349
mid: NIHMS1538027
pii:
doi:
Substances chimiques
Transforming Growth Factor beta
0
USP9X protein, human
0
Ubiquitin Thiolesterase
EC 3.4.19.12
Usp9x protein, mouse
EC 3.4.19.12
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
100-112Subventions
Organisme : NHGRI NIH HHS
ID : U01 HG007672
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD090255
Pays : United States
Organisme : Wellcome Trust
ID : WT098051
Pays : United Kingdom
Organisme : NIMH NIH HHS
ID : R01 MH107182
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Investigateurs
Loren Pena
(L)
Vandana Shashi
(V)
Kelly Schoch
(K)
Jennifer A Sullivan
(JA)
Maria T Acosta
(MT)
David R Adams
(DR)
Aaron Aday
(A)
Mercedes E Alejandro
(ME)
Patrick Allard
(P)
Euan A Ashley
(EA)
Mahshid S Azamian
(MS)
Carlos A Bacino
(CA)
Guney Bademci
(G)
Eva Baker
(E)
Ashok Balasubramanyam
(A)
Dustin Baldridge
(D)
Deborah Barbouth
(D)
Gabriel F Batzli
(GF)
Alan H Beggs
(AH)
Hugo J Bellen
(HJ)
Jonathan A Bernstein
(JA)
Gerard T Berry
(GT)
Anna Bican
(A)
David P Bick
(DP)
Camille L Birch
(CL)
Stephanie Bivona
(S)
Carsten Bonnenmann
(C)
Devon Bonner
(D)
Braden E Boone
(BE)
Bret L Bostwick
(BL)
Lauren C Briere
(LC)
Elly Brokamp
(E)
Donna M Brown
(DM)
Matthew Brush
(M)
Elizabeth A Burke
(EA)
Lindsay C Burrage
(LC)
Manish J Butte
(MJ)
Olveen Carrasquillo
(O)
Ta Chen Peter Chang
(TC)
Hsiao-Tuan Chao
(HT)
Gary D Clark
(GD)
Terra R Coakley
(TR)
Laurel A Cobban
(LA)
Joy D Cogan
(JD)
F Sessions Cole
(FS)
Heather A Colley
(HA)
Cynthia M Cooper
(CM)
Heidi Cope
(H)
William J Craigen
(WJ)
Precilla D'Souza
(P)
Surendra Dasari
(S)
Mariska Davids
(M)
Jean M Davidson
(JM)
Jyoti G Dayal
(JG)
Esteban C Dell'Angelica
(EC)
Shweta U Dhar
(SU)
Naghmeh Dorrani
(N)
Daniel C Dorset
(DC)
Emilie D Douine
(ED)
David D Draper
(DD)
Annika M Dries
(AM)
Laura Duncan
(L)
David J Eckstein
(DJ)
Lisa T Emrick
(LT)
Christine M Eng
(CM)
Gregory M Enns
(GM)
Cecilia Esteves
(C)
Tyra Estwick
(T)
Liliana Fernandez
(L)
Carlos Ferreira
(C)
Elizabeth L Fieg
(EL)
Paul G Fisher
(PG)
Brent L Fogel
(BL)
Irman Forghani
(I)
Noah D Friedman
(ND)
William A Gahl
(WA)
Rena A Godfrey
(RA)
Alica M Goldman
(AM)
David B Goldstein
(DB)
Jean-Philippe F Gourdine
(JF)
Alana Grajewski
(A)
Catherine A Groden
(CA)
Andrea L Gropman
(AL)
Melissa Haendel
(M)
Rizwan Hamid
(R)
Neil A Hanchard
(NA)
Frances High
(F)
Ingrid A Holm
(IA)
Jason Hom
(J)
Alden Huang
(A)
Yong Huang
(Y)
Rosario Isasi
(R)
Fariha Jamal
(F)
Yong-Hui Jiang
(YH)
Jean M Johnston
(JM)
Angela L Jones
(AL)
Lefkothea Karaviti
(L)
Emily G Kelley
(EG)
David M Koeller
(DM)
Isaac S Kohane
(IS)
Jennefer N Kohler
(JN)
Deborah Krakow
(D)
Donna M Krasnewich
(DM)
Susan Korrick
(S)
Mary Koziura
(M)
