De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder

Sébastien Küry, Thomas Besnard, Frédéric Ebstein, Tahir N. Khan, Tomasz Gambin, Jessica Douglas, Carlos A. Bacino, Stephan J. Sanders, Andrea Lehmann, Xénia Latypova, Kamal Khan, Mathilde Pacault, Stephanie Sacharow, Kimberly Glaser, Eric Bieth, Laurence Perrin-Sabourin, Marie Line Jacquemont, Megan T. Cho, Elizabeth Roeder, Anne Sophie Denommé-PichonKristin G. Monaghan, Bo Yuan, Fan Xia, Sylvain Simon, Dominique Bonneau, Philippe Parent, Brigitte Gilbert-Dussardier, Sylvie Odent, Annick Toutain, Laurent Pasquier, Deborah Barbouth, Chad A. Shaw, Ankita Patel, Janice L. Smith, Weimin Bi, Sébastien Schmitt, Wallid Deb, Mathilde Nizon, Sandra Mercier, Marie Vincent, Caroline Rooryck, Valérie Malan, Ignacio Briceño, Alberto Gómez, Kimberly M. Nugent, James B. Gibson, Benjamin Cogné, James R. Lupski, Holly A.F. Stessman, Evan E. Eichler, Kyle Retterer, Yaping Yang, Richard Redon, Nicholas Katsanis, Jill A. Rosenfeld, Peter Michael Kloetzel, Christelle Golzio, Stéphane Bézieau, Paweł Stankiewicz, Bertrand Isidor

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.

Original languageEnglish (US)
Pages (from-to)352-363
Number of pages12
JournalAmerican journal of human genetics
Volume100
Issue number2
DOIs
StatePublished - Feb 2 2017

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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    Küry, S., Besnard, T., Ebstein, F., Khan, T. N., Gambin, T., Douglas, J., Bacino, C. A., Sanders, S. J., Lehmann, A., Latypova, X., Khan, K., Pacault, M., Sacharow, S., Glaser, K., Bieth, E., Perrin-Sabourin, L., Jacquemont, M. L., Cho, M. T., Roeder, E., ... Isidor, B. (2017). De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder. American journal of human genetics, 100(2), 352-363. https://doi.org/10.1016/j.ajhg.2017.01.003