De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability

Sébastien Küry; Geeske M. van Woerden; Thomas Besnard; Martina Proietti Onori; Xénia Latypova; Meghan C. Towne; Megan T. Cho; Trine E. Prescott; Melissa A. Ploeg; Stephan Sanders; Holly A. F. Stessman; Aurora Pujol; Ben Distel; Laurie A. Robak; Jonathan A. Bernstein; Anne-Sophie Denommé-Pichon; Gaëtan Lesca; Elizabeth A. Sellars; Jonathan Berg; Wilfrid Carré; Øyvind Løvold Busk; Bregje W. M. van Bon; Jeff L. Waugh; Matthew Deardorff; George E. Hoganson; Katherine B. Bosanko; Diana S. Johnson; Tabib Dabir; Øystein Lunde Holla; Ajoy Sarkar; Kristian Tveten; Julitta de Bellescize; Geir J. Braathen; Paulien A. Terhal; Dorothy K. Grange; Arie van Haeringen; Christina Lam; Ghayda Mirzaa; Jennifer Burton; Elizabeth J. Bhoj; Jessica Douglas; Avni B. Santani; Addie I. Nesbitt; Katherine L. Helbig; Marisa V. Andrews; Amber Begtrup; Sha Tang; Koen L. I. van Gassen; Jane Juusola; Kimberly Foss; Gregory M. Enns; Ute Moog; Katrin Hinderhofer; Nagarajan Paramasivam; Sharyn Lincoln; Brandon H. Kusako; Pierre Lindenbaum; Eric Charpentier; Catherine B. Nowak; Elouan Cherot; Thomas Simonet; Claudia A. L. Ruivenkamp; Sihoun Hahn; Catherine A. Brownstein; Fan Xia; Sébastien Schmitt; Wallid deb; Dominique Bonneau; Mathilde Nizon; Delphine Quinquis; Jamel Chelly; Gabrielle Rudolf; Damien Sanlaville; Philippe Parent; Brigitte Gilbert-Dussardier; Annick Toutain; Vernon R. Sutton; Jenny Thies; Lisenka E. L. M. Peart-Vissers; Pierre Boisseau; Marie Vincent; Andreas M. Grabrucker; Christèle Dubourg; Wen-Hann Tan; Nienke E. Verbeek; Martin Granzow; Gijs W. E. Santen; Jay Shendure; Bertrand Isidor; Laurent Pasquier; Richard Redon; Yaping Yang; Matthew W. State; Tjitske Kleefstra; Benjamin Cogné; Slavé Petrovski; Kyle Retterer; Evan E. Eichler; Jill A. Rosenfeld; Pankaj B. Agrawal; Stéphane Bézieau; Sylvie Odent; Ype Elgersma; Sandra Mercier

