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

• DOI: 10.7554/elife.32451
• Publication Date: 2018-05-22T00:00:55Z
• Authors: Poh Hui Chia; Franklin Lei Zhong; Shinsuke Niwa; Carine Bonnard; Kagistia Hana Utami; Ruizhu Zeng; Hane Lee; Ascia Eskin; Stanley F Nelson; William H Xie; Samah Al-Tawalbeh; Mohammad El-Khateeb; Mohammad Shboul; Mahmoud A Pouladi; Mohammed Al-Raqad; Bruno Reversade
• Keywords: Exome; Loss function

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 intellectual disability. Using linkage analysis exome sequencing, found this disease maps to chromosome 5q31.1-q34 is caused by biallelic germline mutation CAMK2A . The missense mutation, p.His477Tyr located the association domain critical for its function localization. Biochemically, mutant defective self-oligomerization unable assemble into multimeric holoenzyme. In vivo , H477Y failed rescue neuronal defects C. elegans lacking unc-43 ortholog of human CAMK2A. vitro neurons derived from patient iPSCs displayed profound defects. Together, our data demonstrate leads humans suggest dysfunctional CAMK2 paralogs may contribute other neurological disorders.