The intellectual disability-associated CAMK2G p.Arg292Pro mutation acts as a pathogenic gain-of-function.
Hum Mutat
; 39(12): 2008-2024, 2018 12.
Article
en En
| MEDLINE
| ID: mdl-30184290
ABSTRACT
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina
/
Mutación con Ganancia de Función
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Discapacidad Intelectual
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Animals
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Female
/
Humans
/
Male
Idioma:
En
Revista:
Hum Mutat
Asunto de la revista:
GENETICA MEDICA
Año:
2018
Tipo del documento:
Article
País de afiliación:
Países Bajos