Journal
BIOLOGICAL PSYCHIATRY
Volume 87, Issue 2, Pages 100-112Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2019.05.028
Keywords
Brain malformation; Deubiquitylating enzyme; Hippocampus; Neurodevelopmental disorder; TGF beta; USP9X
Categories
Funding
- Simons Foundation Autism Research Initiative (SFARI) [527556]
- Australian Research Council [ARC DE160100620]
- National Health and Medical Research Council of Australia [628952, 1041920]
- National Institute of Health [R01MH107182]
- Duke University Health System
- UCB Celltech
- Programa EDP SOLIDARIA 2016 (Fundacion EDP)
- The Research Institute, Nationwide Children's Hospital
- Cedars-Sinai Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases and the Undiagnosed Diseases Program
- Wellcome [HICF-1009-003]
- Department of Health [HICF-1009-003]
- Wellcome Sanger Institute [WT098051]
- National Institute for Health Research, through the Comprehensive Clinical Research Network
- Wellcome Trust
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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 signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocannpal-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 beta signaling and hippocampal function.
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