6533b829fe1ef96bd128af73
RESEARCH PRODUCT
De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome
Ghayda M MirzaaDavid A ParryAndrew E FryKristin A GiamancoJeremy SchwartzentruberMegan VanstoneClare V. LoganNicola RobertsColin A. JohnsonShawn SinghStanislav S. KholmanskikhCarissa AdamsRebecca D. HodgeRobert F. HevnerDavid T. BonthronKees P J BraunLaurence FaivreJean-baptiste RivièreJudith St-ongeKaren W. GrippGrazia M S ManciniKi PangElizabeth SweeneyHilde Van EschNienke VerbeekDagmar WieczorekMichelle SteinrathsJacek MajewskiKim M. BoycottDaniela T. PilzElizabeth RossWilliam B. DobynsEamonn G. SheridanJ. FriedmanJ. MichaudF. BernierM. BrudnoB. FernandezB. KnoppersM. SamuelsS. Scherersubject
endocrine systemBlotting WesternMolecular Sequence DataMutantMedizinBiologymedicine.disease_causeArticleAKT3Mice03 medical and health sciences0302 clinical medicineCyclin D2GSK-3GeneticsmedicineAnimalsCyclin D2HumansAbnormalities MultipleExomeMegalencephalyPI3K/AKT/mTOR pathway030304 developmental biology0303 health sciencesMutationBase SequenceSequence Analysis DNASyndromeCell cyclemedicine.diseaseImmunohistochemistryMolecular biologyMegalencephalyMalformations of Cortical DevelopmentPolydactylyElectroporationHEK293 CellsBromodeoxyuridineMicroscopy FluorescenceMutagenesis Site-DirectedFemale030217 neurology & neurosurgeryHydrocephalusdescription
Activating mutations in genes encoding phosphatidylinositol 3-kinase (PI3K)-AKT pathway components cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH, OMIM 603387)(1-3). 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 313 (GSK-3 beta)(4). Mutant CCND2 was resistant to proteasomal degradation in vitro compared to wild-type CCND2. The PI3K-AKT pathway modulates GSK-3 beta activity(4), 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2014-05-31 | Nature Genetics |