Institute of Medical Biology, Immunos, Singapore; Institute of Molecular and Cell Biology, Proteos, Singapore
Shinsuke Niwa
Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai, Japan; Graduate School of Life Sciences, Tohoku University, Sendai, Japan
Carine Bonnard
Institute of Medical Biology, Immunos, Singapore
Kagistia Hana Utami
Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore, Singapore
Ruizhu Zeng
Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore, Singapore
Hane Lee
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States; Department of Human Genetics, David Geffen School of Medicine University of California, Los Angeles, Los Angeles, United States
Ascia Eskin
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States; Department of Human Genetics, David Geffen School of Medicine University of California, Los Angeles, Los Angeles, United States
Stanley F Nelson
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States; Department of Human Genetics, David Geffen School of Medicine University of California, Los Angeles, Los Angeles, United States
William H Xie
Institute of Medical Biology, Immunos, Singapore
Samah Al-Tawalbeh
Queen Rania Paediatric Hospital, King Hussein Medical Centre, Royal Medical Services, Amman, Jordan
Mohammad El-Khateeb
National Center for Diabetes, Endocrinology and Genetics, Amman, Jordan
Mohammad Shboul
Al-Balqa Applied University, Faculty of Science, Al-Salt, Jordan
Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
Mohammed Al-Raqad
Queen Rania Paediatric Hospital, King Hussein Medical Centre, Royal Medical Services, Amman, Jordan
Institute of Medical Biology, Immunos, Singapore; Institute of Molecular and Cell Biology, Proteos, Singapore; Department of Paediatrics, National University of Singapore, Singapore, Singapore; Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey
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.
