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

Sébastien Küry 1 Thomas Besnard 1 Frédéric Ebstein Tahir N. Khan Tomasz Gambin Jessica Douglas 2 Carlos A. Bacino Stephan J. Sanders Andrea Lehmann Xenia Latypova 1 Kamal Khan Mathilde Pacault 3, 1 Stephanie Sacharow 2 Kimberly Glaser Eric Bieth 4 Laurence Perrin-Sabourin Marie-Line Jacquemont 5 Megan T. Cho Elizabeth Roeder 6 Anne-Sophie Denommé-Pichon Kristin G. Monaghan Bo Yuan Fan Xia Sylvain Simon 7, 8, 9 Dominique Bonneau 10, 11 Philippe Parent Brigitte Gilbert-Dussardier 12 Sylvie Odent 13, 14, 15 Annick Toutain 16, 17 Laurent Pasquier 15, 14, 13 Deborah Barbouth Chad A. Shaw Ankita Patel Janice L. Smith Weimin Bi Sébastien Schmitt 1 Wallid Deb 1 Mathilde Nizon 1 Sandra Mercier 1 Marie Vincent 1 Caroline Rooryck 18 Valérie Malan 19 Ignacio Briceno 20 Alberto Gómez 20 Kimberly M. Nugent James B. Gibson Benjamin Cogné 1 James R. Lupski 21 Holly A. F. Stessman Evan E. Eichler Kyle Retterer Yaping Yang 21 Richard Redon 22 Nicholas Katsanis 23 Jill A. Rosenfeld 21 Peter-Michael Kloetzel Christelle Golzio 23 Stéphane Bézieau 9 Paweł Stankiewicz 21 Bertrand Isidor 1
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.
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Sébastien Küry, Thomas Besnard, Frédéric Ebstein, Tahir N. Khan, Tomasz Gambin, et al.. De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder. American Journal of Human Genetics, Elsevier (Cell Press), 2017, 100 (2), pp.352-363. ⟨10.1016/j.ajhg.2017.01.003⟩. ⟨hal-01478814⟩

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