Elevated body temperature exacerbates arrhythmia and seizure-like activity in a zebrafish model of Timothy syndrome
5 affiliations
- 1Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD USA
- 2Bioinformatics and Scientific Programming Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD USA
- 3Laboratory of Biochemistry and Genetics, National Institute of Diabetes, Digestive, and Kidney Diseases, Bethesda, MD USA
- 4Present Address: Department of Cell Biology, Yale School of Medicine, New Haven, CT USA
- 5Zebrafish Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD USA
Abstract
Timothy syndrome (TS) is a multisystem disorder with autistic-like features, seizures and life-threatening arrhythmias. Most TS cases are caused by a de novo missense mutation in the CACNA1C gene that encodes the pore-forming subunit of the voltage-gated L-type calcium channel CaV1.2. Patients show highly variable clinical presentations and survival, which may be impacted by acute episodes of hypoglycemia and respiratory dysfunction. In addition, fever, known to activate CaV1.2 channels, may exacerbate TS, yet its impact is poorly understood. We generated a zebrafish model carrying the homologous cacna1c mutation. These fish exhibited arrhythmias, increased susceptibility to pentylenetetrazole-induced seizures, microcephaly, cerebellar hypotrophy and abnormal GABAergic neuron development. Transcriptomic analysis revealed dysregulated expression of neuropeptides including bdnf and vgf. Notably, elevated water temperature elicited arrhythmia and seizure-like behavior even in overtly normal heterozygotes, implicating fever as a modifiable risk. This model provides a platform for dissecting TS pathophysiology and identifying strategies to mitigate fever-related risk.
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BibTeX
@article{semenova2026elevated,
title = {{Elevated body temperature exacerbates arrhythmia and seizure-like activity in a zebrafish model of Timothy syndrome}},
author = {Svetlana A. Semenova and Amir M. Sams and Deepthi Nammi and Matthew Menold and Gennady Margolin and Jennifer L. Sinclair and Katelyn A. Robertson and Kerry Larkin and Sydney Kelly and Andy Golden and Benjamin Feldman and Harold A. Burgess},
journal = {Communications Biology},
year = {2026},
month = jul,
doi = {10.1038/s42003-026-10657-3},
url = {https://doi.org/10.1038/s42003-026-10657-3},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Elevated body temperature exacerbates arrhythmia and seizure-like activity in a zebrafish model of Timothy syndrome
AU - Svetlana A. Semenova
AU - Amir M. Sams
AU - Deepthi Nammi
AU - Matthew Menold
AU - Gennady Margolin
AU - Jennifer L. Sinclair
AU - Katelyn A. Robertson
AU - Kerry Larkin
AU - Sydney Kelly
AU - Andy Golden
AU - Benjamin Feldman
AU - Harold A. Burgess
PY - 2026
DA - 2026/07/09
JO - Communications Biology
DO - 10.1038/s42003-026-10657-3
UR - https://doi.org/10.1038/s42003-026-10657-3
AB - Timothy syndrome (TS) is a multisystem disorder with autistic-like features, seizures and life-threatening arrhythmias. Most TS cases are caused by a de novo missense mutation in the CACNA1C gene that encodes the pore-forming subunit of the voltage-gated L-type calcium channel CaV1.2. Patients show highly variable clinical presentations and survival, which may be impacted by acute episodes of hypoglycemia and respiratory dysfunction. In addition, fever, known to activate CaV1.2 channels, may exacerbate TS, yet its impact is poorly understood. We generated a zebrafish model carrying the homologous cacna1c mutation. These fish exhibited arrhythmias, increased susceptibility to pentylenetetrazole-induced seizures, microcephaly, cerebellar hypotrophy and abnormal GABAergic neuron development. Transcriptomic analysis revealed dysregulated expression of neuropeptides including bdnf and vgf. Notably, elevated water temperature elicited arrhythmia and seizure-like behavior even in overtly normal heterozygotes, implicating fever as a modifiable risk. This model provides a platform for dissecting TS pathophysiology and identifying strategies to mitigate fever-related risk.
SN - 2399-3642
ER -