Partial loss of USP9X function leads to a male neurodevelopmental and behavioral disorder converging on transforming growth factor beta signaling
In: Biological Psychiatry, 2020
Online
academicJournal
Zugriff:
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. ; Genetics of disease, diagnosis ...
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Partial loss of USP9X function leads to a male neurodevelopmental and behavioral disorder converging on transforming growth factor beta signaling
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| Autor/in / Beteiligte Person: | Johnson, B.V. ; Kumar, R. ; Oishi, S. ; Alexander, S. ; Kasherman, M. ; Vega, M.S. ; Ivancevic, A. ; Gardner, A. ; Domingo, D. ; Corbett, M. ; Parnell, E. ; Yoon, S. ; Oh, T. ; Lines, M. ; Lefroy, H. ; Kini, U. ; Allen, M. van ; Gronborg, S. ; Mercier, S. ; Kury, S. ; Bezieau, S. ; Pasquier, L. ; Raynaud, M. ; Afenjar, A. ; Villemeur, T.B. de ; Keren, B. ; Desir, J. ; Maldergem, L. van ; Marangoni, M. ; Dikow, N. ; Koolen, D.A. ; VanHasselt, P.M. ; Weiss, M. ; Zwijnenburg, P. ; Sa, J. ; Reis, C.F. ; Lopez-Otin, C. ; Santiago-Fernandez, O. ; Fernandez-Jaen, 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, J.A. ; Vairo, F.P.E. ; Pichurin, P.N. ; Ewing, S.A. ; Barnett, S.S. ; Klee, E.W. ; Perry, M.S. ; Koenig, M.K. ; Keegan, C.E. ; Schuette, J.L. ; Asher, S. ; Perilla-Young, Y. ; Smith, L.D. ; Rosenfeld, J.A. ; Bhoj, E. ; Kaplan, P. ; Li, D. ; Oegema, R. ; Binsbergen, E. van ; Zwaag, B. van der ; Smeland, M.F. ; Cutcutache, I. ; Page, M. ; Armstrong, M. ; Lin, A.E. ; Steeves, M.A. ; Hollander, N. den ; Hoffer, M.J.V. ; Reijnders, M.R.F. ; Demirdas, S. ; Koboldt, D.C. ; Bartholomew, D. ; Mosher, T.M. ; Hickey, S.E. ; Shieh, C. ; Sanchez-Lara, P.A. ; Graham, J.M. ; Tezcan, K. ; Schaefer, G.B. ; Danylchuk, N.R. ; Asamoah, A. ; Jackson, K.E. ; Yachelevich, N. ; Au, M. ; Perez-Jurado, L.A. ; Kleefstra, T. ; Penzes, P. ; Wood, S.A. ; Burne, T. ; Pierson, T.M. ; Piper, M. ; Gecz, J. ; Jolly, L.A. ; Acosta, M.T. ; Adams, D.R. ; Aday, A. ; Alejandro, M.E. ; Allard, P. ; Ashley, E.A. ; Azamian, M.S. ; Bacino, C.A. ; Bademci, G. ; Baker, E. ; Balasubramanyam, A. ; Baldridge, D. ; Barbouth, D. ; Batzli, G.F. ; Beggs, A.H. ; Bellen, H.J. ; Bernstein, J.A. ; Berry, G.T. ; Bican, A. ; Bick, D.P. ; Birch, C.L. ; Bivona, S. ; Bonnenmann, C. ; Bonner, D. ; Boone, B.E. ; Bostwick, B.L. ; Briere, L.C. ; Brokamp, E. ; Brown, D.M. ; Brush, M. ; Burke, E.A. ; Burrage, L.C. ; Butte, M.J. ; Carrasquillo, O. ; Chang, T.C.P. ; Chao, H.T. ; Clark, G.D. ; Coakley, T.R. ; Cobban, L.A. ; Cogan, J.D. ; Cole, F.S. ; Colley, H.A. ; Cooper, C.M. ; Cope, H. ; Craigen, W.J. ; D'Souza, P. ; Dasari, S. ; Davids, M. ; Davidson, J.M. ; Dayal, J.G. ; Dell'Angelica, E.C. ; Dhar, S.U. ; Dorrani, N. ; Dorset, D.C. ; Douine, E.D. ; Draper, D.D. ; Dries, A.M. ; Duncan, L. ; Eckstein, D.J. ; Emrick, L.T. ; Eng, C.M. ; Enns, G.M. ; Esteves, C. ; Estwick, T. ; Fernandez, L. ; Ferreira, C. ; Fieg, E.L. ; Fisher, P.G. ; Fogel, B.L. ; Forghani, I. ; Friedman, N.D. ; Gahl, W.A. ; Godfrey, R.A. ; Goldman, A.M. ; Goldstein, D.B. ; Gourdine, J.P.F. ; Grajewski, A. ; Groden, C.A. ; Gropman, A.L. ; Haendel, M. ; Hamid, R. ; Hanchard, N.A. ; High, F. ; Holm, I.A. ; Hom, J. ; Huang, A. ; Huang, Y. ; Isasi, R. ; Jamal, F. ; Jiang, Y.H. ; Johnston, J.M. ; Jones, A.L. ; Karaviti, L. ; Kelley, E.G. ; Koeller, D.M. ; Kohane, I.S. ; Kohler, J.N. ; Krakow, D. ; Krasnewich, D.M. ; Korrick, S. ; Koziura, M. ; Krier, J.B. ; Kyle, J.E. ; Lalani, S.R. ; Lam, B. ; Lanpher, B.C. ; Lanza, I.R. ; Lau, C.C. ; Lazar, J. ; LeBlanc, K. ; Lee, B.H. ; Lee, H. ; Levitt, R. ; Levy, S.E. ; Lewis, R.A. ; Lincoln, S.A. ; Liu, P.F. ; Liu, X.Z. ; Loo, S.K. ; Loscalzo, J. ; Maas, R.L. ; Macnamara, E.F. ; MacRae, C.A. ; Maduro, V.V. ; Majcherska, M.M. ; Malicdan, M.C.V. ; Mamounas, L.A. ; Manolio, T.A. ; Markello, T.C. ; Marom, R. ; Martin, M.G. ; Martinez-Agosto, J.A. ; Marwaha, S. ; May, T. ; McCauley, J. ; McConkie-Rosell, A. ; McCormack, C.E. ; McCray, A.T. ; Merker, J.D. ; Metz, T.O. ; Might, M. ; Morava-Kozicz, E. ; Moretti, P.M. ; Morimoto, M. ; Mulvihill, J.J. ; Murdock, D.R. ; Nath, A. ; Nelson, S.F. ; Newberry, J.S. ; Newman, J.H. ; Nicholas, S.K. ; Novacic, D. ; Oglesbee, D. ; Orengo, J.P. ; Pak, S. ; Pallais, J.C. ; Palmer, C.G.S. ; Papp, J.C. ; Parker, N.H. ; Phillips, J.A. ; Posey, J.E. ; Postlethwait, J.H. ; Potocki, L. ; Pusey, B.N. ; Renteri, G. ; Reuter, C.M. ; Rives, L. ; Robertson, A.K. ; Rodan, L.H. ; Rowley, R.K. ; Sacco, R. ; Sampson, J.B. ; Samson, S.L. ; Saporta, M. ; Schaechter, J. ; Schedl, T. ; Scott, D.A. ; Shakachite, L. ; Sharma, P. ; Shields, K. ; S |
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| Zeitschrift: | Biological Psychiatry, 2020 |
| Veröffentlichung: | 2020 |
| Medientyp: | academicJournal |
| DOI: | 10.1016/j.biopsych.2019.05.028 |
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