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The intellectual disability‐associated CAMK2G p.Arg292Pro mutation acts as a pathogenic gain‐of‐function
Author(s) -
Proietti Onori Martina,
Koopal Balwina,
Everman David B.,
Worthington Jessica D.,
Jones Julie R.,
Ploeg Melissa A.,
Mientjes Edwin,
Bon Bregje W.,
Kleefstra Tjitske,
Schulman Howard,
Kushner Steven A.,
Küry Sébastien,
Elgersma Ype,
Woerden Geeske M.
Publication year - 2018
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23647
Subject(s) - biology , mutation , gene isoform , gene knockdown , gene silencing , phosphorylation , kinase , genetics , microbiology and biotechnology , gene
The abundantly expressed calcium/calmodulin‐dependent protein kinase II (CAMK2), alpha (CAMK2A), and beta (CAMK2B) isoforms are essential for learning and memory formation. Recently, a de novo candidate mutation (p.Arg292Pro) in the gamma isoform of CAMK2 (CAMK2G) was identified in a patient with severe intellectual disability (ID), but the mechanism(s) by which this mutation causes ID is unknown. Here, we identified a second, unrelated individual, with a de novo CAMK2G p.Arg292Pro mutation, and used in vivo and in vitro assays to assess the impact of this mutation on CAMK2G and neuronal function. We found that knockdown of CAMK2G results in inappropriate precocious neuronal maturation. We further found that the CAMK2G p.Arg292Pro mutation acts as a highly pathogenic gain‐of‐function mutation, leading to increased phosphotransferase activity and impaired neuronal maturation as well as impaired targeting of the nuclear CAMK2G isoform. Silencing the catalytic site of the CAMK2G p.Arg292Pro protein reversed the pathogenic effect of the p.Arg292Pro mutation on neuronal maturation, without rescuing its nuclear targeting. Taken together, our results reveal an indispensable function of CAMK2G in neurodevelopment and indicate that the CAMK2G p.Arg292Pro protein acts as a pathogenic gain‐of‐function mutation, through constitutive activity toward cytosolic targets, rather than impaired targeting to the nucleus.