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. Gripp; Grazia 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

doi:10.1038/ng.2948

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

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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 language	English (US)
Pages (from-to)	510-515
Number of pages	6
Journal	Nature Genetics
Volume	46
Issue number	5
DOIs	https://doi.org/10.1038/ng.2948
State	Published - May 2014
Externally published	Yes

Bibliographical note

Funding Information:
We thank the study patients and their families, without whose participation this work would not be possible. We thank M. O’Driscoll (University of Sussex) for advice and help. This work was funded by the Government of Canada through Genome Canada, the Canadian Institutes of Health Research (CIHR), the Ontario Genomics Institute (OGI-049), Genome Quebec and Genome British Columbia (to K.M.B.). The work was selected for study by the FORGE Canada Steering Committee, consisting of K. Boycott (University of Ottawa), J. Friedman (University of British Columbia), J. Michaud (Université de Montreal), F. Bernier (University of Calgary), M. Brudno (University of Toronto), B. Fernandez (Memorial University), B. Knoppers (McGill University), M. Samuels (Université de Montreal) and S. Scherer (University of Toronto). Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke (NINDS) of the US National Institutes of Health under award numbers P01-NS048120 (to M.E.R.), NRSA F32 NS086173 (to K.A.G.) and R01NS058721 (to W.B.D.), by The Baily Thomas Charitable Fund (to D.T.P.) and by the Sir Jules Thorn Charitable Trust and Great Ormond Street Children’s Hospital Charity (to E.G.S.).

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Mirzaa, G. M., Parry, D. A., Fry, A. E., Giamanco, K. A., Schwartzentruber, J., Vanstone, M., Logan, C. V., Roberts, N., Johnson, C. A., Singh, S., Kholmanskikh, S. S., Adams, C., Hodge, R. D., Hevner, R. F., Bonthron, D. T., Braun, K. P. J., Faivre, L., Rivière, J. B., St-Onge, J., ... Scherer, S. (2014). De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. Nature Genetics, 46(5), 510-515. https://doi.org/10.1038/ng.2948

Mirzaa, GM, 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, JB, St-Onge, J, Gripp, KW, Mancini, GMS, Pang, K, Sweeney, E, Van Esch, H, Verbeek, N, Wieczorek, D, Steinraths, M, Majewski, J, Boycott, KM, Pilz, DT, Ross, ME, Dobyns, WB, Sheridan, EG, Friedman, J, Michaud, J, Bernier, F, Brudno, M, Fernandez, B, Knoppers, B, Samuels, M & Scherer, S 2014, 'De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome', Nature Genetics, vol. 46, no. 5, pp. 510-515. https://doi.org/10.1038/ng.2948

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title = "De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus 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 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.",

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

note = "Funding Information: We thank the study patients and their families, without whose participation this work would not be possible. We thank M. O{\textquoteright}Driscoll (University of Sussex) for advice and help. This work was funded by the Government of Canada through Genome Canada, the Canadian Institutes of Health Research (CIHR), the Ontario Genomics Institute (OGI-049), Genome Quebec and Genome British Columbia (to K.M.B.). The work was selected for study by the FORGE Canada Steering Committee, consisting of K. Boycott (University of Ottawa), J. Friedman (University of British Columbia), J. Michaud (Universit{\'e} de Montreal), F. Bernier (University of Calgary), M. Brudno (University of Toronto), B. Fernandez (Memorial University), B. Knoppers (McGill University), M. Samuels (Universit{\'e} de Montreal) and S. Scherer (University of Toronto). Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke (NINDS) of the US National Institutes of Health under award numbers P01-NS048120 (to M.E.R.), NRSA F32 NS086173 (to K.A.G.) and R01NS058721 (to W.B.D.), by The Baily Thomas Charitable Fund (to D.T.P.) and by the Sir Jules Thorn Charitable Trust and Great Ormond Street Children{\textquoteright}s Hospital Charity (to E.G.S.).",

year = "2014",

month = may,

doi = "10.1038/ng.2948",

language = "English (US)",

volume = "46",

pages = "510--515",

journal = "Nature Genetics",

issn = "1061-4036",

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T1 - De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome

AU - Mirzaa, Ghayda M.

AU - Parry, David A.

AU - Fry, Andrew E.

AU - Giamanco, Kristin A.

AU - Schwartzentruber, Jeremy

AU - Vanstone, Megan

AU - Logan, Clare V.

AU - Roberts, Nicola

AU - Johnson, Colin A.

AU - Singh, Shawn

AU - Kholmanskikh, Stanislav S.

AU - Adams, Carissa

AU - Hodge, Rebecca D.

AU - Hevner, Robert F.

AU - Bonthron, David T.

AU - Braun, Kees P.J.

AU - Faivre, Laurence

AU - Rivière, Jean Baptiste

AU - St-Onge, Judith

AU - Gripp, Karen W.

AU - Mancini, Grazia M.S.

AU - Pang, Ki

AU - Sweeney, Elizabeth

AU - Van Esch, Hilde

AU - Verbeek, Nienke

AU - Wieczorek, Dagmar

AU - Steinraths, Michelle

AU - Majewski, Jacek

AU - Boycott, Kym M.

AU - Pilz, Daniela T.

AU - Ross, M. Elizabeth

AU - Dobyns, William B.

AU - Sheridan, Eamonn G.

AU - Friedman, J.

AU - Michaud, J.

AU - Bernier, F.

AU - Brudno, M.

AU - Fernandez, B.

AU - Knoppers, B.

AU - Samuels, M.

AU - Scherer, S.

N1 - Funding Information: We thank the study patients and their families, without whose participation this work would not be possible. We thank M. O’Driscoll (University of Sussex) for advice and help. This work was funded by the Government of Canada through Genome Canada, the Canadian Institutes of Health Research (CIHR), the Ontario Genomics Institute (OGI-049), Genome Quebec and Genome British Columbia (to K.M.B.). The work was selected for study by the FORGE Canada Steering Committee, consisting of K. Boycott (University of Ottawa), J. Friedman (University of British Columbia), J. Michaud (Université de Montreal), F. Bernier (University of Calgary), M. Brudno (University of Toronto), B. Fernandez (Memorial University), B. Knoppers (McGill University), M. Samuels (Université de Montreal) and S. Scherer (University of Toronto). Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke (NINDS) of the US National Institutes of Health under award numbers P01-NS048120 (to M.E.R.), NRSA F32 NS086173 (to K.A.G.) and R01NS058721 (to W.B.D.), by The Baily Thomas Charitable Fund (to D.T.P.) and by the Sir Jules Thorn Charitable Trust and Great Ormond Street Children’s Hospital Charity (to E.G.S.).

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N2 - 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.

AB - 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.

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

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