Advances in molecular genetics of genetic epilepsy with febrile seizure plus caused by <i>GABRG2</i> mutation_Journal of Epilepsy

Authors：

 LI Xinxiao ^1,2 , GUO Shengnan ³ , JIANG Zhansheng ^1,2 , LI Peidong ^1,2

1. Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China;
2. Systematic Epilepsy Treatment Center in Henan, Zhengzhou 450052, China;
3. Department of Rehabilitative Medicine, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China;

Corresponding author：

LI Xinxiao, Email: lxx985@163.com

Keywords：

Gamma aminobutyric acid type A receptor gamma 2 subunit; Gene mutation; Genetic epilepsy with febrile seizures plus

DOI：

10.7507/2096-0247.202303007

Video：

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Abstract Full text Figures/Tables Video References Cited by

Genetic epilepsy with febrile seizures plus (GEFS+) is a new type of genetic epilepsy syndrome with a marked hereditary tendency. Febrile seizure is the most common clinical symptom, followed by febrile seizure plus, and with/without absence seizures, focal seizures, and generalized tonic-clonic seizures. Results of the polymerase chain reaction (PCR), exon sequencing and single nucleotide polymorphism (SNP) analysis showed that the occurrence of GEFS+ is mainly related to the mutation of gamma aminobutyric acid type A receptor gamma 2 subunit (GABRG2), but its pathogenesis was still unclear. The main types of GABRG2 mutations include missense mutation, nonsense mutation, frameshift mutation, point mutation and splice site mutation. All these types of mutations can reduce the function of ion channels on cell membrane, but the degree and mechanism of dysfunction are different, which may be the main mechanism of epilepsy. This article will focus on the relationship between GEFS+ and the mutation types of GABRG2 in recent years, which is of great significance for clinical accurate diagnosis, anti-epileptic treatment strategy and new drug development.

Citation： LI Xinxiao, GUO Shengnan, JIANG Zhansheng, LI Peidong. Advances in molecular genetics of genetic epilepsy with febrile seizure plus caused by GABRG2 mutation. Journal of Epilepsy, 2023, 9(3): 235-242. doi: 10.7507/2096-0247.202303007 Copy

