دورية أكاديمية
Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling
| العنوان: | Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling |
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| المؤلفون: | 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, Schoch, K, Sullivan, JA, Acosta, MT, Adams, DR, Aday, A, Alejandro, ME, Allard, P, Ashley, EA, Azamian, MS, Bacino, CA, Bademci, G, Baker, E, Balasubramanyam, A, Baldridge, D, Barbouth, D, Batzli, GF, Beggs, AH, Bellen, HJ, Bernstein, JA, Berry, GT, Bican, A, Bick, DP, Birch, CL, Bivona, S, Bonnenmann, C, Bonner, D, Boone, BE, Bostwick, BL, Briere, LC, Brokamp, E, Brown, DM, Brush, M, Burke, EA, Burrage, LC, Butte, MJ, Carrasquillo, O, Peter Chang, TC, Chao, HT, Clark, GD, Coakley, TR, Cobban, LA, Cogan, JD, Cole, FS, Colley, HA, Cooper, CM, Cope, H, Craigen, WJ, D'Souza, P, Wood, Stephen |
| بيانات النشر: | Elsevier |
| سنة النشر: | 2019 |
| المجموعة: | Griffith University: Griffith Research Online |
| مصطلحات موضوعية: | Biological sciences, Biomedical and clinical sciences, Clinical sciences, Neurosciences, Psychology |
| الوصف: | 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. ; Full Text |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 0006-3223 |
| العلاقة: | Biological Psychiatry; 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; Schoch, K; Sullivan, JA; Acosta, MT; Adams, DR; Aday, A; Alejandro, ME; Allard, P; Ashley, EA; Azamian, MS; Bacino, CA; Bademci, G; Baker, E; Balasubramanyam, A; Baldridge, D; Barbouth, D; Batzli, GF; Beggs, AH; Bellen, HJ; Bernstein, JA; Berry, GT; Bican, A; Bick, DP; Birch, CL; Bivona, S; Bonnenmann, C; Bonner, D; Boone, BE; Bostwick, BL; Briere, LC; Brokamp, E; Brown, DM; Brush, M; Burke, EA; Burrage, LC; Butte, MJ; Carrasquillo, O; Peter Chang, TC; Chao, HT; Clark, GD; Coakley, TR; Cobban, LA; Cogan, JD; Cole, FS; Colley, HA; Cooper, CM; Cope, H; Craigen, WJ; D'Souza, P, Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling, Biological Psychiatry, 2019; http://hdl.handle.net/10072/386708Test |
| DOI: | 10.1016/j.biopsych.2019.05.028 |
| الإتاحة: | https://doi.org/10.1016/j.biopsych.2019.05.028Test http://hdl.handle.net/10072/386708Test |
| حقوق: | http://creativecommons.org/licenses/by-nc-nd/4.0Test/ ; © 2019 Society of Biological Psychiatr. Published by Elsevier Ltd. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence (http://creativecommons.org/licenses/by-nc-nd/4.0Test/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited. ; open access |
| رقم الانضمام: | edsbas.EC3D1328 |
| قاعدة البيانات: | BASE |
| تدمد: | 00063223 |
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| DOI: | 10.1016/j.biopsych.2019.05.028 |