The Ankrd11 mutation in the Yoda mouse mirrors the human gene defect and provides new insights into KBG syndrome. K. Walz1,2, D. Cohen1, P. M. Neilsen3, J. Foster II1, F. Brancati4,5, K. Demir6, R. Fisher7, M. Moffat8, N. E. Verbeek9, K. Bjorgo10, A. Lo-Castro11, P. Curatolo11, G. Novelli5, C. Abad1, C. Lei1, O. Diaz-Horta1, J. I. Young1, D. F. Callen12, M. Tekin1 1) Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, FL, 33136, USA; 2) Department of Medicine, Miller School of Medicine, University of Miami, FL, 33136, USA; 3) Swinburne University of Technology Sarawak Campus, Kuching, Sarawak, Malaysia; 4) Department of Medical, Oral and Biotechnological Sciences, Gabriele D'Annunzio University, 66100 Chieti, Italy; 5) Medical Genetics Unit, Policlinico Tor Vergata University Hospital, Viale Oxford 81, 00133 Rome, Italy; 6) Division of Pediatric Endocrinology, Dokuz Eylül University Faculty of Medicine, Narlidere, İzmir, Turkey; 7) Northern Genetics Service Teesside Genetics Unit, The James Cook University Hospital Marton Road Middlesbrough TS4 3BW, UK; 8) Department of Paediatric Dentistry, Newcastle Dental Hospital and School, Richardson Road, Newcastle upon Tyne, Newcastle NE2 4AZ, UK; 9) Department of Medical Genetics, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, Netherlands; 10) Department of Medical Genetics, Oslo University Hospital, Kirkeveien 166 0450 Oslo, Norway; 11) Department of Neuroscience, Pediatric Neurology and Psychiatry Unit, Tor Vergata University of Rome, Italy; 12) 3Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide SA 5000, Australia.

   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 wildtype ANKRD11 and the effects of mutations in humans and mice. The characterization of a mouse model of KBG syndrome carrying a missense mutation in Ankrd11 showed hypo-activity, increased anxiety, presence of repetitive behaviors, impaired learning and memory, and sociability and preference for social novelty for the mutant mice, consistent with the human phenotype. In addition, we show that the abundance of ANKRD11 is tightly regulated during the cell cycle through degradation by proteasome, which requires the proteasome-dependent destruction boxes (D-box) at the ANKRD11 C-terminus. Analysis of 11 pathogenic ANKRD11 variants in humans, including six reported in this work, and one reported in the Ankrd11Yod/+ mouse, shows that all mutations affect the D-box signals at the C-terminus and the mutant protein accumulates aberrantly in the nucleoli. We conclude that ANKRD11 C-terminus D-boxes play an important role in regulating the abundance of the protein during the cell cycle, and disturbance of this role by a mutation leads to KBG syndrome.

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