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Human Genetics

, Volume 134, Issue 2, pp 181–190 | Cite as

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

  • Katherina WalzEmail author
  • Devon Cohen
  • Paul M. Neilsen
  • Joseph FosterII.
  • 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 TekinEmail author
Original Investigation

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.

Keywords

Intellectual Disability Intellectual Disability Nocodazole Yellow Fluorescent Protein Angelman Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We thank Karen Neagley for the administrative support and the English proofreading of the manuscript, Professor Stephen Michnick for the PCA expression constructs, and Dr. Raman Sharma for his useful discussions. This work was partially funded by the Hayward Foundation and NHMRC Project Grant APP1009452.

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

439_2014_1509_MOESM1_ESM.docx (7.9 mb)
Supplementary material 1 (DOCX 8098 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Katherina Walz
    • 1
    • 2
    Email author
  • Devon Cohen
    • 1
  • Paul M. Neilsen
    • 3
  • Joseph FosterII.
    • 1
  • Francesco Brancati
    • 4
    • 5
  • Korcan Demir
    • 6
  • Richard Fisher
    • 7
  • Michelle Moffat
    • 8
  • Nienke E. Verbeek
    • 9
  • Kathrine Bjørgo
    • 10
  • Adriana Lo Castro
    • 11
  • Paolo Curatolo
    • 11
  • Giuseppe Novelli
    • 5
  • Clemer Abad
    • 1
  • Cao Lei
    • 1
  • Lily Zhang
    • 1
  • Oscar Diaz-Horta
    • 1
  • Juan I. Young
    • 1
  • David F. Callen
    • 3
  • Mustafa Tekin
    • 1
    Email author
  1. 1.Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human GenomicsMiller School of Medicine, University of MiamiMiamiUSA
  2. 2.Department of MedicineMiller School of Medicine, University of MiamiMiamiUSA
  3. 3.Swinburne University of Technology Sarawak CampusKuchingMalaysia
  4. 4.Department of Medical, Oral and Biotechnological SciencesGabriele D’Annunzio UniversityChietiItaly
  5. 5.Medical Genetics UnitPoliclinico Tor Vergata University HospitalRomeItaly
  6. 6.Division of Pediatric EndocrinologyDokuz Eylül University Faculty of MedicineİzmirTurkey
  7. 7.Northern Genetics Service Teesside Genetics UnitThe James Cook University HospitalMiddlesbroughUK
  8. 8.Department of Paediatric DentistryNewcastle Dental Hospital and SchoolNewcastle upon TyneUK
  9. 9.Department of Medical GeneticsUniversity Medical Center UtrechtUtrechtThe Netherlands
  10. 10.Department of Medical GeneticsOslo University HospitalOsloNorway
  11. 11.Department of Neuroscience, Pediatric Neurology and Psychiatry UnitTor Vergata University of RomeRomeItaly

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