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A Novel Strategy Combining Array-CGH, Whole-exome Sequencing and In Utero Electroporation in Rodents to Identify Causative Genes for Brain Malformations
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De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability

Sébastien Küry1, Geeske M van Woerden2, Thomas Besnard1

  • 1CHU Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093 Nantes Cedex 1, France.

American Journal of Human Genetics
|November 4, 2017
PubMed

Insights

Rare genetic variants in CAMK2A and CAMK2B genes are linked to intellectual disability in humans. These mutations disrupt Calcium/calmodulin-dependent protein kinase II (CAMK2) auto-phosphorylation, impacting neuronal migration and brain development.

Area of Science:

  • Neuroscience
  • Human Genetics
  • Molecular Biology

Background:

  • Calcium/calmodulin-dependent protein kinase II (CAMK2) is crucial for learning and synaptic plasticity in mice.
  • Its role in human brain development and intellectual disability remains largely unestablished.

Purpose of the Study:

  • To investigate the role of CAMK2A and CAMK2B variants in human intellectual disability.
  • To assess the impact of these variants on CAMK2 function and neuronal migration.

Main Methods:

  • Whole-exome sequencing in a multi-center collaborative study.
  • Identification and functional assessment of rare de novo CAMK2A/CAMK2B variants.
  • Evaluation of CAMK2 auto-phosphorylation and neuronal migration.

Main Results:

  • Identified 19 rare de novo variants in CAMK2A or CAMK2B in 24 individuals with intellectual disability.
  • Mutations were found to alter CAMK2 auto-phosphorylation (Thr286/Thr287) in both activating and inhibitory ways.
  • All identified mutations affecting auto-phosphorylation also impaired neuronal migration.

Conclusions:

  • Establishes the critical role of CAMK2A and CAMK2B auto-phosphorylation in human brain function and neurodevelopment.
  • Expands the known phenotypic spectrum of disorders associated with variants in glutamatergic signaling pathway components.
  • Highlights CAMK2 auto-phosphorylation as a key regulatory mechanism in neuronal development.
Keywords:
AMPARCAMK2CAMK2ACAMK2BNMDARde novo mutationsintellectual disabilitysynaptic plasticity

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