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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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dc.contributor.author Johnson, Brett V.
dc.contributor.author Pérez Jurado, Luis Alberto
dc.contributor.author Jolly, Lachlan A.
dc.date.accessioned 2020-02-20T08:20:51Z
dc.date.issued 2020
dc.identifier.citation Johnson BV, Kumar R, Oishi S, Alexander S, Kasherman M, Vega MS. Et al. Partial loss of USP9X function leads to a male neurodevelopmental and behavioral disorder converging on transforming growth factor β signaling. Biol Psychiatry. 2020 Jan 15;87(2):100-12. DOI: 10.1016/j.biopsych.2019.05.028
dc.identifier.issn 0006-3223
dc.identifier.uri http://hdl.handle.net/10230/43664
dc.description.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.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Elsevier
dc.rights © Elsevier http://dx.doi.org/10.1016/j.biopsych.2019.05.028
dc.title Partial loss of USP9X function leads to a male neurodevelopmental and behavioral disorder converging on transforming growth factor β signaling
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1016/j.biopsych.2019.05.028
dc.subject.keyword Brain malformation
dc.subject.keyword Deubiquitylating enzyme
dc.subject.keyword Hippocampus
dc.subject.keyword Neurodevelopmental disorder
dc.subject.keyword TGFβ
dc.subject.keyword USP9X
dc.rights.accessRights info:eu-repo/semantics/embargoedAccess
dc.type.version info:eu-repo/semantics/acceptedVersion
dc.embargo.liftdate 2021-01-31
dc.date.embargoEnd info:eu-repo/date/embargoEnd/2021-01-31

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