Joel B Krier
(JB)
Jennifer E Kyle
(JE)
Seema R Lalani
(SR)
Byron Lam
(B)
Brendan C Lanpher
(BC)
Ian R Lanza
(IR)
C Christopher Lau
(CC)
Jozef Lazar
(J)
Kimberly LeBlanc
(K)
Brendan H Lee
(BH)
Hane Lee
(H)
Roy Levitt
(R)
Shawn E Levy
(SE)
Richard A Lewis
(RA)
Sharyn A Lincoln
(SA)
Pengfei Liu
(P)
Xue Zhong Liu
(XZ)
Sandra K Loo
(SK)
Joseph Loscalzo
(J)
Richard L Maas
(RL)
Ellen F Macnamara
(EF)
Calum A MacRae
(CA)
Valerie V Maduro
(VV)
Marta M Majcherska
(MM)
May Christine V Malicdan
(MCV)
Laura A Mamounas
(LA)
Teri A Manolio
(TA)
Thomas C Markello
(TC)
Ronit Marom
(R)
Martin G Martin
(MG)
Julian A Martínez-Agosto
(JA)
Shruti Marwaha
(S)
Thomas May
(T)
Jacob McCauley
(J)
Allyn McConkie-Rosell
(A)
Colleen E McCormack
(CE)
Alexa T McCray
(AT)
Jason D Merker
(JD)
Thomas O Metz
(TO)
Matthew Might
(M)
Eva Morava-Kozicz
(E)
Paolo M Moretti
(PM)
Marie Morimoto
(M)
John J Mulvihill
(JJ)
David R Murdock
(DR)
Avi Nath
(A)
Stan F Nelson
(SF)
J Scott Newberry
(JS)
John H Newman
(JH)
Sarah K Nicholas
(SK)
Donna Novacic
(D)
Devin Oglesbee
(D)
James P Orengo
(JP)
Stephen Pak
(S)
J Carl Pallais
(JC)
Christina Gs Palmer
(CG)
Jeanette C Papp
(JC)
Neil H Parker
(NH)
John A Phillips
(JA)
Jennifer E Posey
(JE)
John H Postlethwait
(JH)
Lorraine Potocki
(L)
Barbara N Pusey
(BN)
Genecee Renteri
(G)
Chloe M Reuter
(CM)
Lynette Rives
(L)
Amy K Robertson
(AK)
Lance H Rodan
(LH)
Jill A Rosenfeld
(JA)
Robb K Rowley
(RK)
Ralph Sacco
(R)
Jacinda B Sampson
(JB)
Susan L Samson
(SL)
Mario Saporta
(M)
Judy Schaechter
(J)
Timothy Schedl
(T)
Daryl A Scott
(DA)
Lisa Shakachite
(L)
Prashant Sharma
(P)
Kathleen Shields
(K)
Jimann Shin
(J)
Rebecca Signer
(R)
Catherine H Sillari
(CH)
Edwin K Silverman
(EK)
Janet S Sinsheimer
(JS)
Kevin S Smith
(KS)
Lilianna Solnica-Krezel
(L)
Rebecca C Spillmann
(RC)
Joan M Stoler
(JM)
Nicholas Stong
(N)
David A Sweetser
(DA)
Cecelia P Tamburro
(CP)
Queenie K-G Tan
(QK)
Mustafa Tekin
(M)
Fred Telischi
(F)
Willa Thorson
(W)
Cynthia J Tifft
(CJ)
Camilo Toro
(C)
Alyssa A Tran
(AA)
Tiina K Urv
(TK)
Tiphanie P Vogel
(TP)
Daryl M Waggott
(DM)
Colleen E Wahl
(CE)
Nicole M Walley
(NM)
Chris A Walsh
(CA)
Melissa Walker
(M)
Jennifer Wambach
(J)
Jijun Wan
(J)
Lee-Kai Wang
(LK)
Michael F Wangler
(MF)
Patricia A Ward
(PA)
Katrina M Waters
(KM)
Bobbie-Jo M Webb-Robertson
(BM)
Daniel Wegner
(D)
Monte Westerfield
(M)
Matthew T Wheeler
(MT)
Anastasia L Wise
(AL)
Lynne A Wolfe
(LA)
Jeremy D Woods
(JD)
Elizabeth A Worthey
(EA)
Shinya Yamamoto
(S)
John Yang
(J)
Amanda J Yoon
(AJ)
Guoyun Yu
(G)
Diane B Zastrow
(DB)
Chunli Zhao
(C)
Stephan Zuchner
(S)
William Gahl
(W)
Informations de copyright
Copyright © 2019 Society of Biological Psychiatry. All rights reserved.
