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


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.

SUBMITTER: Kury S 

PROVIDER: S-EPMC5294671 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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

Küry Sébastien S   Besnard Thomas T   Ebstein Frédéric F   Khan Tahir N TN   Gambin Tomasz T   Douglas Jessica J   Bacino Carlos A CA   Craigen William J WJ   Sanders Stephan J SJ   Lehmann Andrea A   Latypova Xénia X   Khan Kamal K   Pacault Mathilde M   Sacharow Stephanie S   Glaser Kimberly K   Bieth Eric E   Perrin-Sabourin Laurence L   Jacquemont Marie-Line ML   Cho Megan T MT   Roeder Elizabeth E   Denommé-Pichon Anne-Sophie AS   Monaghan Kristin G KG   Yuan Bo B   Xia Fan F   Simon Sylvain S   Bonneau Dominique D   Parent Philippe P   Gilbert-Dussardier Brigitte B   Odent Sylvie S   Toutain Annick A   Pasquier Laurent L   Barbouth Deborah D   Shaw Chad A CA   Patel Ankita A   Smith Janice L JL   Bi Weimin W   Schmitt Sébastien S   Deb Wallid W   Nizon Mathilde M   Mercier Sandra S   Vincent Marie M   Rooryck Caroline C   Rooryck Caroline C   Malan Valérie V   Briceño Ignacio I   Gómez Alberto A   Nugent Kimberly M KM   Gibson James B JB   Cogné Benjamin B   Lupski James R JR   Stessman Holly A F HAF   Eichler Evan E EE   Retterer Kyle K   Yang Yaping Y   Redon Richard R   Katsanis Nicholas N   Rosenfeld Jill A JA   Kloetzel Peter-Michael PM   Golzio Christelle C   Bézieau Stéphane S   Stankiewicz Paweł P   Isidor Bertrand B  

American journal of human genetics 20170126 2


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 indiv  ...[more]

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