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Article

A de novo GRIA3 variant with complex hyperkinetic movement disorder in a girl with developmental delay and self-limited epilepsy

Necpál, Ján
Author Necpál, Ján 2nd Department of Neurology, Faculty of Medicine, Comenius University, Bratislava, Slovakia Department of Neurology, Zvolen Hospital, Zvolen, Slovakia. Electronic address: necpal.neuro@gmail.com
Winkelmann, Juliane
Author Winkelmann, Juliane Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, Germany Lehrstuhl für Neurogenetik, Technische Universität München, Munich, Germany Munich Cluster for Systems Neurology, SyNergy, Munich, Germany
Zech, Michael
Author Zech, Michael Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, Germany
Jech, Robert
Author Jech, Robert Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic

Parkinsonism & related disorders. 2023 ; 111 (-) : 105437. [pub] 20230505

Parkinsonism Relat Disord
ISSN 1873-5126
Medvik
Source

MeSH
Epilepsy * genetics MeSH
Attention Deficit Disorder with Hyperactivity * MeSH
Hyperkinesis genetics MeSH
Humans MeSH
Check Tag
Humans MeSH
Female MeSH
Publication type
Letter MeSH
Research Support, Non-U.S. Gov't MeSH

Online article

A unique de novo gain-of-function variant in CAMK4 associated with intellectual disability and hyperkinetic movement disorder

Cold Spring Harbor molecular case studies. 2018 ; 4 (6) : . [pub] 20181217

Cold Spring Harb Mol Case Stud
ISSN 2373-2873 (online)
Medvik
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Calcium/calmodulin-dependent protein kinases (CaMKs) are key mediators of calcium signaling and underpin neuronal health. Although widely studied, the contribution of CaMKs to Mendelian disease is rather enigmatic. Here, we describe an unusual neurodevelopmental phenotype, characterized by milestone delay, intellectual disability, autism, ataxia, and mixed hyperkinetic movement disorder including severe generalized dystonia, in a proband who remained etiologically undiagnosed despite exhaustive testing. We performed trio whole-exome sequencing to identify a de novo essential splice-site variant (c.981+1G>A) in CAMK4, encoding CaMKIV. Through in silico evaluation and cDNA analyses, we demonstrated that c.981+1G>A alters CAMK4 pre-mRNA processing and results in a stable mRNA transcript containing a 77-nt out-of-frame deletion and a premature termination codon within the last exon. The expected protein, p.Lys303Serfs*28, exhibits selective loss of the carboxy-terminal regulatory domain of CaMKIV and bears striking structural resemblance to previously reported synthetic mutants that confer constitutive CaMKIV activity. Biochemical studies in proband-derived cells confirmed an activating effect of c.981+1G>A and indicated that variant-induced excessive CaMKIV signaling is sensitive to pharmacological manipulation. Additionally, we found that variants predicted to cause selective depletion of CaMKIV's regulatory domain are unobserved in diverse catalogs of human variation, thus revealing that c.981+1G>A is a unique molecular event. We propose that our proband's phenotype is explainable by a dominant CAMK4 splice-disrupting mutation that acts through a gain-of-function mechanism. Our findings highlight the importance of CAMK4 in human neurodevelopment, provide a foundation for future clinical research of CAMK4, and suggest the CaMKIV signaling pathway as a potential drug target in neurological disease.