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; Xenia 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-Pichon; Kristin 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 Briceno; 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

doi:10.1016/j.ajhg.2017.01.003

Journal articles

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, *}

* Corresponding author

1 Service de génétique médicale - Unité de génétique clinique [Nantes]

2 Boston Children's Hospital

3 Department of Medicine

4 Service de Génétique [Purpan]

5 CHU La Réunion - Centre Hospitalier Universitaire de La Réunion

6 Department of Pediatrics

7 LabEX IGO Immunothérapie Grand Ouest

8 Service de Cancéro-Dermatologie

9 CRCINA-ÉQUIPE 3 - Anti-Tumor Immunosurveillance and Immunotherapy

CRCINA - Centre de Recherche en Cancérologie et Immunologie Nantes-Angers

10 Mitochondrie : Régulations et Pathologie

11 Service de génétique [Angers]

12 Génétique Médicale

13 IGDR - Institut de Génétique et Développement de Rennes

14 Service de génétique clinique [Rennes]

15 CHU Pontchaillou [Rennes]

16 Service de génétique [Tours]

17 iBrain - Inserm U1253 - UNIV Tours - Imagerie et cerveau

18 CHU Bordeaux [Bordeaux]

19 Laboratoire Histologie Embryologie Cytogénétique [CHU Necker]

20 Instituto de Genetica Humana, Pontificia Universidad Javeriana

21 BCM - Baylor College of Medicine

22 ITX - unité de recherche de l'institut du thorax UMR1087 UMR6291

23 Center for Human Disease Modeling

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.

Keywords : syndromic neurodevelopmental disorder proteasome 26S intellectual disability RPN5 PSMD12 ubiquitin

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Journal articles

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Life Sciences [q-bio] / Genetics

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

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

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