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

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.

• Authors: Katherina Walz, Devon Cohen, Paul M Neilsen, Joseph Foster 2nd, 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
• Journal: Human genetics (Hum Genet) Vol. 134 Issue 2 Pg. 181-90 (Feb 2015) ISSN: 1432-1203 [Electronic] Germany
• PMID: 25413698 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ANKRD11 protein, human
• Ankrd11 protein, mouse
• DNA-Binding Proteins
• Repressor Proteins
• Proteasome Endopeptidase Complex

Topics

• Abnormalities, Multiple (genetics, metabolism)
• Animals
• Bone Diseases, Developmental (genetics, metabolism)
• Cell Cycle (genetics)
• Cell Line, Tumor
• DNA-Binding Proteins (genetics, metabolism)
• Facies
• Female
• Humans
• Intellectual Disability (genetics, metabolism)
• Male
• Mice
• Mice, Mutant Strains
• Mutation
• Proteasome Endopeptidase Complex (genetics, metabolism)
• Protein Stability
• Protein Structure, Tertiary
• Proteolysis
• Repressor Proteins (genetics, metabolism)
• Tooth Abnormalities (genetics, metabolism)