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

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dc.contributor.authorWalz, K.
dc.contributor.authorCohen, D.
dc.contributor.authorNeilsen, P.
dc.contributor.authorFoster, J.
dc.contributor.authorBrancati, F.
dc.contributor.authorDemir, K.
dc.contributor.authorFisher, R.
dc.contributor.authorMoffat, M.
dc.contributor.authorVerbeek, N.
dc.contributor.authorBjørgo, K.
dc.contributor.authorLo Castro, A.
dc.contributor.authorCuratolo, P.
dc.contributor.authorNovelli, G.
dc.contributor.authorAbad, C.
dc.contributor.authorLei, C.
dc.contributor.authorZhang, L.
dc.contributor.authorDiaz-Horta, O.
dc.contributor.authorYoung, J.
dc.contributor.authorCallen, D.
dc.contributor.authorTekin, M.
dc.date.issued2015
dc.description.abstractMutations 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.
dc.description.statementofresponsibilityKatherina Walz, Devon Cohen, Paul M. Neilsen, Joseph Foster II., 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
dc.identifier.citationHuman Genetics, 2015; 134(2):181-190
dc.identifier.doi10.1007/s00439-014-1509-2
dc.identifier.issn0340-6717
dc.identifier.issn1432-1203
dc.identifier.orcidCallen, D. [0000-0002-6189-9991]
dc.identifier.urihttp://hdl.handle.net/2440/90842
dc.language.isoen
dc.publisherSpringer Berlin Heidelberg
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1009452
dc.rights© Springer-Verlag Berlin Heidelberg 2014
dc.source.urihttps://doi.org/10.1007/s00439-014-1509-2
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectMice, Mutant Strains
dc.subjectBone Diseases, Developmental
dc.subjectTooth Abnormalities
dc.subjectAbnormalities, Multiple
dc.subjectFacies
dc.subjectProteasome Endopeptidase Complex
dc.subjectDNA-Binding Proteins
dc.subjectRepressor Proteins
dc.subjectCell Cycle
dc.subjectProtein Structure, Tertiary
dc.subjectMutation
dc.subjectFemale
dc.subjectMale
dc.subjectProtein Stability
dc.subjectIntellectual Disability
dc.subjectProteolysis
dc.titleCharacterization of ANKRD11 mutations in humans and mice related to KBG syndrome
dc.typeJournal article
pubs.publication-statusPublished

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