Identification of Epilepsy Genes in Human and Mouse

Overview

Journal Annu Rev Genet

Publisher Annual Reviews

Specialty Genetics

Date 2001 Nov 9

PMID 11700294

Citations 42

Authors

M H Meisler

J Kearney

R Ottman

A Escayg

Affiliations

Soon will be listed here.

Abstract

The development of molecular markers and genomic resources has facilitated the isolation of genes responsible for rare monogenic epilepsies in human and mouse. Many of the identified genes encode ion channels or other components of neuronal signaling. The electrophysiological properties of mutant alleles indicate that neuronal hyperexcitability is one cellular mechanism underlying seizures. Genetic heterogeneity and allelic variability are hallmarks of human epilepsy. For example, mutations in three different sodium channel genes can produce the same syndrome, GEFS+, while individuals with the same allele can experience different types of seizures. Haploinsufficiency for the sodium channel SCN1A has been demonstrated by the severe infantile epilepsy and cognitive deficits in heterozygotes for de novo null mutations. Large-scale patient screening is in progress to determine whether less severe alleles of the genes responsible for monogenic epilepsy may contribute to the common types of epilepsy in the human population. The development of pharmaceuticals directed towards specific epilepsy genotypes can be anticipated, and the introduction of patient mutations into the mouse genome will provide models for testing these targeted therapies.

Citing Articles

Association of genetic variants with autism spectrum disorder in Japanese children revealed by targeted sequencing.

Shiota Y, Nishiyama T, Yokoyama S, Yoshimura Y, Hasegawa C, Tanaka S Front Genet. 2024; 15:1352480.

PMID: 39280100 PMC: 11395840. DOI: 10.3389/fgene.2024.1352480.

Altered Hippocampal Activation in Seizure-Prone Knock-out Mice.

Danis A, Gallagher A, Anderson A, Isakharov A, Beeson K, Schnell E eNeuro. 2024; 11(5).

PMID: 38749701 PMC: 11097259. DOI: 10.1523/ENEURO.0486-23.2024.

Altered hippocampal activation in seizure-prone knockout mice.

Danis A, Gallagher A, Anderson A, Isakharov A, Beeson K, Schnell E bioRxiv. 2023; .

PMID: 37986872 PMC: 10659305. DOI: 10.1101/2023.11.08.565511.

Epilepsy Characteristics in Neurodevelopmental Disorders: Research from Patient Cohorts and Animal Models Focusing on Autism Spectrum Disorder.

Chakraborty S, Parayil R, Mishra S, Nongthomba U, Clement J Int J Mol Sci. 2022; 23(18).

PMID: 36142719 PMC: 9501968. DOI: 10.3390/ijms231810807.

Effects of pyrethroids on brain development and behavior: Deltamethrin.

Pitzer E, Williams M, Vorhees C Neurotoxicol Teratol. 2021; 87:106983.

PMID: 33848594 PMC: 8440325. DOI: 10.1016/j.ntt.2021.106983.

References

Benlounis A, Nabbout R, Feingold J, Parmeggiani A, Guerrini R, Kaminska A . Genetic predisposition to severe myoclonic epilepsy in infancy. Epilepsia. 2001; 42(2):204-9. View

WALLACE R, Scheffer I, Barnett S, Richards M, Dibbens L, Desai R . Neuronal sodium-channel alpha1-subunit mutations in generalized epilepsy with febrile seizures plus. Am J Hum Genet. 2001; 68(4):859-65. PMC: 1275639. DOI: 10.1086/319516. View

Escayg A, Heils A, MacDonald B, Haug K, Sander T, Meisler M . A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus--and prevalence of variants in patients with epilepsy. Am J Hum Genet. 2001; 68(4):866-73. PMC: 1275640. DOI: 10.1086/319524. View

Durner M, Keddache M, Tomasini L, Shinnar S, Resor S, Cohen J . Genome scan of idiopathic generalized epilepsy: evidence for major susceptibility gene and modifying genes influencing the seizure type. Ann Neurol. 2001; 49(3):328-35. View

