A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability
| Title: | A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability |
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| 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 |
| Source: | eLife, Vol 7 (2018) |
| Publisher Information: | eLife Sciences Publications Ltd, 2018. |
| Publication Year: | 2018 |
| Collection: | LCC:Medicine LCC:Science LCC:Biology (General) |
| Subject Terms: | neurological disease, Mendelian disorder, oligomerization, intellectual disability, seizures, CAMK2, Medicine, Science, Biology (General), QH301-705.5 |
| More Details: | 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. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 2050-084X |
| Relation: | https://elifesciences.org/articles/32451; https://doaj.org/toc/2050-084X |
| DOI: | 10.7554/eLife.32451 |
| Access URL: | https://doaj.org/article/db6a2998912a4cdc9e37796ad1f08f29 |
| Accession Number: | edsdoj.b6a2998912a4cdc9e37796ad1f08f29 |
| Database: | Directory of Open Access Journals |
| ISSN: | 2050084X |
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| DOI: | 10.7554/eLife.32451 |
| Published in: | eLife |
| Language: | English |