Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/122802
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Type: Journal article
Title: Partial loss of USP9X function leads to a male neurodevelopmental and behavioural disorder converging on TGFβ signalling
Other Titles: Partial loss of USP9X function leads to a male neurodevelopmental and behavioural disorder converging on TGFbeta signalling
Author: Johnson, B.
Gecz, J.
Jolly, L.
Citation: Biological Psychiatry, 2020; 87(2):100-112
Publisher: Elsevier
Issue Date: 2020
ISSN: 0006-3223
1873-2402
Statement of
Responsibility: 
Brett V. Johnson, Raman Kumar … Atma Ivancevic … Alison Gardner … Deepti Domingo, Mark Corbett … Luis A. Pérez-Jurado … Jozef Gécz, and Lachlan A. Jolly
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
Rights: © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
RMID: 0030133441
DOI: 10.1016/j.biopsych.2019.05.028
Grant ID: http://purl.org/au-research/grants/arc/DE160100620
http://purl.org/au-research/grants/nhmrc/628952
http://purl.org/au-research/grants/nhmrc/1041920
Appears in Collections:Medicine publications

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