Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling.
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.
Johnson, BV; Kumar, R; Oishi, S; Alexander, S; Kasherman, M; Vega, MS; Ivancevic, A; Gardner, A; Domingo, D; Corbett, M; Parnell, E; Yoon, S; Oh, T; Lines, M; Lefroy, H; Kini, U; Van Allen, M; Grønborg, S; Mercier, S; Küry, S; Bézieau, S; Pasquier, L; Raynaud, M; Afenjar, A; Billette de Villemeur, T; Keren, B; Désir, J; Van Maldergem, L; Marangoni, M; Dikow, N; Koolen, DA; VanHasselt, PM; Weiss, M; Zwijnenburg, P; Sa, J; Reis, CF; López-Otín, C; Santiago-Fernández, O; Fernández-Jaén, A; Rauch, A; Steindl, K; Joset, P; Goldstein, A; Madan-Khetarpal, S; Infante, E; Zackai, E; Mcdougall, C; Narayanan, V; Ramsey, K; Mercimek-Andrews, S; Pena, L; Shashi, V; Undiagnosed Diseases Network, ; Schoch, K; Sullivan, JA; Pinto E Vairo, F; Pichurin, PN; Ewing, SA; Barnett, SS; Klee, EW; Perry, MS; Koenig, MK; Keegan, CE; Schuette, JL; Asher, S; Perilla-Young, Y; Smith, LD; Rosenfeld, JA; Bhoj, E; Kaplan, P; Li, D; Oegema, R; van Binsbergen, E; van der Zwaag, B; Smeland, MF; Cutcutache, I; Page, M; Armstrong, M; Lin, AE; Steeves, MA; Hollander, ND; Hoffer, MJV; Reijnders, MRF; Demirdas, S; Koboldt, DC; Bartholomew, D; Mosher, TM; Hickey, SE; Shieh, C; Sanchez-Lara, PA; Graham, JM; Tezcan, K; Schaefer, GB; Danylchuk, NR; Asamoah, A; Jackson, KE; Yachelevich, N; Au, M; Pérez-Jurado, LA; Kleefstra, T; Penzes, P; Wood, SA; Burne, T; Pierson, TM; Piper, M; Gécz, J; Jolly, LA
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