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

• Published in: American journal of human genetics Vol. 100; no. 2; pp. 352 - 363
• Main Authors: Küry, Sébastien, Besnard, Thomas, Ebstein, Frédéric, Khan, Tahir N., Gambin, Tomasz, Douglas, Jessica, Bacino, Carlos A., Craigen, William J., Sanders, Stephan J., Lehmann, Andrea, Latypova, Xénia, Khan, Kamal, Pacault, Mathilde, Sacharow, Stephanie, Glaser, Kimberly, Bieth, Eric, Perrin-Sabourin, Laurence, Jacquemont, Marie-Line, Cho, Megan T., Roeder, Elizabeth, Denommé-Pichon, Anne-Sophie, Monaghan, Kristin G., Yuan, Bo, Xia, Fan, Simon, Sylvain, Bonneau, Dominique, Parent, Philippe, Gilbert-Dussardier, Brigitte, Odent, Sylvie, Toutain, Annick, Pasquier, Laurent, Barbouth, Deborah, Shaw, Chad A., Patel, Ankita, Smith, Janice L., Bi, Weimin, Schmitt, Sébastien, Deb, Wallid, Nizon, Mathilde, Mercier, Sandra, Vincent, Marie, Rooryck, Caroline, Malan, Valérie, Briceño, Ignacio, Gómez, Alberto, Nugent, Kimberly M., Gibson, James B., Cogné, Benjamin, Lupski, James R., Stessman, Holly A.F., Eichler, Evan E., Retterer, Kyle, Yang, Yaping, Redon, Richard, Katsanis, Nicholas, Rosenfeld, Jill A., Kloetzel, Peter-Michael, Golzio, Christelle, Bézieau, Stéphane, Stankiewicz, Paweł, Isidor, Bertrand
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.02.2017; Cell Press; Elsevier (Cell Press); Elsevier
• Subjects: Adolescent; Animals; Child; Child, Preschool; Developmental disabilities; Disease Models, Animal; DNA Copy Number Variations; Down-Regulation; Eukaryotes; Female; Gene Deletion; Genetics; Genomics; Humans; Infant; intellectual disability; Intellectual Disability - genetics; Life Sciences; Male; Microcephaly - genetics; Mutation; Neurodegeneration; Neurodevelopmental Disorders - genetics; Polymorphism, Single Nucleotide; proteasome 26S; Proteasome Endopeptidase Complex - genetics; Proteins; PSMD12; RPN5; syndromic neurodevelopmental disorder; ubiquitin; Zebrafish - genetics; PSMD12; RPN5; proteasome 26S; intellectual disability; ubiquitin; syndromic neurodevelopmental disorder
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2017.01.003

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.