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3. Singh R, Scheffer IE, Crossland K, et al. Generalized epilepsy with febrile seizures plus: a common childhood-onset genetic epilepsy syndrome. Ann Neurol, 1999, 45(1): 75-81.
4. Lerche H, Weber YG, Baier H, et al. Generalized epilepsy with febrile seizures plus: further heterogeneity in a large family. Neurology, 2001, 57(7): 1191-1198.
5. Scheffer IE, Zhang YH, Jansen FE, et al. Dravet syndrome or genetic (generalized) epilepsy with febrile seizures plus? Brain Dev, 2009, 31(5): 394-400.
6. Scanlon A, Cook SS. Febrile seizures, genetic (generalized) epilepsy with febrile seizures plus, and Dravet's syndrome. J Spec Pediatr Nurs, 2010, 15(2): 154-159.
7. Lin H, Li J, Wang M, et al. Mutation screening of three Chinese families with genetic epilepsy with febrile seizures plus. Neurosci Lett, 2011, 500(2): 123-128.
8. Whiting PJ. The GABA_A receptor gene family: new targets for therapeutic intervention. Neurochem Int, 1999, 34(5): 387-390.
9. Kang JQ, Macdonald RL. Molecular pathogenic basis for GABRG2 mutations associated with a spectrum of epilepsy syndromes, from generalized absence epilepsy to Dravet Syndrome. JAMA Neurol, 2016, 73(8): 1009-1016.
10. McKernan RM, Whiting PJ. Which GABA_A receptor subtypes really occur in the brain? Trends Neurosci, 1996, 19(4): 139-143.
11. Haas KF, Macdonald RL. GABA_A receptor subunit gamma2 and delta subtypes confer unique kinetic properties on recombinant GABA_A receptor currents in mouse fibroblasts. J Physiol, 1999, 514(Pt1): 27-45.
12. Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia, 2017, 58(4): 512-521.
13. Fisher RS, Cross JH, French JA, et al. Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology. Epilepsia, 2017, 58(4): 522-530.
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15. Scheffer IE, Harkin LA, Grinton BE, et al. Temporal lobe epilepsy and GEFS+ phenotypes associated with SCN1B mutations. Brain, 2007, 130(Pt1): 100-109.
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17. Bouthour W, Leroy F, Emmanuelli C, et al. A human mutation in Gabrg2 associated with generalized epilepsy alters the membrane dynamics of GABA_A receptors. Cereb Cortex, 2012, 22(7): 1542-1553.
18. Polizzi A, Incorpora G, Pavone P, et al. Generalised epilepsy with febrile seizures plus GEFS+: molecular analysis in a restricted area. Childs Nerv Syst, 2012, 28(1): 141-145.
19. Zhang YH, Burgess R, Malone JP, et al. Genetic epilepsy with febrile seizures plus: Refining the spectrum. Neurology, 2017, 89(12): 1210-1219.
20. Kivity S, Oliver KL, Afawi Z, et al. SCN1A clinical spectrum includes the self-limited focal epilepsies of childhood. Epilepsy Res, 2017, 131: 9-14.
21. Wallace RH, Wang DW, Singh R, et al. Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B. Nat Genet, 1998, 19(4): 366-70.
22. Escayg A, MacDonald BT, Meisler MH, et al. Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+. Nat Genet, 2000, 24(4): 343-345.
23. Sugawara T, Tsurubuchi Y, Agarwala KL, et al. A missense mutation of the Na+ channel alpha II subunit gene Na(v)1. 2 in a patient with febrile and afebrile seizures causes channel dysfunction. Proc Natl Acad Sci USA, 2001, 98(11): 6384-6389.
24. Chou IC, Lin WD, Wang CH, et al. Interleukin (IL)-1beta, IL-1 receptor antagonist, IL-6, IL-8, IL-10, and tumor necrosis factor alpha gene polymorphisms in patients with febrile seizures. J Clin Lab Anal, 2010, 24(3): 154-159.
25. Wallace RH, Marini C, Petrou S, et al. Mutant GABA_A receptor γ2-subunit in childhood absence epilepsy and febrile seizures. Nat Genet, 2001, 28(1): 49-52.
26. Bowser DN, Wagner DA, Czajkowski C, et al. Altered kinetics and benzodiazepine sensitivity of a GABA_A receptor subunit mutation [γ2(R43Q)] found in human epilepsy. Proc Natl Acad Sci USA, 2002, 99(23): 15170-15175.
27. Nicolazzo JA, Steuten JA, Charman SA, et al. Brain uptake of diazepam and phenytoin in a genetic animal model of absence epilepsy. Clin Exp Pharmacol Physiol, 2010, 37(5-6): 647-649.
28. Sancar F, Czajkowski C. A GABA_A receptor mutation linked to human epilepsy (γ2R43Q) impairs cell surface expression of αβγ receptors. J Biol Chem, 2004, 279(45): 47034-47039.
29. Kang JQ, Macdonald RL. The GABA_A receptor γ2 subunit R43Q mutation linked to childhood absence epilepsy and febrile seizures causes retention of α1β2γ2S receptors in the endoplasmic reticulum. J Neurosci, 2004, 24(40): 8672-8677.
30. Hales TG, Tang H, Bollan KA, et al. The epilepsy mutation, γ2(R43Q) disrupts a highly conserved inter-subunit contact site, perturbing the biogenesis of GABA_A receptors. Mol Cell Neurosci, 2005, 29(1): 120-127.
31. Tan HO, Reid CA, Single FN, et al. Reduced cortical inhibition in a mouse model of familial childhood absence epilepsy. Proc Natl Acad Sci USA, 2007, 104(44): 17536-17541.
32. Witsch J, Golkowski D, Hahn TT, et al. Cortical alterations in a model for absence epilepsy and febrile seizures: in vivo findings in mice carrying a human GABA(A)R gamma2 subunit mutation. Neurobiol Dis, 2015, 77: 62-70.
33. Chaumont S, André C, Perrais D, et al. Agonist-dependent endocytosis of γ-aminobutyric acid type A (GABA_A) receptors revealed by a γ2(R43Q) epilepsy mutation. J Biol Chem, 2013, 288(39): 28254-65.
34. Chiu C, Reid CA, Tan HO, et al. Developmental impact of a familial GABAA receptor epilepsy mutation. Ann Neurol, 2008, 64(3): 284-293.
35. Richards KL, Kurniawan ND, Yang Z, et al. Hippocampal volume and cell density changes in a mouse model of human genetic epilepsy. Neurology, 2013, 80(13): 1240-1246.
36. Wimmer VC, Li MY, Berkovic SF, et al. Cortical microarchitecture changes in genetic epilepsy. Neurology, 2015, 84(13): 1308-1316.
37. Currie SP, Luz LL, Booker SA, et al. Reduced local input to fast-spiking interneurons in the somatosensory cortex in the GABA_A γ2 R43Q mouse model of absence epilepsy. Epilepsia, 2017, 58(4): 597-607.
38. Audenaert D, Schwartz E, Claeys KG, et al. A novel GABRG2 mutation associated with febrile seizures. Neurology, 2006, 67(4): 687-690.
39. Baulac S, Huberfeld G, Gourfinkel-An I, et al. First genetic evidence of GABA_A receptor dysfunction in epilepsy: a mutation in the γ2-subunit gene. Nat Genet, 2001, 28(1): 46-48.
40. Bianchi MT, Macdonald RL. Agonist trapping by GABA_A receptor channels. J Neurosci, 2001, 21(23): 9083-9091.
41. Bianchi MT, Song L, Zhang H, et al. Two different mechanisms of disinhibition produced by GABA_A receptor mutations linked to epilepsy in humans. J Neurosci, 2002, 22(13): 5321-5327.
42. Macdonald RL, Bianchi MT, Feng H. Mutations linked to generalized epilepsy in humans reduce GABA_A receptor current. Exp Neurol, 2003, 184(Suppl 1): 58-67.
43. Eugène E, Depienne C, Baulac S, et al. GABAA receptor γ2 subunit mutations linked to human epileptic syndromes differentially affect phasic and tonic inhibition. J Neurosci, 2007, 27(51): 14108-14116.
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