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; Jan-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; Nienke E Verbeek

doi: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, Jan-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, Nienke E Verbeek,

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

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
Number of pages	21
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 - 2 Nov 2017

Keywords

AMPAR
CAMK2
CAMK2A
CAMK2B
NMDAR
de novo mutations
synaptic plasticity
intellectual disability

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10.1016/j.ajhg.2017.10.003

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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, J.-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. (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{d29f513248674ef0b89149ef3817a0de,

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.",

keywords = " AMPAR, CAMK2, CAMK2A, CAMK2B, NMDAR, de novo mutations, synaptic plasticity, intellectual disability",

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 Jan-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 Verbeek, {Nienke E}",

note = "Publisher Copyright: {\textcopyright} 2017 American Society of Human Genetics",

year = "2017",

month = nov,

day = "2",

doi = "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",

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Küry, S, van Woerden, GM, Besnard, T, Proietti Onori, M, Latypova, X, Towne, MC, Cho, MT, Prescott, TE, Ploeg, MA, Sanders, J-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, Verbeek, NE 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, Jan-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 - Verbeek, Nienke E

PY - 2017/11/2

Y1 - 2017/11/2

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.

KW - AMPAR

KW - CAMK2

KW - CAMK2A

KW - CAMK2B

KW - NMDAR

KW - de novo mutations

KW - synaptic plasticity

KW - intellectual disability

U2 - 10.1016/j.ajhg.2017.10.003

DO - 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 -

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

Abstract

Keywords

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