doi:https://doi.org/10.1016/j.ajhg.2017.10.003

De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability

Sébastien Küry, Geeske M. van Woerden, Thomas Besnard, Martina Proietti Onori, Xénia Latypova, Meghan C. Towne, Megan T. Cho, Trine E. Prescott, Melissa A. Ploeg, Stephan Sanders, Holly A. F. Stessman, Aurora Pujol, Ben Distel, Laurie A. Robak, Jonathan A. Bernstein, Anne-Sophie Denommé-Pichon, Gaëtan Lesca, Elizabeth A. Sellars, Jonathan Berg, Wilfrid CarréØyvind Løvold Busk, Bregje W. M. van Bon, Jeff L. Waugh, Matthew Deardorff, George E. Hoganson, Katherine B. Bosanko, Diana S. Johnson, Tabib Dabir, Øystein Lunde Holla, Ajoy Sarkar, Kristian Tveten, Julitta de Bellescize, Geir J. Braathen, Paulien A. Terhal, Dorothy K. Grange, Arie van Haeringen, Christina Lam, Ghayda Mirzaa, Jennifer Burton, Elizabeth J. Bhoj, Jessica Douglas, Avni B. Santani, Addie I. Nesbitt, Katherine L. Helbig, Marisa V. Andrews, Amber Begtrup, Sha Tang, Koen L. I. van Gassen, Jane Juusola, Kimberly Foss, Gregory M. Enns, Ute Moog, Katrin Hinderhofer, Nagarajan Paramasivam, Sharyn Lincoln, Brandon H. Kusako, Pierre Lindenbaum, Eric Charpentier, Catherine B. Nowak, Elouan Cherot, Thomas Simonet, Claudia A. L. Ruivenkamp, Sihoun Hahn, Catherine A. Brownstein, Fan Xia, Sébastien Schmitt, Wallid deb, Dominique Bonneau, Mathilde Nizon, Delphine Quinquis, Jamel Chelly, Gabrielle Rudolf, Damien Sanlaville, Philippe Parent, Brigitte Gilbert-Dussardier, Annick Toutain, Vernon R. Sutton, Jenny Thies, Lisenka E. L. M. Peart-Vissers, Pierre Boisseau, Marie Vincent, Andreas M. Grabrucker, Christèle Dubourg, Wen-Hann Tan, Nienke E. Verbeek, Martin Granzow, Gijs W. E. Santen, Jay Shendure, Bertrand Isidor, Laurent Pasquier, Richard Redon, Yaping Yang, Matthew W. State, Tjitske Kleefstra, Benjamin Cogné, Slavé Petrovski, Kyle Retterer, Evan E. Eichler, Jill A. Rosenfeld, Pankaj B. Agrawal, Stéphane Bézieau, Sylvie Odent, Ype Elgersma, Sandra Mercier

Research output: Contribution to journal › Article › Academic › peer-review

114 Citations (Scopus)

Abstract

Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway

Original language	English
Pages (from-to)	768-788
Journal	American journal of human genetics
Volume	101
Issue number	5
DOIs	https://doi.org/10.1016/j.ajhg.2017.10.003
Publication status	Published - 2017

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https://doi.org/10.1016/j.ajhg.2017.10.003

Cite this

Küry, S., van Woerden, G. M., Besnard, T., Proietti Onori, M., Latypova, X., Towne, M. C., Cho, M. T., Prescott, T. E., Ploeg, M. A., Sanders, S., Stessman, H. A. F., Pujol, A., Distel, B., Robak, L. A., Bernstein, J. A., Denommé-Pichon, A.-S., Lesca, G., Sellars, E. A., Berg, J., ... Mercier, S. (2017). De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability. American journal of human genetics, 101(5), 768-788. https://doi.org/10.1016/j.ajhg.2017.10.003

@article{8613fe0f0c364392847566acf5875057,

title = "De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability",

abstract = "Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway",

author = "S{\'e}bastien K{\"u}ry and {van Woerden}, {Geeske M.} and Thomas Besnard and {Proietti Onori}, Martina and X{\'e}nia Latypova and Towne, {Meghan C.} and Cho, {Megan T.} and Prescott, {Trine E.} and Ploeg, {Melissa A.} and Stephan Sanders and Stessman, {Holly A. F.} and Aurora Pujol and Ben Distel and Robak, {Laurie A.} and Bernstein, {Jonathan A.} and Anne-Sophie Denomm{\'e}-Pichon and Ga{\"e}tan Lesca and Sellars, {Elizabeth A.} and Jonathan Berg and Wilfrid Carr{\'e} and Busk, {{\O}yvind L{\o}vold} and {van Bon}, {Bregje W. M.} and Waugh, {Jeff L.} and Matthew Deardorff and Hoganson, {George E.} and Bosanko, {Katherine B.} and Johnson, {Diana S.} and Tabib Dabir and Holla, {{\O}ystein Lunde} and Ajoy Sarkar and Kristian Tveten and {de Bellescize}, Julitta and Braathen, {Geir J.} and Terhal, {Paulien A.} and Grange, {Dorothy K.} and {van Haeringen}, Arie and Christina Lam and Ghayda Mirzaa and Jennifer Burton and Bhoj, {Elizabeth J.} and Jessica Douglas and Santani, {Avni B.} and Nesbitt, {Addie I.} and Helbig, {Katherine L.} and Andrews, {Marisa V.} and Amber Begtrup and Sha Tang and {van Gassen}, {Koen L. I.} and Jane Juusola and Kimberly Foss and Enns, {Gregory M.} and Ute Moog and Katrin Hinderhofer and Nagarajan Paramasivam and Sharyn Lincoln and Kusako, {Brandon H.} and Pierre Lindenbaum and Eric Charpentier and Nowak, {Catherine B.} and Elouan Cherot and Thomas Simonet and Ruivenkamp, {Claudia A. L.} and Sihoun Hahn and Brownstein, {Catherine A.} and Fan Xia and S{\'e}bastien Schmitt and Wallid deb and Dominique Bonneau and Mathilde Nizon and Delphine Quinquis and Jamel Chelly and Gabrielle Rudolf and Damien Sanlaville and Philippe Parent and Brigitte Gilbert-Dussardier and Annick Toutain and Sutton, {Vernon R.} and Jenny Thies and Peart-Vissers, {Lisenka E. L. M.} and Pierre Boisseau and Marie Vincent and Grabrucker, {Andreas M.} and Christ{\`e}le Dubourg and Wen-Hann Tan and Verbeek, {Nienke E.} and Martin Granzow and Santen, {Gijs W. E.} and Jay Shendure and Bertrand Isidor and Laurent Pasquier and Richard Redon and Yaping Yang and State, {Matthew W.} and Tjitske Kleefstra and Benjamin Cogn{\'e} and Slav{\'e} Petrovski and Kyle Retterer and Eichler, {Evan E.} and Rosenfeld, {Jill A.} and Agrawal, {Pankaj B.} and St{\'e}phane B{\'e}zieau and Sylvie Odent and Ype Elgersma and Sandra Mercier",

