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

GEM HUGO, Deciphering Developmental Disorders Study, Undiagnosed Diseases Network

Research output: Contribution to journalArticle

15 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 languageEnglish (US)
Pages (from-to)768-788
Number of pages21
JournalAmerican Journal of Human Genetics
Volume101
Issue number5
DOIs
StatePublished - Nov 2 2017

Fingerprint

Intellectual Disability
Protein Kinases
Phosphorylation
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Mutation
Genes
Exome
Calcium-Calmodulin-Dependent Protein Kinases
Neuronal Plasticity
Brain
Human Development
Learning
Proteins

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

GEM HUGO, Deciphering Developmental Disorders Study, & Undiagnosed Diseases Network (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

De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability. / GEM HUGO; Deciphering Developmental Disorders Study; Undiagnosed Diseases Network.

In: American Journal of Human Genetics, Vol. 101, No. 5, 02.11.2017, p. 768-788.

Research output: Contribution to journalArticle

GEM HUGO, Deciphering Developmental Disorders Study & Undiagnosed Diseases Network 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
GEM HUGO, Deciphering Developmental Disorders Study, Undiagnosed Diseases Network. De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability. American Journal of Human Genetics. 2017 Nov 2;101(5):768-788. https://doi.org/10.1016/j.ajhg.2017.10.003
GEM HUGO ; Deciphering Developmental Disorders Study ; Undiagnosed Diseases Network. / De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability. In: American Journal of Human Genetics. 2017 ; Vol. 101, No. 5. pp. 768-788.
@article{d503bfaf5b2d45b5a3fbe40a72aafce7,
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 = "{GEM HUGO} and {Deciphering Developmental Disorders Study} and {Undiagnosed Diseases Network} and 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 Holly Stessman and Aurora Pujol and Ben Distel and Robak, {Laurie A.} and Bernstein, {Jonathan A.} and Denomm{\'e}-Pichon, {Anne Sophie} 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",
year = "2017",
month = "11",
day = "2",
doi = "10.1016/j.ajhg.2017.10.003",
language = "English (US)",
volume = "101",
pages = "768--788",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "5",

}

TY - JOUR

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

AU - GEM HUGO

AU - Deciphering Developmental Disorders Study

AU - Undiagnosed Diseases Network

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

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

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.

UR - http://www.scopus.com/inward/record.url?scp=85033605045&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85033605045&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2017.10.003

DO - 10.1016/j.ajhg.2017.10.003

M3 - Article

VL - 101

SP - 768

EP - 788

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 5

ER -