Références
J Biol Chem. 2006 Dec 15;281(50):38738-47
pubmed: 17038327
J Biol Chem. 2012 Jun 15;287(25):21164-75
pubmed: 22544753
Genes Dev. 2002 Feb 1;16(3):289-94
pubmed: 11825870
Behav Brain Funct. 2007 Oct 23;3:54
pubmed: 17956622
Nat Rev Mol Cell Biol. 2011 Jun 23;12(7):439-52
pubmed: 21697901
Am J Hum Genet. 2014 Mar 6;94(3):470-8
pubmed: 24607389
Sci Rep. 2015 Jun 10;5:11252
pubmed: 26059637
Nucleic Acids Res. 2019 Jan 8;47(D1):D886-D894
pubmed: 30371827
J Dermatol Sci. 2004 Aug;35(2):83-92
pubmed: 15265520
Nat Neurosci. 2013 Dec;16(12):1773-82
pubmed: 24162655
Acta Biochim Biophys Sin (Shanghai). 2018 Jan 1;50(1):106-120
pubmed: 29190314
Am J Hum Genet. 2009 Apr;84(4):524-33
pubmed: 19344873
Sci Rep. 2017 Mar 24;7(1):391
pubmed: 28341829
Nature. 2013 Sep 12;501(7466):217-21
pubmed: 23934111
Cell. 2009 Jan 9;136(1):123-35
pubmed: 19135894
Sci Rep. 2016 May 16;6:25783
pubmed: 27181636
Clin Genet. 2016 Nov;90(5):413-419
pubmed: 26752331
Genes Cells. 1999 Dec;4(12):757-67
pubmed: 10620020
PLoS One. 2014 Apr 08;9(4):e93394
pubmed: 24714733
J Biol Chem. 2013 Feb 1;288(5):2976-85
pubmed: 23184937
Physiol Res. 2013;62(Suppl 1):S1-S19
pubmed: 24329689
Hippocampus. 2007;17(1):5-9
pubmed: 17094084
PLoS Genet. 2015 Mar 18;11(3):e1005079
pubmed: 25785854
Nat Commun. 2020 Nov 20;11(1):5918
pubmed: 33219223
Genes Brain Behav. 2003 Jun;2(3):156-66
pubmed: 12931789
Eur J Med Genet. 2015 May;58(5):324-7
pubmed: 25858702
Hum Mol Genet. 2015 Jun 15;24(12):3335-47
pubmed: 25740848
PLoS One. 2013 Jul 05;8(7):e68287
pubmed: 23861879
Mol Biol Cell. 2009 Apr;20(7):2015-29
pubmed: 19176755
Nucleic Acids Res. 2010 Sep;38(16):e164
pubmed: 20601685
Development. 2004 Nov;131(21):5355-66
pubmed: 15469967
PLoS One. 2013 Jun 11;8(6):e65478
pubmed: 23776487
J Neurochem. 2013 Jul;126(2):165-82
pubmed: 23574039
Nat Protoc. 2007;2(2):329-33
pubmed: 17406593
PLoS Genet. 2015 Mar 12;11(3):e1005022
pubmed: 25763846
Hum Mutat. 2019 Jan;40(1):5-24
pubmed: 30328660
Genet Med. 2015 May;17(5):405-24
pubmed: 25741868
J Biol Chem. 2001 Apr 20;276(16):12477-80
pubmed: 11278251
J Hum Genet. 2019 Jan;64(1):3-9
pubmed: 30401917
Int J Dev Neurosci. 2005 Aug;23(5):413-24
pubmed: 15936920
Nat Rev Neurol. 2016 Jul;12(7):379-92
pubmed: 27340022
Am J Hum Genet. 2015 Aug 6;97(2):343-52
pubmed: 26235985
Sci Rep. 2017 Aug 14;7(1):8109
pubmed: 28808228
Development. 2018 Jun 26;145(12):
pubmed: 29945986
Neurosci Biobehav Rev. 2016 Sep;68:563-574
pubmed: 27345143
Cell Mol Life Sci. 2015 Jun;72(11):2075-89
pubmed: 25672900
Am J Hum Genet. 2016 Feb 4;98(2):373-81
pubmed: 26833328
Mech Dev. 2001 Dec;109(2):151-60
pubmed: 11731229
Mamm Genome. 1997 Oct;8(10):711-3
pubmed: 9321461