Please use this identifier to cite or link to this item: 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
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