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

Hum Genet. 2015 Feb;134(2):181-90. doi: 10.1007/s00439-014-1509-2. Epub 2014 Nov 21.


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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

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


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

Supplementary concepts

  • KBG syndrome