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

• DOI: 10.1007/s00439-014-1509-2
• Publication Date: 2014-11-21T11:29:10Z
• Authors: Katherina Walz; Devon Cohen; Paul M. Neilsen; Joseph Foster; 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
• Keywords: Male; 060102 Bioinformatics; Cell Wall); Settore MED/03 - GENETICA MEDICA; Mutant Strain; Mice; 060106 Cellular Interactions (incl. Adhesion; Developmental; Genetics(clinical); Animals; Cell Cycle; Cell Line, Tumor; Female; Humans; Male; Mice; Mice, Mutant Strains; Proteasome Endopeptidase Complex; Protein Stability; Protein Structure, Tertiary; Abnormalities, Multiple; Bone Diseases, Developmental; DNA-Binding Proteins; Facies; Intellectual Disability; Mutation; Proteolysis; Repressor Proteins; Tooth Abnormalities; Proteolysi; 0303 health sciences; Tumor; Protein Stability; Research Support, Non-U.S. Gov't; Animals; Cell Cycle; Cell Line, Tumor; Female; Humans; Male; Mice; Mice, Mutant Strains; Proteasome Endopeptidase Complex; Protein Stability; Protein Structure, Tertiary; Abnormalities, Multiple; Bone Diseases, Developmental; DNA-Binding Proteins; Facies; Intellectual Disability; Mutation; Proteolysis; Repressor Proteins; Tooth Abnormalities; Genetics (clinical); Genetics; Cell Cycle; 110199 Medical Biochemistry and Metabolomics not elsewhere classified; Clinical Trial; 3. Good health; Mutant Strains; DNA-Binding Proteins; Female; Abnormalities; Bone Diseases; Multiple; Animals; Cell Cycle; Cell Line; Tumor; Female; Humans; Male; Mice; Mutant Strains; Proteasome Endopeptidase Complex; Protein Stability; Protein Structure; Tertiary; Abnormalities; Multiple; Bone Diseases; Developmental; DNA-Binding Proteins; Facies; Intellectual Disability; Mutation; Proteolysis; Repressor Proteins; Tooth Abnormalities; Genetics (clinical); Genetics; Human; Protein Structure; 570; Proteasome Endopeptidase Complex; DNA-Binding Protein; Cell Line; 03 medical and health sciences; Cell Line, Tumor; Intellectual Disability; Genetics; Journal Article; Animals; Humans; Abnormalities, Multiple; Bone Diseases, Developmental; Matrix; Animal; Tooth Abnormalities; Facies; Repressor Protein; Facie; Mice, Mutant Strains; Protein Structure, Tertiary; Repressor Proteins; Mutation; Proteolysis; Tertiary

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.