@article{331c02abdff94edc856d0a0d2b54524f,
title = "Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling",
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 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.",
keywords = "brain malformation, cell-migration, deubiquitinating enzyme, deubiquitylating enzyme, fam/usp9x, hippocampus, in-vitro, intellectual disability, interacts, liquid facets, neurodevelopmental disorder, of-function mutations, phenotype, tgf beta, usp9x, DEUBIQUITINATING ENZYME, Deubiquitylating enzyme, Neurodevelopmental disorder, OF-FUNCTION MUTATIONS, LIQUID FACETS, Brain malformation, INTELLECTUAL DISABILITY, IN-VITRO, INTERACTS, TGF beta, USP9X, PHENOTYPE, CELL-MIGRATION, DEUBIQUITYLATING ENZYME, Hippocampus, FAM/USP9X",
author = "B.V. Johnson and R. Kumar and S. Oishi and S. Alexander and M. Kasherman and M.S. Vega and A. Ivancevic and A. Gardner and D. Domingo and M. Corbett and E. Parnell and S. Yoon and T. Oh and M. Lines and H. Lefroy and U. Kini and {Van Allen}, M. and S. Gronborg and S. Mercier and S. Kury and S. Bezieau and L. Pasquier and M. Raynaud and A. Afenjar and {de Villemeur}, T.B. and B. Keren and J. Desir and {Van Maldergem}, L. and M. Marangoni and N. Dikow and D.A. Koolen and P.M. VanHasselt and M. Weiss and P. Zwijnenburg and J. Sa and C.F. Reis and C. Lopez-Otin and O. Santiago-Fernandez and A. Fernandez-Jaen and A. Rauch and K. Steindl and P. Joset and A. Goldstein and S. Madan-Khetarpal and E. Infante and E. Zackai and C. Mcdougall and V. Narayanan and K. Ramsey and S. Mercimek-Andrews and {Undiagnosed Diseases Network} and Margot Reijnders and Jozef Gecz",
note = "Funding Information: CL-O and OS-F were supported by Programa EDP SOLIDARIA 2016 (Fundaci{\'o}n EDP). DCK, DB, and TMM were supported by The Research Institute , Nationwide Children's Hospital . TMP was funded by the Cedars-Sinai Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases and the Undiagnosed Diseases Program. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (Grant No. HICF-1009–003 ), a parallel funding partnership between Wellcome and the Department of Health , and the Wellcome Sanger Institute (Grant No. WT098051 ). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC , and GEN/284/12 granted by the Republic of Ireland REC ). The research team acknowledges the support of the National Institute for Health Research , through the Comprehensive Clinical Research Network. This study makes use of DECIPHER ( http://decipher.sanger.ac.uk ), which is funded by the Wellcome Trust . Funding Information: This work was supported by Simons Foundation Autism Research Initiative ( SFARI Explorer Grant No. 527556 to [MPi, SW, LJ]), Australian Research Council (Grant No. ARC DE160100620 [to LJ]), the National Health and Medical Research Council of Australia (Program Grant No. 628952 and Research Fellowship 1041920 [to JG]), National Institute of Health (Grant NO. R01MH107182 [to PP]). USA 26 was evaluated through the Duke Genome Sequencing Clinic, supported by the Duke University Health System and partially funded by UCB Celltech. Funding Information: This work was supported by Simons Foundation Autism Research Initiative (SFARI Explorer Grant No. 527556 to [MPi, SW, LJ]), Australian Research Council (Grant No. ARC DE160100620 [to LJ]), the National Health and Medical Research Council of Australia (Program Grant No. 628952 and Research Fellowship 1041920 [to JG]), National Institute of Health (Grant NO. R01MH107182 [to PP]). USA 26 was evaluated through the Duke Genome Sequencing Clinic, supported by the Duke University Health System and partially funded by UCB Celltech. CL-O and OS-F were supported by Programa EDP SOLIDARIA 2016 (Fundaci?n EDP). DCK, DB, and TMM were supported by The Research Institute, Nationwide Children's Hospital. TMP was funded by the Cedars-Sinai Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases and the Undiagnosed Diseases Program. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (Grant No. HICF-1009?003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (Grant No. WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. This study makes use of DECIPHER (http://decipher.sanger.ac.uk), which is funded by the Wellcome Trust. We are grateful for the support and contributions of all families involved in this study. We are thankful for the funding received from Creola Pora with the help of her friends and colleagues. IC, MPa, and MA are employees of UCB. JAR belongs to the Department of Molecular and Human Genetics at Baylor College of Medicine, which receives revenue from clinical genetic testing conducted at Baylor Genetics Laboratories. LAP-J is scientific advisor and founding partner of qGenomics Laboratory. CL-O is a scientific advisor and shareholder of DreamGenics Ltd. All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: {\textcopyright} 2019 Society of Biological Psychiatry",
year = "2020",
month = jan,
day = "15",
doi = "10.1016/j.biopsych.2019.05.028",
language = "English",
volume = "87",
pages = "100--112",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier Science",
number = "2",
}