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

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• 作者：Sé ; bastien Kü ; ry¹ ; Thomas Besnard¹ ; Fré ; dé ; ric Ebstein² ; Tahir N. Khan³ ; Tomasz Gambin⁴ ; ⁵ ; ⁶ ; Jessica Douglas⁷ ; Carlos A. Bacino⁴ ; ⁸ ; Stephan J. Sanders⁹ ; Andrea Lehmann² ; Xé ; nia Latypova¹ ; Kamal Khan³ ; Mathilde Pacault¹ ; Stephanie Sacharow⁷ ; Kimberly Glaser¹⁰ ; Eric Bieth¹¹ ; Laurence Perrin-Sabourin¹² ; Marie-Line Jacquemont¹³ ; Megan T. Cho¹⁴ ; Elizabeth Roeder⁴ ; ¹⁵ ; Anne-Sophie Denommé ; -Pichon¹⁶ ; Kristin G. Monaghan¹⁴ ; Bo Yuan⁴ ; ⁸ ; Fan Xia⁴ ; ⁸ ; Sylvain Simon¹⁷ ; ¹⁸ ; ¹⁹ ; Dominique Bonneau¹⁶ ; ²⁰ ; Philippe Parent²¹ ; Brigitte Gilbert-Dussardier²² ; ²³ ; Sylvie Odent²⁴ ; ²⁵ ; Annick Toutain²⁶ ; ²⁷ ; Laurent Pasquier²⁴ ; ²⁵ ; Deborah Barbouth¹⁰ ; Chad A. Shaw⁴ ; ⁸ ; Ankita Patel⁴ ; ⁸ ; Janice L. Smith⁴ ; ⁸ ; Weimin Bi⁴ ; ⁸ ; Sé ; bastien Schmitt¹ ; Wallid Deb¹ ; Mathilde Nizon¹ ; Sandra Mercier¹ ; Marie Vincent¹ ; Caroline Rooryck²⁸ ; Valé ; rie Malan²⁹ ; Ignacio Briceñ ; o³⁰ ; Alberto Gó ; mez³⁰ ; Kimberly M. Nugent¹⁵ ; James B. Gibson³¹ ; Benjamin Cogné ; ¹ ; James R. Lupski⁴ ; ³² ; ³³ ; Holly A.F. Stessman³⁴ ; Evan E. Eichler³⁴ ; ³⁵
• 关键词：PSMD12 ; intellectual disability ; proteasome 26S ; RPN5 ; ubiquitin ; syndromic neurodevelopmental disorder
• 刊名：The American Journal of Human Genetics
• 出版年：2017
• 出版时间：2 February 2017
• 年：2017
• 卷：100
• 期：2
• 页码：352-363
• 全文大小：1868 K
• 卷排序：100

文摘

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.