TY - JOUR TI - A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability AU - Chia, Poh Hui AU - Zhong, Franklin Lei AU - Niwa, Shinsuke AU - Bonnard, Carine AU - Utami, Kagistia Hana AU - Zeng, Ruizhu AU - Lee, Hane AU - Eskin, Ascia AU - Nelson, Stanley F AU - Xie, William H AU - Al-Tawalbeh, Samah AU - El-Khateeb, Mohammad AU - Shboul, Mohammad AU - Pouladi, Mahmoud A AU - Al-Raqad, Mohammed AU - Reversade, Bruno A2 - Majumder, Partha VL - 7 PY - 2018 DA - 2018/05/22 SP - e32451 C1 - eLife 2018;7:e32451 DO - 10.7554/eLife.32451 UR - https://doi.org/10.7554/eLife.32451 AB - 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. KW - neurological disease KW - Mendelian disorder KW - oligomerization KW - intellectual disability KW - seizures KW - CAMK2 JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -