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Characterization of ANKRD11 mutations in humans and mice related to KBG syndrome

journal contribution
posted on 13.11.2018, 00:00 by K Walz, D Cohen, Paul Neilsen, J Foster, F Brancati, K Demir, R Fisher, M Moffat, NE Verbeek, K Bjørgo
© 2014, Springer-Verlag Berlin Heidelberg. 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.

History

Volume

134

Issue

2

Start Page

181

End Page

190

Number of Pages

10

eISSN

1432-1203

ISSN

0340-6717

Publisher

Springer

Peer Reviewed

Yes

Open Access

No

External Author Affiliations

University of Miami; Swinburne University of Technology; Gabriele D’Annunzio University;

Era Eligible

Yes

Journal

Human Genetics