Role of CAMK2D in neurodevelopment and associated conditions

基因亚型 神经发育障碍 损失函数 心肌病 同工酶 智力残疾 扩张型心肌病 基因 生物 遗传学 神经科学 医学 表型 内科学 心力衰竭 生物化学
作者
Pomme M.F. Rigter,Charlotte de Konink,Matthew J. Dunn,Martina Proietti Onori,Jennifer Humberson,Matthew Thomas,Caitlin Barnes,Carlos E. Prada,K. Nicole Weaver,Thomas Ryan,Oana Caluseriu,Jennifer Conway,Emily Calamaro,Chin‐To Fong,Wim Wuyts,Marije Meuwissen,Eva Hordijk,Carsten N. Jonkers,Lucas A. Anderson,Berfin Yuseinova,Sarah Polonia,Diane Beysen,Zornitza Stark,Elena Savva,Cathryn Poulton,F. Ellis McKenzie,Elizabeth Bhoj,Caleb Bupp,Stéphane Bézieau,Sandra Mercier,Amy Blevins,Ingrid M. Wentzensen,Fan Xia,Jill A. Rosenfeld,Tzung‐Chien Hsieh,Peter Krawitz,Miriam Elbracht,Danielle Veenma,Howard Schulman,Margaret M. Stratton,Sébastien Küry,Geeske M. van Woerden
出处
期刊:American Journal of Human Genetics [Elsevier BV]
卷期号:111 (2): 364-382 被引量:3
标识
DOI:10.1016/j.ajhg.2023.12.016
摘要

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.
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