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A homozygous loss-of-function camk2a mutation causes growth delay, frequent seizures and severe intellectual disability

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
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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.
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
Source Title
eLife
Publisher
Series/Report No.
Organizational Units
Organizational Unit
MEDICINE
dept
Organizational Unit
PAEDIATRICS
dept
Rights
Attribution 4.0 International
Date
2018
DOI
10.7554/eLife.32451
Type
Article
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