Please use this identifier to cite or link to this item: https://doi.org/10.7554/eLife.32451
Title: A homozygous loss-of-function camk2a mutation causes growth delay, frequent seizures and severe intellectual disability
Authors: Chia, P.H
Zhong, F.L
Niwa, S
Bonnard, C
Utami, K.H
Zeng, R
Lee, H
Eskin, A
Nelson, S.F
Xie, W.H
Al-Tawalbeh, S
El-Khateeb, M
Shboul, M
Pouladi, M.A 
Al-Raqad, M
Reversade, B 
Keywords: calcium calmodulin dependent protein kinase II
histone
protein
protein unc 43
tyrosine
unclassified drug
calcium calmodulin dependent protein kinase II
CAMK2A protein, human
animal experiment
animal model
Article
Caenorhabditis elegans
case report
chromosome 5q
clinical article
consanguineous marriage
controlled study
convulsion
developmental delay
firing rate
germline mutation
growth disorder
homozygote
human
human cell
induced pluripotent stem cell
intellectual impairment
loss of function mutation
missense mutation
myoclonus seizure
nonhuman
protein function
protein localization
seizure
synapse
whole exome sequencing
chromosome 5
consanguinity
developmental disorder
DNA sequence
family health
genetic linkage
genetics
intellectual impairment
Jordan
seizure
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Chromosomes, Human, Pair 5
Consanguinity
Developmental Disabilities
Family Health
Genetic Linkage
Homozygote
Humans
Intellectual Disability
Jordan
Loss of Function Mutation
Mutation, Missense
Seizures
Sequence Analysis, DNA
Issue Date: 2018
Citation: Chia, P.H, Zhong, F.L, Niwa, S, Bonnard, C, Utami, K.H, Zeng, R, Lee, H, Eskin, A, Nelson, S.F, Xie, W.H, Al-Tawalbeh, S, El-Khateeb, M, Shboul, M, Pouladi, M.A, Al-Raqad, M, Reversade, B (2018). A homozygous loss-of-function camk2a mutation causes growth delay, frequent seizures and severe intellectual disability. eLife 7 : e32451. ScholarBank@NUS Repository. https://doi.org/10.7554/eLife.32451
Rights: Attribution 4.0 International
Abstract: Calcium/calmodulin-dependent protein kinase II (CAMK2) plays fundamental roles in synaptic plasticity that underlies learning and memory. Here, we describe a new recessive neurodevelopmental syndrome with global developmental delay, seizures and intellectual disability. Using linkage analysis and exome sequencing, we found that this disease maps to chromosome 5q31.1-q34 and is caused by a biallelic germline mutation in CAMK2A. The missense mutation, p. His477Tyr is located in the CAMK2A association domain that is critical for its function and localization. Biochemically, the p.His477Tyr mutant is defective in self-oligomerization and unable to assemble into the multimeric holoenzyme.In vivo, CAMK2A H477Y failed to rescue neuronal defects in C. elegans lacking unc-43, the ortholog of human CAMK2A. In vitro, neurons derived from patient iPSCs displayed profound synaptic defects. Together, our data demonstrate that a recessive germline mutation in CAMK2A leads to neurodevelopmental defects in humans and suggest that dysfunctional CAMK2 paralogs may contribute to other neurological disorders. © Chia et al.
Source Title: eLife
URI: https://scholarbank.nus.edu.sg/handle/10635/177855
ISSN: 2050084X
DOI: 10.7554/eLife.32451
Rights: Attribution 4.0 International
Appears in Collections:Staff Publications
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