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

TitleDe novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome.
Publication TypeJournal Article
Year of Publication2014
AuthorsMirzaa G, Parry DA, Fry AE, Giamanco KA, Schwartzentruber J, Vanstone M, Logan CV, Roberts N, Johnson CA, Singh S, Kholmanskikh SS, Adams C, Hodge RD, Hevner RF, Bonthron DT, Braun KPJ, Faivre L, Rivière J-B, St-Onge J, Gripp KW, Mancini GMs, Pang K, Sweeney E, van Esch H, Verbeek N, Wieczorek D, Steinraths M, Majewski J, Boycot KM, Pilz DT, M Ross E, Dobyns WB, Sheridan EG
Corporate AuthorsFORGE Canada Consortium
JournalNat Genet
Volume46
Issue5
Pagination510-515
Date Published2014 May
ISSN1546-1718
KeywordsAbnormalities, Multiple, Animals, Base Sequence, Blotting, Western, Bromodeoxyuridine, Cyclin D2, Electroporation, Exome, Female, HEK293 Cells, Humans, Hydrocephalus, Immunohistochemistry, Malformations of Cortical Development, Megalencephaly, Mice, Microscopy, Fluorescence, Molecular Sequence Data, Mutagenesis, Site-Directed, Polydactyly, Sequence Analysis, DNA, Syndrome
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.

DOI10.1038/ng.2948
Alternate JournalNat. Genet.
PubMed ID24705253
PubMed Central IDPMC4004933
Grant ListP01 NS048120 / NS / NINDS NIH HHS / United States
F32 NS086173 / NS / NINDS NIH HHS / United States
P01-NS048120 / NS / NINDS NIH HHS / United States
MR/K011154/1 / / Medical Research Council / United Kingdom
R01NS058721 / NS / NINDS NIH HHS / United States
OGI-049 / / Canadian Institutes of Health Research / Canada
R01 NS058721 / NS / NINDS NIH HHS / United States
MR/L01629X/1 / / Medical Research Council / United Kingdom