Rare functional missense variants in CACNA1H
| Autor: | Ivana A. Souza, Miaozhen Huang, Fang-Xiong Zhang, Richard J. Sinke, Tjerk J. Lagrand, Dineke S. Verbeek, Johannes H. T. M. Koelman, Marina A. J. Tijssen, Gerald W. Zamponi, Justus L. Groen, Maria A. Gandini, Noam Adir, Esther A. R. Nibbeling |
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| Přispěvatelé: | Neurology, Amsterdam Neuroscience - Neurodegeneration, Movement Disorder (MD), Molecular Neuroscience and Ageing Research (MOLAR) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Candidate gene Mutation Missense lcsh:RC346-429 Micro Report Calcium Channels T-Type 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Structural and functional analysis Chromosome Segregation medicine CACNA1H Humans Missense mutation Genetic Predisposition to Disease Molecular Biology Gene Exome sequencing lcsh:Neurology. Diseases of the nervous system 030304 developmental biology Dystonia Genetics 0303 health sciences biology Writer's cramp Rare variants Focal dystonia medicine.disease Pedigree Writer’s cramp Phenotype Dystonic Disorders biology.protein Female 030217 neurology & neurosurgery |
| Zdroj: | Molecular Brain, Vol 14, Iss 1, Pp 1-4 (2021) Molecular Brain Molecular Brain, 14(1):18. BioMed Central Ltd. Molecular brain, 14(1):18, 1-4. BMC Molecular Brain, 14(1). BMC |
| ISSN: | 1756-6606 |
| Popis: | Writer’s cramp (WC) is a task-specific focal dystonia that occurs selectively in the hand and arm during writing. Previous studies have shown a role for genetics in the pathology of task-specific focal dystonia. However, to date, no causal gene has been reported for task-specific focal dystonia, including WC. In this study, we investigated the genetic background of a large Dutch family with autosomal dominant‒inherited WC that was negative for mutations in known dystonia genes. Whole exome sequencing identified 4 rare variants of unknown significance that segregated in the family. One candidate gene was selected for follow-up, Calcium Voltage-Gated Channel Subunit Alpha1 H, CACNA1H, due to its links with the known dystonia gene Potassium Channel Tetramerization Domain Containing 17, KCTD17, and with paroxysmal movement disorders. Targeted resequencing of CACNA1H in 82 WC cases identified another rare, putative damaging variant in a familial WC case that did not segregate. Using structural modelling and functional studies in vitro, we show that both the segregating p.Arg481Cys variant and the non-segregating p.Glu1881Lys variant very likely cause structural changes to the Cav3.2 protein and lead to similar gains of function, as seen in an accelerated recovery from inactivation. Both mutant channels are thus available for re-activation earlier, which may lead to an increase in intracellular calcium and increased neuronal excitability. Overall, we conclude that rare functional variants in CACNA1H need to be interpreted very carefully, and additional studies are needed to prove that the p.Arg481Cys variant is the cause of WC in the large Dutch family. |
| Databáze: | OpenAIRE |
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