year = "2017",

doi = "https://doi.org/10.1016/j.ajhg.2017.10.003",

language = "English",

volume = "101",

pages = "768--788",

journal = "American journal of human genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "5",

}

Küry, S, van Woerden, GM, Besnard, T, Proietti Onori, M, Latypova, X, Towne, MC, Cho, MT, Prescott, TE, Ploeg, MA, Sanders, S, Stessman, HAF, Pujol, A, Distel, B, Robak, LA, Bernstein, JA, Denommé-Pichon, A-S, Lesca, G, Sellars, EA, Berg, J, Carré, W, Busk, ØL, van Bon, BWM, Waugh, JL, Deardorff, M, Hoganson, GE, Bosanko, KB, Johnson, DS, Dabir, T, Holla, ØL, Sarkar, A, Tveten, K, de Bellescize, J, Braathen, GJ, Terhal, PA, Grange, DK, van Haeringen, A, Lam, C, Mirzaa, G, Burton, J, Bhoj, EJ, Douglas, J, Santani, AB, Nesbitt, AI, Helbig, KL, Andrews, MV, Begtrup, A, Tang, S, van Gassen, KLI, Juusola, J, Foss, K, Enns, GM, Moog, U, Hinderhofer, K, Paramasivam, N, Lincoln, S, Kusako, BH, Lindenbaum, P, Charpentier, E, Nowak, CB, Cherot, E, Simonet, T, Ruivenkamp, CAL, Hahn, S, Brownstein, CA, Xia, F, Schmitt, S, deb, W, Bonneau, D, Nizon, M, Quinquis, D, Chelly, J, Rudolf, G, Sanlaville, D, Parent, P, Gilbert-Dussardier, B, Toutain, A, Sutton, VR, Thies, J, Peart-Vissers, LELM, Boisseau, P, Vincent, M, Grabrucker, AM, Dubourg, C, Tan, W-H, Verbeek, NE, Granzow, M, Santen, GWE, Shendure, J, Isidor, B, Pasquier, L, Redon, R, Yang, Y, State, MW, Kleefstra, T, Cogné, B, Petrovski, S, Retterer, K, Eichler, EE, Rosenfeld, JA, Agrawal, PB, Bézieau, S, Odent, S, Elgersma, Y & Mercier, S 2017, 'De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability', American journal of human genetics, vol. 101, no. 5, pp. 768-788. https://doi.org/10.1016/j.ajhg.2017.10.003

TY - JOUR

T1 - De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability

AU - Küry, Sébastien

AU - van Woerden, Geeske M.

