期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 24, 页码 E5516-E5525出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1800077115
关键词
de novo SCN2A mutation; dynamic action potential clamp; epilepsy; voltage clamp; modeling
资金
- Australian Research Council Centre of Excellence for Integrative Brain Function Grant [CE14010007]
- National Health and Medical Research Council (NHMRC) programme [10915693]
- NHMRC Fellowship [GNT1005050]
- Practitioner fellowship
- Murdoch Childrens Research Institute
- RogCon, Inc.
- Victorian State Government infrastructure funds
De novo variants in SCN2A developmental and epileptic encephalopathy (DEE) show distinctive genotype-phenotype correlations. The two most recurrent SCN2A variants in DEE, R1882Q and R853Q, are associated with different ages and seizure types at onset. R1882Q presents on day 1 of life with focal seizures, while infantile spasms is the dominant seizure type seen in R853Q cases, presenting at a median age of 8 months. Voltage clamp, which characterizes the functional properties of ion channels, predicted gain-of-function for R1882Q and loss-of-function for R853Q. Dynamic action potential clamp, that we implement here as a method for modeling neurophysiological consequences of a given epilepsy variant, predicted that the R1882Q variant would cause a dramatic increase in firing, whereas the R853Q variant would cause a marked reduction in action potential firing. Dynamic clamp was also able to functionally separate the L1563V variant, seen in benign familial neonatal-infantile seizures from R1882Q, seen in DEE, suggesting a diagnostic potential for this type of analysis. Overall, the study shows a strong correlation between clinical phenotype, SCN2A genotype, and functional modeling. Dynamic clamp is well positioned to impact our understanding of pathomechanisms and for development of disease mechanism-targeted therapies in genetic epilepsy.
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