Forskning
Udskriv Udskriv
Switch language
Region Hovedstaden - en del af Københavns Universitetshospital
Udgivet

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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  1. Diagnostic pitfalls in vitamin B6-dependent epilepsy caused by mutations in the PLPBP gene

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. A Faroese founder variant in TBCD causes early onset, progressive encephalopathy with a homogenous clinical course

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  4. Neuroimaging findings in Mowat-Wilson syndrome: a study of 54 patients

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  5. Exome sequencing for syndrome diagnostics

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  • Brett V Johnson
  • Raman Kumar
  • Sabrina Oishi
  • Suzy Alexander
  • Maria Kasherman
  • Michelle Sanchez Vega
  • Atma Ivancevic
  • Alison Gardner
  • Deepti Domingo
  • Mark Corbett
  • Euan Parnell
  • Sehyoun Yoon
  • Tracey Oh
  • Matthew Lines
  • Henrietta Lefroy
  • Usha Kini
  • Margot Van Allen
  • Sabine Grønborg
  • Sandra Mercier
  • Sébastien Küry
  • Stéphane Bézieau
  • Laurent Pasquier
  • Martine Raynaud
  • Alexandra Afenjar
  • Thierry Billette de Villemeur
  • Boris Keren
  • Julie Désir
  • Lionel Van Maldergem
  • Martina Marangoni
  • Nicola Dikow
  • David A Koolen
  • Peter M VanHasselt
  • Marjan Weiss
  • Petra Zwijnenburg
  • Joaquim Sa
  • Claudia Falcao Reis
  • Carlos López-Otín
  • Olaya Santiago-Fernández
  • Alberto Fernández-Jaén
  • Anita Rauch
  • Katharina Steindl
  • Pascal Joset
  • Amy Goldstein
  • Suneeta Madan-Khetarpal
  • Elena Infante
  • Elaine Zackai
  • Carey Mcdougall
  • Vinodh Narayanan
  • Keri Ramsey
  • Saadet Mercimek-Andrews
  • Undiagnosed Diseases Network
Vis graf over relationer

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.

OriginalsprogEngelsk
TidsskriftBiological Psychiatry
Vol/bind87
Udgave nummer2
Sider (fra-til)100-112
Antal sider13
ISSN0006-3223
DOI
StatusUdgivet - 15 jan. 2020

Bibliografisk note

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

ID: 58998327