AU - Besnard, Thomas

AU - Proietti Onori, Martina

AU - Latypova, Xénia

AU - Towne, Meghan C.

AU - Cho, Megan T.

AU - Prescott, Trine E.

AU - Ploeg, Melissa A.

AU - Sanders, Stephan

AU - Stessman, Holly A. F.

AU - Pujol, Aurora

AU - Distel, Ben

AU - Robak, Laurie A.

AU - Bernstein, Jonathan A.

AU - Denommé-Pichon, Anne-Sophie

AU - Lesca, Gaëtan

AU - Sellars, Elizabeth A.

AU - Berg, Jonathan

AU - Carré, Wilfrid

AU - Busk, Øyvind Løvold

AU - van Bon, Bregje W. M.

AU - Waugh, Jeff L.

AU - Deardorff, Matthew

AU - Hoganson, George E.

AU - Bosanko, Katherine B.

AU - Johnson, Diana S.

AU - Dabir, Tabib

AU - Holla, Øystein Lunde

AU - Sarkar, Ajoy

AU - Tveten, Kristian

AU - de Bellescize, Julitta

AU - Braathen, Geir J.

AU - Terhal, Paulien A.

AU - Grange, Dorothy K.

AU - van Haeringen, Arie

AU - Lam, Christina

AU - Mirzaa, Ghayda

AU - Burton, Jennifer

AU - Bhoj, Elizabeth J.

AU - Douglas, Jessica

AU - Santani, Avni B.

AU - Nesbitt, Addie I.

AU - Helbig, Katherine L.

AU - Andrews, Marisa V.

AU - Begtrup, Amber

AU - Tang, Sha

AU - van Gassen, Koen L. I.

AU - Juusola, Jane

AU - Foss, Kimberly

AU - Enns, Gregory M.

AU - Moog, Ute

AU - Hinderhofer, Katrin

AU - Paramasivam, Nagarajan

AU - Lincoln, Sharyn

AU - Kusako, Brandon H.

AU - Lindenbaum, Pierre

AU - Charpentier, Eric

AU - Nowak, Catherine B.

AU - Cherot, Elouan

AU - Simonet, Thomas

AU - Ruivenkamp, Claudia A. L.

AU - Hahn, Sihoun

AU - Brownstein, Catherine A.

AU - Xia, Fan

AU - Schmitt, Sébastien

AU - deb, Wallid

AU - Bonneau, Dominique

AU - Nizon, Mathilde

AU - Quinquis, Delphine

AU - Chelly, Jamel

AU - Rudolf, Gabrielle

AU - Sanlaville, Damien

AU - Parent, Philippe

AU - Gilbert-Dussardier, Brigitte

AU - Toutain, Annick

AU - Sutton, Vernon R.

AU - Thies, Jenny

AU - Peart-Vissers, Lisenka E. L. M.

AU - Boisseau, Pierre

AU - Vincent, Marie

AU - Grabrucker, Andreas M.

AU - Dubourg, Christèle

AU - Tan, Wen-Hann

AU - Verbeek, Nienke E.

AU - Granzow, Martin

AU - Santen, Gijs W. E.

AU - Shendure, Jay

AU - Isidor, Bertrand

AU - Pasquier, Laurent

AU - Redon, Richard

AU - Yang, Yaping

AU - State, Matthew W.

AU - Kleefstra, Tjitske

AU - Cogné, Benjamin

AU - Petrovski, Slavé

AU - Retterer, Kyle

AU - Eichler, Evan E.

AU - Rosenfeld, Jill A.

AU - Agrawal, Pankaj B.

AU - Bézieau, Stéphane

AU - Odent, Sylvie

AU - Elgersma, Ype

AU - Mercier, Sandra

PY - 2017

Y1 - 2017

N2 - Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway

AB - Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway

U2 - https://doi.org/10.1016/j.ajhg.2017.10.003

DO - https://doi.org/10.1016/j.ajhg.2017.10.003

M3 - Article

C2 - 29100089

SN - 0002-9297

VL - 101

SP - 768

EP - 788

JO - American journal of human genetics

JF - American journal of human genetics

IS - 5

ER -