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https://hdl.handle.net/2440/90842
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Type: | Journal article |
Title: | Characterization of ANKRD11 mutations in humans and mice related to KBG syndrome |
Author: | Walz, K. Cohen, D. Neilsen, P. Foster, J. Brancati, F. Demir, K. Fisher, R. Moffat, M. Verbeek, N. Bjørgo, K. Lo Castro, A. Curatolo, P. Novelli, G. Abad, C. Lei, C. Zhang, L. Diaz-Horta, O. Young, J. Callen, D. Tekin, M. |
Citation: | Human Genetics, 2015; 134(2):181-190 |
Publisher: | Springer Berlin Heidelberg |
Issue Date: | 2015 |
ISSN: | 0340-6717 1432-1203 |
Statement of Responsibility: | Katherina Walz, Devon Cohen, Paul M. Neilsen, Joseph Foster II., Francesco Brancati, Korcan Demir, Richard Fisher, Michelle Moffat, Nienke E. Verbeek, Kathrine Bjørgo, Adriana Lo Castro, Paolo Curatolo, Giuseppe Novelli, Clemer Abad, Cao Lei, Lily Zhang, Oscar Diaz-Horta, Juan I. Young, David F. Callen, Mustafa Tekin |
Abstract: | Mutations in ANKRD11 have recently been reported to cause KBG syndrome, an autosomal dominant condition characterized by intellectual disability (ID), behavioral problems, and macrodontia. To understand the pathogenic mechanism that relates ANKRD11 mutations with the phenotype of KBG syndrome, we studied the cellular characteristics of wild-type ANKRD11 and the effects of mutations in humans and mice. We show that the abundance of wild-type ANKRD11 is tightly regulated during the cell cycle, and that the ANKRD11 C-terminus is required for the degradation of the protein. Analysis of 11 pathogenic ANKRD11 variants in humans, including six reported in this study, and one reported in the Ankrd11 Yod/+ mouse, shows that all mutations affect the C-terminal regions and that the mutant proteins accumulate aberrantly. In silico analysis shows the presence of D-box sequences that are signals for proteasome degradation. We suggest that ANKRD11 C-terminus plays an important role in regulating the abundance of the protein, and a disturbance of the protein abundance due to the mutations leads to KBG syndrome. |
Keywords: | Cell Line, Tumor Animals Humans Mice Mice, Mutant Strains Bone Diseases, Developmental Tooth Abnormalities Abnormalities, Multiple Facies Proteasome Endopeptidase Complex DNA-Binding Proteins Repressor Proteins Cell Cycle Protein Structure, Tertiary Mutation Female Male Protein Stability Intellectual Disability Proteolysis |
Rights: | © Springer-Verlag Berlin Heidelberg 2014 |
DOI: | 10.1007/s00439-014-1509-2 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1009452 |
Published version: | http://dx.doi.org/10.1007/s00439-014-1509-2 |
Appears in Collections: | Aurora harvest 2 Medicine publications |
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