ZFIN ID: ZDB-PUB-170131-7
De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder
Küry, S., Besnard, T., Ebstein, F., Khan, T.N., Gambin, T., Douglas, J., Bacino, C.A., Sanders, S.J., Lehmann, A., Latypova, X., Khan, K., Pacault, M., Sacharow, S., Glaser, K., Bieth, E., Perrin-Sabourin, L., Jacquemont, M.L., Cho, M.T., Roeder, E., Denommé-Pichon, A.S., Monaghan, K.G., Yuan, B., Xia, F., Simon, S., Bonneau, D., Parent, P., Gilbert-Dussardier, B., Odent, S., Toutain, A., Pasquier, L., Barbouth, D., Shaw, C.A., Patel, A., Smith, J.L., Bi, W., Schmitt, S., Deb, W., Nizon, M., Mercier, S., Vincent, M., Rooryck, C., Malan, V., Briceño, I., Gómez, A., Nugent, K.M., Gibson, J.B., Cogné, B., Lupski, J.R., Stessman, H.A., Eichler, E.E., Retterer, K., Yang, Y., Redon, R., Katsanis, N., Rosenfeld, J.A., Kloetzel, P.M., Golzio, C., Bézieau, S., Stankiewicz, P., Isidor, B.
Date: 2017
Source: American journal of human genetics   100(2): 352-363 (Journal)
Registered Authors: Katsanis, Nicholas
Keywords: PSMD12, RPN5, intellectual disability, proteasome 26S, syndromic neurodevelopmental disorder, ubiquitin
MeSH Terms:
  • Adolescent
  • Animals
  • Child
  • Child, Preschool
  • DNA Copy Number Variations
  • Disease Models, Animal
  • Down-Regulation
  • Female
  • Gene Deletion
  • Humans
  • Infant
  • Intellectual Disability/genetics
  • Male
  • Microcephaly/genetics
  • Neurodevelopmental Disorders/genetics*
  • Polymorphism, Single Nucleotide
  • Proteasome Endopeptidase Complex/genetics*
  • Zebrafish/genetics
PubMed: 28132691 Full text @ Am. J. Hum. Genet.
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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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