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Published on: May 12, 2015
Role of CAMK2D in neurodevelopment and associated conditions
Pomme M F Rigter1, Charlotte de Konink2, Matthew J Dunn3
1Department of Clinical Genetics, Erasmus Medical Center, Rotterdam 3015 GD, the Netherlands; ENCORE Expertise Centre for Neurodevelopmental Disorders, Erasmus Medical Center, Rotterdam 3015 GD, the Netherlands.
Abstract:
The calcium/calmodulin-dependent protein kinase type 2 (CAMK2) family consists of four different isozymes, encoded by four different genes-CAMK2A, CAMK2B, CAMK2G, and CAMK2D-of which the first three have been associated recently with neurodevelopmental disorders. CAMK2D is one of the major CAMK2 proteins expressed in the heart and has been associated with cardiac anomalies. Although this CAMK2 isoform is also known to be one of the major CAMK2 subtypes expressed during early brain development, it has never been linked with neurodevelopmental disorders until now. Here we show that CAMK2D plays an important role in neurodevelopment not only in mice but also in humans. We identified eight individuals harboring heterozygous variants in CAMK2D who display symptoms of intellectual disability, delayed speech, behavioral problems, and dilated cardiomyopathy. The majority of the variants tested lead to a gain of function (GoF), which appears to cause both neurological problems and dilated cardiomyopathy. In contrast, loss-of-function (LoF) variants appear to induce only neurological symptoms. Together, we describe a cohort of individuals with neurodevelopmental disorders and cardiac anomalies, harboring pathogenic variants in CAMK2D, confirming an important role for the CAMK2D isozyme in both heart and brain function.
Insights
Calcium/calmodulin-dependent protein kinase type 2 D (CAMK2D) variants are linked to neurodevelopmental disorders and cardiac issues. Gain-of-function variants cause both, while loss-of-function variants affect only neurological symptoms.
Area of Science:
- Neuroscience
- Genetics
- Cardiology
Background:
- The calcium/calmodulin-dependent protein kinase type 2 (CAMK2) family has four isozymes (CAMK2A, CAMK2B, CAMK2G, CAMK2D).
- CAMK2A, CAMK2B, and CAMK2G are linked to neurodevelopmental disorders.
- CAMK2D is prominent in the heart and brain, associated with cardiac anomalies, but not previously with neurodevelopmental disorders.
Purpose of the Study:
- To investigate the role of CAMK2D in neurodevelopment.
- To identify genetic variants in CAMK2D associated with neurodevelopmental disorders and cardiac anomalies.
Main Methods:
- Genetic analysis of eight individuals with neurodevelopmental symptoms and dilated cardiomyopathy.
- Functional assessment of identified CAMK2D variants (gain-of-function and loss-of-function).
Main Results:
- Eight individuals with heterozygous CAMK2D variants presented with intellectual disability, speech delay, behavioral issues, and dilated cardiomyopathy.
- Most variants resulted in a gain-of-function (GoF) phenotype, causing both neurological and cardiac problems.
- Loss-of-function (LoF) variants were associated solely with neurological symptoms.
Conclusions:
- CAMK2D plays a critical role in both human brain and heart development.
- Pathogenic CAMK2D variants are associated with a spectrum of neurodevelopmental disorders and cardiac anomalies.
- The type of CAMK2D variant (GoF vs. LoF) influences the resulting clinical presentation.
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