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

Ghayda M. Mirzaa, David A. Parry, Andrew E. Fry, Kristin A. Giamanco, Jeremy Schwartzentruber, Megan Vanstone, Clare V. Logan, Nicola Roberts, Colin A. Johnson, Shawn Singh, Stanislav S. Kholmanskikh, Carissa Adams, Rebecca D. Hodge, Robert F. Hevner, David T. Bonthron, Kees P.J. Braun, Laurence Faivre, Jean Baptiste Rivière, Judith St-Onge, Karen W. GrippGrazia M.S. Mancini, Ki Pang, Elizabeth Sweeney, Hilde Van Esch, Nienke Verbeek, Dagmar Wieczorek, Michelle Steinraths, Jacek Majewski, Kym M. Boycott, Daniela T. Pilz, M. Elizabeth Ross, William B. Dobyns, Eamonn G. Sheridan, J. Friedman, J. Michaud, F. Bernier, M. Brudno, B. Fernandez, B. Knoppers, M. Samuels, S. Scherer

Research output: Contribution to journalArticle

67 Scopus citations

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 2 (GSK-3β 2). Mutant CCND2 was resistant to proteasomal degradation in vitro compared to wild-type CCND2. The PI3K-AKT pathway modulates GSK-3β 2 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.

Original languageEnglish (US)
Pages (from-to)510-515
Number of pages6
JournalNature Genetics
Volume46
Issue number5
DOIs
StatePublished - May 2014

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