De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome.
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.
Department of Pediatrics, University of Washington; and Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA.
Ghayda
G
Mirzaa
Leeds Institute of Biomedical and Clinical Science, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, UK.
David A
DA
Parry
Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.
Andrew E
AE
Fry
Neurogenetics and Development, Feil Family Brain and Mind Research institute, Weill Cornell Medical College, New York, NY.
Kristin A
KA
Giamanco
Mcgill University and Genome Quebec Innovation centre, Montreal, QC H3A 1A4, Canada.
Jeremy
J
Schwartzentruber
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Megan
M
Vanstone
Leeds Institute of Biomedical and Clinical Science, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, UK.
Clare V
CV
Logan
Leeds Institute of Biomedical and Clinical Science, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, UK.
Nicola
N
Roberts
Leeds Institute of Biomedical and Clinical Science, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, UK.
Colin A
CA
Johnson
Neurogenetics and Development, Feil Family Brain and Mind Research institute, Weill Cornell Medical College, New York, NY.
Shawn
S
Singh
Neurogenetics and Development, Feil Family Brain and Mind Research institute, Weill Cornell Medical College, New York, NY.
Stanislav S
SS
Kholmanskikh
Department of Pediatrics, University of Washington; and Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA.
Carissa
C
Adams
Department of Pediatrics, University of Washington; and Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA.
Rebecca D
RD
Hodge
Departments of Neurological Surgery and Pathology, University of Washington; and Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle.
Robert F
RF
Hevner
Leeds Institute of Biomedical and Clinical Science, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, UK.
David T
DT
Bonthron
Department of Child Neurology, UMC Utrecht, Utrecht, The Netherlands.
Kees P J
KPJ
Braun
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.
Laurence
L
Faivre
Université de Bourgogne Equipe GAD, EA 4271 Dijon F-21000 France.
Jean-Baptiste
JB
Rivière
Université de Bourgogne Equipe GAD, EA 4271 Dijon F-21000 France.
Judith
J
St-Onge
Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, Delaware.
Karen W
KW
Gripp
Department of Clinical Genetics and Expertise Centre for Neurodevelopmental Disorders, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
Grazia Ms
GM
Mancini
Department of Paediatric Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
Ki
K
Pang
Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, UK.
Elizabeth
E
Sweeney
Centre for Human Genetics, University Hospital Gasthuisberg, Herestraat, Leuven, Belgium.
Hilde
H
van Esch
Department of Medical Genetics, UMC Utrecht, Utrecht, The Netherlands.
Nienke
N
Verbeek
Institut fur Humangenetik, Universitatsklinikum Essen, Essen, Germany.
Dagmar
D
Wieczorek
Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Michelle
M
Steinraths
Mcgill University and Genome Quebec Innovation centre, Montreal, QC H3A 1A4, Canada.
Jacek
J
Majewski
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Kym M
KM
Boycot
Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.
Daniela T
DT
Pilz
Neurogenetics and Development, Feil Family Brain and Mind Research institute, Weill Cornell Medical College, New York, NY.
M Elizabeth
ME
Ross
Department of Pediatrics, University of Washington; and Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA.
William B
WB
Dobyns
Leeds Institute of Biomedical and Clinical Science, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, UK.
Eamonn G
EG
Sheridan
D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D056742:Cyclin D2 / Q000235:genetics*; D018274:Electroporation; D059472:Exome / Q000235:genetics; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D006849:Hydrocephalus / Q000235:genetics*; D007150:Immunohistochemistry; D054220:Malformations of Cortical Development / Q000235:genetics*; D058627:Megalencephaly / Q000235:genetics*; D051379:Mice; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017689:Polydactyly / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013577:Syndrome
C080336:CCND2 protein, human; D056742:Cyclin D2; D001973:Bromodeoxyuridine