title: 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.affiliation: Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, 1501 NW 10 Ave, BRB 610, M-860, Miami, FL, 33136, USA, kwalz@med.miami.edu.
authors.forename: Katherina
authors.initials: K
authors.lastname: Walz
authors.forename: Devon
authors.initials: D
authors.lastname: Cohen
authors.forename: Paul M
authors.initials: PM
authors.lastname: Neilsen
authors.forename: Joseph
authors.initials: J
authors.lastname: Foster
authors.forename: Francesco
authors.initials: F
authors.lastname: Brancati
authors.forename: Korcan
authors.initials: K
authors.lastname: Demir
authors.forename: Richard
authors.initials: R
authors.lastname: Fisher
authors.forename: Michelle
authors.initials: M
authors.lastname: Moffat
authors.forename: Nienke E
authors.initials: NE
authors.lastname: Verbeek
authors.forename: Kathrine
authors.initials: K
authors.lastname: Bjørgo
authors.forename: Adriana
authors.initials: A
authors.lastname: Lo Castro
authors.forename: Paolo
authors.initials: P
authors.lastname: Curatolo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Novelli
authors.forename: Clemer
authors.initials: C
authors.lastname: Abad
authors.forename: Cao
authors.initials: C
authors.lastname: Lei
authors.forename: Lily
authors.initials: L
authors.lastname: Zhang
authors.forename: Oscar
authors.initials: O
authors.lastname: Diaz-Horta
authors.forename: Juan I
authors.initials: JI
authors.lastname: Young
authors.forename: David F
authors.initials: DF
authors.lastname: Callen
authors.forename: Mustafa
authors.initials: M
authors.lastname: Tekin
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001848:Bone Diseases, Developmental / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019066:Facies; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014071:Tooth Abnormalities / Q000235:genetics / Q000378:metabolism
chemical_list: C492515:ANKRD11 protein, human; C528115:Ankrd11 protein, mouse; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D046988:Proteasome Endopeptidase Complex