Moran O, Conti F . Skeletal muscle sodium channel is affected by an epileptogenic beta1 subunit mutation. Biochem Biophys Res Commun. 2001; 282(1):55-9. DOI: 10.1006/bbrc.2001.4502. View

Baulac S, Huberfeld G, Gourfinkel-An I, Mitropoulou G, Beranger A, Prudhomme J . First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene. Nat Genet. 2001; 28(1):46-8. DOI: 10.1038/ng0501-46. View

WALLACE R, Marini C, Petrou S, Harkin L, Bowser D, Panchal R . Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures. Nat Genet. 2001; 28(1):49-52. DOI: 10.1038/ng0501-49. View

Junaid M, Pullarkat R . Biochemistry of neuronal ceroid lipofuscinoses. Adv Genet. 2001; 45:93-106. DOI: 10.1016/s0065-2660(01)45005-x. View

Chioza B, Wilkie H, Nashef L, Blower J, McCormick D, Sham P . Association between the alpha(1a) calcium channel gene CACNA1A and idiopathic generalized epilepsy. Neurology. 2001; 56(9):1245-6. DOI: 10.1212/wnl.56.9.1245. View

10.

Fletcher C, Tottene A, Lennon V, Wilson S, DUBEL S, Paylor R . Dystonia and cerebellar atrophy in Cacna1a null mice lacking P/Q calcium channel activity. FASEB J. 2001; 15(7):1288-90. DOI: 10.1096/fj.00-0562fje. View

11.

Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, De Jonghe P . De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet. 2001; 68(6):1327-32. PMC: 1226119. DOI: 10.1086/320609. View

12.

Sugawara T, Tsurubuchi Y, Agarwala K, Ito M, Fukuma G, Nagafuji H . 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 U S A. 2001; 98(11):6384-9. PMC: 33477. DOI: 10.1073/pnas.111065098. View

13.

Pritchard J . Are rare variants responsible for susceptibility to complex diseases?. Am J Hum Genet. 2001; 69(1):124-37. PMC: 1226027. DOI: 10.1086/321272. View

14.

Frankel W, Taylor L, Beyer B, Tempel B, White H . Electroconvulsive thresholds of inbred mouse strains. Genomics. 2001; 74(3):306-12. DOI: 10.1006/geno.2001.6564. View

15.

Barclay J, Balaguero N, Mione M, Ackerman S, Letts V, Brodbeck J . Ducky mouse phenotype of epilepsy and ataxia is associated with mutations in the Cacna2d2 gene and decreased calcium channel current in cerebellar Purkinje cells. J Neurosci. 2001; 21(16):6095-104. PMC: 6763162. View

16.

Singh R, Andermann E, Whitehouse W, Harvey A, Keene D, Seni M . Severe myoclonic epilepsy of infancy: extended spectrum of GEFS+?. Epilepsia. 2001; 42(7):837-44. DOI: 10.1046/j.1528-1157.2001.042007837.x. View

17.

Meisler M, Kearney J, Escayg A, MacDonald B, Sprunger L . Sodium channels and neurological disease: insights from Scn8a mutations in the mouse. Neuroscientist. 2001; 7(2):136-45. DOI: 10.1177/107385840100700208. View

18.

Kang M, Chen C, Felix R, Letts V, Frankel W, Mori Y . Biochemical and biophysical evidence for gamma 2 subunit association with neuronal voltage-activated Ca2+ channels. J Biol Chem. 2001; 276(35):32917-24. DOI: 10.1074/jbc.M100787200. View

19.

Spampanato J, Escayg A, Meisler M, Goldin A . Functional effects of two voltage-gated sodium channel mutations that cause generalized epilepsy with febrile seizures plus type 2. J Neurosci. 2001; 21(19):7481-90. PMC: 6762922. View

20.

. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia. 1981; 22(4):489-501. DOI: 10.1111/j.1528-1157.1981.tb06159.x. View