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

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...

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Autores principales: Zech, Michael, Lam, Daniel D., Weber, Sandrina, Berutti, Riccardo, Poláková, Kamila, Havránková, Petra, Fečíková, Anna, Strom, Tim M., Růžička, Evžen, Jech, Robert, Winkelmann, Juliane
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318768/
https://www.ncbi.nlm.nih.gov/pubmed/30262571
http://dx.doi.org/10.1101/mcs.a003293
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author Zech, Michael
Lam, Daniel D.
Weber, Sandrina
Berutti, Riccardo
Poláková, Kamila
Havránková, Petra
Fečíková, Anna
Strom, Tim M.
Růžička, Evžen
Jech, Robert
Winkelmann, Juliane
author_facet Zech, Michael
Lam, Daniel D.
Weber, Sandrina
Berutti, Riccardo
Poláková, Kamila
Havránková, Petra
Fečíková, Anna
Strom, Tim M.
Růžička, Evžen
Jech, Robert
Winkelmann, Juliane
author_sort Zech, Michael
collection PubMed
description 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.
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spelling pubmed-63187682019-01-13 A unique de novo gain-of-function variant in CAMK4 associated with intellectual disability and hyperkinetic movement disorder Zech, Michael Lam, Daniel D. Weber, Sandrina Berutti, Riccardo Poláková, Kamila Havránková, Petra Fečíková, Anna Strom, Tim M. Růžička, Evžen Jech, Robert Winkelmann, Juliane Cold Spring Harb Mol Case Stud Research Article 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. Cold Spring Harbor Laboratory Press 2018-12 /pmc/articles/PMC6318768/ /pubmed/30262571 http://dx.doi.org/10.1101/mcs.a003293 Text en © 2018 Zech et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted reuse and redistribution provided that the original author and source are credited.
spellingShingle Research Article
Zech, Michael
Lam, Daniel D.
Weber, Sandrina
Berutti, Riccardo
Poláková, Kamila
Havránková, Petra
Fečíková, Anna
Strom, Tim M.
Růžička, Evžen
Jech, Robert
Winkelmann, Juliane
A unique de novo gain-of-function variant in CAMK4 associated with intellectual disability and hyperkinetic movement disorder
title A unique de novo gain-of-function variant in CAMK4 associated with intellectual disability and hyperkinetic movement disorder
title_full A unique de novo gain-of-function variant in CAMK4 associated with intellectual disability and hyperkinetic movement disorder
title_fullStr A unique de novo gain-of-function variant in CAMK4 associated with intellectual disability and hyperkinetic movement disorder
title_full_unstemmed A unique de novo gain-of-function variant in CAMK4 associated with intellectual disability and hyperkinetic movement disorder
title_short A unique de novo gain-of-function variant in CAMK4 associated with intellectual disability and hyperkinetic movement disorder
title_sort unique de novo gain-of-function variant in camk4 associated with intellectual disability and hyperkinetic movement disorder
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318768/
https://www.ncbi.nlm.nih.gov/pubmed/30262571
http://dx.doi.org/10.1101/mcs.a003293
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