Multiple molecular mechanisms for a single GABAA mutation in epilepsy

Christopher A. Reid, Taehwan Kim, A. Marie Phillips, Jun Low, Samuel F. Berkovic, Bernhard Luscher, Steven Petrou

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Objective: To understand the molecular basis and differential penetrance of febrile seizures and absence seizures in patients with the γ2(R43Q) GABAA receptor mutation. Methods: Spike-and-wave discharges and thermal seizure susceptibility were measured in heterozygous GABAA γ2 knock-out and GABAA γ2(R43Q) knock-in mice models crossed to different mouse strains. Results: By comparing the GABAA γ2 knock-out with the GABAA γ2(R43Q) knock-in mouse model we show that haploinsufficiency underlies the genesis of absence seizures but cannot account for the thermal seizure susceptibility. Additionally, while the expression of the absence seizure phenotype was very sensitive to mouse background genetics, the thermal seizure phenotype was not. Conclusions: Our results show that a single gene mutation can cause distinct seizure phenotypes through independent molecular mechanisms. A lack of effect of genetic background on thermal seizure susceptibility is consistent with the higher penetrance of febrile seizures compared to absence seizures seen in family members with the mutation. These mouse studies help to provide a conceptual framework within which clinical heterogeneity seen in genetic epilepsy can be explained.

Original languageEnglish (US)
Pages (from-to)1003-1008
Number of pages6
JournalNeurology
Volume80
Issue number11
DOIs
StatePublished - Mar 12 2013

Fingerprint

Absence Epilepsy
Epilepsy
Seizures
Mutation
Hot Temperature
Febrile Seizures
Penetrance
Phenotype
Haploinsufficiency
GABA-A Receptors
Genes
Genetic Background

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

Cite this

Reid, C. A., Kim, T., Phillips, A. M., Low, J., Berkovic, S. F., Luscher, B., & Petrou, S. (2013). Multiple molecular mechanisms for a single GABAA mutation in epilepsy. Neurology, 80(11), 1003-1008. https://doi.org/10.1212/WNL.0b013e3182872867
Reid, Christopher A. ; Kim, Taehwan ; Phillips, A. Marie ; Low, Jun ; Berkovic, Samuel F. ; Luscher, Bernhard ; Petrou, Steven. / Multiple molecular mechanisms for a single GABAA mutation in epilepsy. In: Neurology. 2013 ; Vol. 80, No. 11. pp. 1003-1008.
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Reid, CA, Kim, T, Phillips, AM, Low, J, Berkovic, SF, Luscher, B & Petrou, S 2013, 'Multiple molecular mechanisms for a single GABAA mutation in epilepsy', Neurology, vol. 80, no. 11, pp. 1003-1008. https://doi.org/10.1212/WNL.0b013e3182872867

Multiple molecular mechanisms for a single GABAA mutation in epilepsy. / Reid, Christopher A.; Kim, Taehwan; Phillips, A. Marie; Low, Jun; Berkovic, Samuel F.; Luscher, Bernhard; Petrou, Steven.

In: Neurology, Vol. 80, No. 11, 12.03.2013, p. 1003-1008.

Research output: Contribution to journalArticle

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Reid CA, Kim T, Phillips AM, Low J, Berkovic SF, Luscher B et al. Multiple molecular mechanisms for a single GABAA mutation in epilepsy. Neurology. 2013 Mar 12;80(11):1003-1008. https://doi.org/10.1212/WNL.0b013e3182872867