Role of CAMK2D in neurodevelopment and associated conditions.
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Rigter Pomme M F, de Konink Charlotte, Dunn Matthew J, Proietti Onori Martina, Humberson Jennifer B, Thomas Matthew, Barnes Caitlin, Prada Carlos E, Weaver K Nicole, Ryan Thomas D, Caluseriu Oana, Conway Jennifer, Calamaro Emily, Fong Chin-To, Wuyts Wim, Meuwissen Marije, Hordijk Eva, Jonkers Carsten N, Anderson Lucas, Yuseinova Berfin, Polonia Sarah, Beysen Diane, Stark Zornitza, Savva Elena, Poulton Cathryn, McKenzie Fiona, Bhoj Elizabeth, Bupp Caleb P, Bézieau Stéphane, Mercier Sandra, Blevins Amy, Wentzensen Ingrid M, Xia Fan, Rosenfeld Jill A, Hsieh Tzung-Chien, Krawitz Peter M, Elbracht Miriam, Veenma Danielle C M, Schulman Howard, Stratton Margaret M, Küry Sébastien, van Woerden Geeske M
Аннотация
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.