2. Academic Validation
  3. A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability

A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability

  • Elife. 2018 May 22;7:e32451. doi: 10.7554/eLife.32451.
Poh Hui Chia # 1,  Franklin Lei Zhong # 1 2,  Shinsuke Niwa # 3 4,  Carine Bonnard 1,  Kagistia Hana Utami 5,  Ruizhu Zeng 5,  Hane Lee 6 7,  Ascia Eskin 6 7,  Stanley F Nelson 6 7,  William H Xie 1,  Samah Al-Tawalbeh 8,  Mohammad El-Khateeb 9,  Mohammad Shboul 10,  Mahmoud A Pouladi 5 11,  Mohammed Al-Raqad 8,  Bruno Reversade 1 2 12 13
Affiliations

Affiliations

  • 1 Institute of Medical Biology, Immunos, Singapore.
  • 2 Institute of Molecular and Cell Biology, Proteos, Singapore.
  • 3 Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai, Japan.
  • 4 Graduate School of Life Sciences, Tohoku University, Sendai, Japan.
  • 5 Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore, Singapore.
  • 6 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
  • 7 Department of Human Genetics, David Geffen School of Medicine University of California, Los Angeles, Los Angeles, United States.
  • 8 Queen Rania Paediatric Hospital, King Hussein Medical Centre, Royal Medical Services, Amman, Jordan.
  • 9 National Center for Diabetes, Endocrinology and Genetics, Amman, Jordan.
  • 10 Al-Balqa Applied University, Faculty of Science, Al-Salt, Jordan.
  • 11 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 12 Department of Paediatrics, National University of Singapore, Singapore, Singapore.
  • 13 Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey.
  • # Contributed equally.
PMID: 29784083 DOI: 10.7554/eLife.32451
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, CAMK2AH477Y 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.

Keywords

C. elegans; CAMK2; Mendelian disorder; human; human biology; intellectual disability; medicine; neurological disease; neuroscience; oligomerization; seizures.

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