Exp Neurol 2003 Nov 01;184 Suppl 1:S58-67. doi: 10.1016/j.expneurol.2003.08.011.

Mutations linked to generalized epilepsy in humans reduce GABA(A) receptor current.

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The first mutations of the GABA(A) receptor channel linked to familial epilepsy in humans were reported in the gamma2L subunit. When expressed in Xenopus oocytes, the gamma2 subunit R43Q mutation abolished current enhancement by the benzodiazepine, diazepam, and the gamma2 subunit K289M mutation decreased current amplitudes. In this study, single channel recording and concentration jump techniques were used to evaluate the effects of these mutations on GABA(A) receptor currents from receptors expressed in human embryonic kidney cells. When co-expressed with alpha1 and beta3 subunits, the mutated gamma2 subunits did not alter current activation rates or rates or extent of desensitization during prolonged (400 ms) GABA application (1 mM). Deactivation following brief (5 ms) or prolonged (400 ms) GABA application was accelerated for the K289M, but not the R43Q mutation. Single channel analysis showed shorter mean open duration, suggesting that the faster deactivation was likely caused by altered gating efficacy. Interestingly, the R43Q mutation did not alter diazepam potentiation. However, significantly smaller current amplitudes were observed that were not explained by decreased single channel conductance or open time, suggesting this mutation resulted in reduced surface expression of functional receptors. These two gamma mutations likely produce disinhibition and familial epilepsy by distinct mechanisms, suggesting that maintenance of normal neuronal inhibition depends on both the peak amplitude of IPSCs and their time course.

???displayArticle.pubmedLink??? 14597328
???displayArticle.link??? Exp Neurol
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Species referenced: Xenopus
Genes referenced: cacna1a chrna4 chrnb2 gabra1 gabrg2 kcnq2 kcnq3 scn1a scn1b scn2a

???displayArticle.disOnts??? generalized epilepsy with febrile seizures plus [+]
???displayArticle.omims??? GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 1; GEFSP1 [+]