A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability
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 ex...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2018-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/32451 |
| _version_ | 1811181057294204928 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Poh Hui Chia |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T09:13:15Z |
| format | Article |
| id | doaj.art-db6a2998912a4cdc9e37796ad1f08f29 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:13:15Z |
| publishDate | 2018-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-db6a2998912a4cdc9e37796ad1f08f292022-12-22T04:32:26ZengeLife Sciences Publications LtdeLife2050-084X2018-05-01710.7554/eLife.32451A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disabilityPoh Hui Chia0https://orcid.org/0000-0001-8070-112XFranklin Lei Zhong1https://orcid.org/0000-0002-0516-6021Shinsuke Niwa2Carine Bonnard3Kagistia Hana Utami4Ruizhu Zeng5Hane Lee6Ascia Eskin7Stanley F Nelson8William H Xie9Samah Al-Tawalbeh10Mohammad El-Khateeb11Mohammad Shboul12Mahmoud A Pouladi13https://orcid.org/0000-0002-9030-0976Mohammed Al-Raqad14Bruno Reversade15https://orcid.org/0000-0002-4070-7997Institute of Medical Biology, Immunos, SingaporeInstitute of Medical Biology, Immunos, Singapore; Institute of Molecular and Cell Biology, Proteos, SingaporeFrontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai, Japan; Graduate School of Life Sciences, Tohoku University, Sendai, JapanInstitute of Medical Biology, Immunos, SingaporeTranslational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore, SingaporeTranslational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore, SingaporeDepartment 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 StatesDepartment 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 StatesDepartment 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 StatesInstitute of Medical Biology, Immunos, SingaporeQueen Rania Paediatric Hospital, King Hussein Medical Centre, Royal Medical Services, Amman, JordanNational Center for Diabetes, Endocrinology and Genetics, Amman, JordanAl-Balqa Applied University, Faculty of Science, Al-Salt, JordanTranslational 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, SingaporeQueen Rania Paediatric Hospital, King Hussein Medical Centre, Royal Medical Services, Amman, JordanInstitute 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, TurkeyCalcium/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.https://elifesciences.org/articles/32451neurological diseaseMendelian disorderoligomerizationintellectual disabilityseizuresCAMK2 |
| spellingShingle | 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 A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability eLife neurological disease Mendelian disorder oligomerization intellectual disability seizures CAMK2 |
| title | A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability |
| title_full | A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability |
| title_fullStr | A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability |
| title_full_unstemmed | A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability |
| title_short | A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability |
| title_sort | homozygous loss of function camk2a mutation causes growth delay frequent seizures and severe intellectual disability |
| topic | neurological disease Mendelian disorder oligomerization intellectual disability seizures CAMK2 |
| url | https://elifesciences.org/articles/32451 |
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