ID31443933
Published Date2020-01-15
JournalBiological psychiatry, 2020-01-15, Volume 87 Find other publications in this journal
Author Info
  • University of Adelaide and Robinson Research Institute, Adelaide, Australia.
  • School of Biomedical Sciences, The University of Queensland, Brisbane, Australia.
  • Queensland Brain Institute, The University of Queensland, Brisbane, Australia; Queensland Centre for Mental Health Research, Wacol, Queensland, Australia.
  • School of Biomedical Sciences, The University of Queensland, Brisbane, Australia; Griffith Institute for Drug Discovery, Griffith University, Brisbane, Australia.
  • Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
  • University of Adelaide and Robinson Research Institute, Adelaide, Australia; BioFrontiers Institute, University of Colorado Boulder, Boulder, Colorado.
  • Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
  • Department of Medical Genetics, British Columbia Women's Hospital and University of British Columbia, Vancouver, British Columbia, Canada.
  • Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
  • Oxford Centre for Genomic Medicine, Oxford University Hospitals National Health Services Foundation Trust, Oxford, United Kingdom.
  • and 57 more

Abstract

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.