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Nat Genet. 2014 May;46(5):510-515. doi: 10.1038/ng.2948. Epub 2014 Apr 6.

De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome.

Author information

1
Department of Pediatrics, University of Washington; and Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA.
2
Leeds Institute of Biomedical and Clinical Science, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, UK.
3
Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.
4
Neurogenetics and Development, Feil Family Brain and Mind Research institute, Weill Cornell Medical College, New York, NY.
5
Mcgill University and Genome Quebec Innovation centre, Montreal, QC H3A 1A4, Canada.
6
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
7
Departments of Neurological Surgery and Pathology, University of Washington; and Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle.
8
Department of Child Neurology, UMC Utrecht, Utrecht, The Netherlands.
9
Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Hôpital d'Enfants, CHU Dijon, Université de Bourgogne, Dijon F-21000, France.
10
Université de Bourgogne Equipe GAD, EA 4271 Dijon F-21000 France.
11
Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, Delaware.
12
Department of Clinical Genetics and Expertise Centre for Neurodevelopmental Disorders, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
13
Department of Paediatric Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
14
Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, UK.
15
Centre for Human Genetics, University Hospital Gasthuisberg, Herestraat, Leuven, Belgium.
16
Department of Medical Genetics, UMC Utrecht, Utrecht, The Netherlands.
17
Institut fur Humangenetik, Universitatsklinikum Essen, Essen, Germany.
18
Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
#
Contributed equally

Abstract

Activating mutations in genes encoding phosphatidylinositol 3-kinase (PI3K)-AKT pathway components cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH, OMIM 603387). Here we report that individuals with MPPH lacking upstream PI3K-AKT pathway mutations carry de novo mutations in CCND2 (encoding cyclin D2) that are clustered around a residue that can be phosphorylated by glycogen synthase kinase 3β (GSK-3β). Mutant CCND2 was resistant to proteasomal degradation in vitro compared to wild-type CCND2. The PI3K-AKT pathway modulates GSK-3β activity, and cells from individuals with PIK3CA, PIK3R2 or AKT3 mutations showed similar CCND2 accumulation. CCND2 was expressed at higher levels in brains of mouse embryos expressing activated AKT3. In utero electroporation of mutant CCND2 into embryonic mouse brains produced more proliferating transfected progenitors and a smaller fraction of progenitors exiting the cell cycle compared to cells electroporated with wild-type CCND2. These observations suggest that cyclin D2 stabilization, caused by CCND2 mutation or PI3K-AKT activation, is a unifying mechanism in PI3K-AKT-related megalencephaly syndromes.

PMID:
24705253
PMCID:
PMC4004933
DOI:
10.1038/ng.2948
[Indexed for MEDLINE]
Free PMC Article

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