Identification of a New Locus for Generalized Epilepsy with Febrile Seizures Plus (GEFS+) on Chromosome 2q24-q33

Moulard, Bruno; Guipponi, Michel; Chaigne, Denys; Mouthon, Dominique; Burési, Catherine; Malafosse, Alain

doi:10.1086/302621

Cited by 122 publications

(81 citation statements)

References 21 publications

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“…These, therefore, suggest that other genes might also be involved in GEFSϩ and FS associated with afebrile seizures. The chromosomal locus 2q24, in which GEFSϩ has been mapped, harbors not only Na v 1.1 but also other ␣-subunits including Na v 1.2 (SCN2A) (10,(13)(14)(15). Given that Na v 1.2 is also expressed in high levels in the central nervous system with a tissue-specific profile (16), Na v 1.2 is an intriguing candidate.…”

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confidence: 99%

A missense mutation of the Na ⁺ channel α _II subunit gene Na _v 1.2 in a patient with febrile and afebrile seizures causes channel dysfunction

Sugawara

Tsurubuchi

Agarwala

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

357

186

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Acad. Sci. USA (97, 13913-13918; First Published November 28, 2000; 10.1073͞pnas.250478897), the authors note that the exponents of some entries in Table 1 were misprinted. The correct values appear below. www.pnas.org͞cgi͞doi͞10.1073͞pnas.191384698 STATISTICS, GENETICS. For the article ''Significance analysis of microarrays applied to the ionizing radiation response'' by Virginia Goss Tusher, Robert Tibshirani, and Gilbert Chu, which appeared in number 9, April 24, 2001, of Proc. Natl. Acad. Sci. USA (98, 5116-5121; First Published April 17, 2001; 10.1073͞pnas.091062498), the authors note the following: ''In our discussion of the pairwise fold change method on page 5118, we cited a paper by Ly et al., crediting them for the method. We did not mean to imply that it was deficient for the analysis of their experiments. In fact, Ly et al. incorporate (98,(6384)(6385)(6386)(6387)(6388)(6389), the authors wish to correct the position given for the amino acid that was mutated in the patient. The mutation ''R187W'' should be ''R188W. '' www.pnas.org͞cgi͞doi͞10.1073͞pnas.191390798 FEB2, 19p; FEB3, and FEB4,. A small population of individuals with FS has additional generalized epilepsy (1) or afebrile seizures. Genes for a ␤-subunit (␤1) and an ␣ I -subunit (Na v 1.1: SCN1A) (10) of the neuronal voltage-gated Na ϩ channel have been identified to be responsible for generalized epilepsy with febrile seizures plus (GEFSϩ) type 1 and 2, respectively (11, 12). However, a large number of patients with GEFSϩ still show no mutation for those genes. These, therefore, suggest that other genes might also be involved in GEFSϩ and FS associated with afebrile seizures. The chromosomal locus 2q24, in which GEFSϩ has been mapped, harbors not only Na v 1.1 but also other ␣-subunits including Na v 1.2 (SCN2A) (10,(13)(14)(15). Given that Na v 1.2 is also expressed in high levels in the central nervous system with a tissue-specific profile (16), Na v 1.2 is an intriguing candidate. In the present study, we report a mutation of Na v 1.2 found in a patient with FS and afebrile seizures. A channel harboring the mutation shows abnormal electrophysiological properties that may underlie the neuronal hyperexcitability that triggers seizure activity. Materials and MethodsPatients and Pedigrees. This study recruited nineteen unrelated Japanese families with members clinically diagnosed with GEFSϩ or febrile seizures associated with afebrile seizures. Each participating subject or a responsible adult signed an informed consent form approved by the Ethics Review Committee of Fukuoka University or similar committees of the participating institutions. The proband of family K1 is a 6-yr-old boy with normal development (Fig. 1A). He had the first febrile seizure (FS) at 8 months of age and suffered 17 episodes of FS thereafter at both high and low grade fever. The FS were generalized tonic or tonic-clonic convulsions with duration of 1-5 min per episode. Since 4 yr of age, he also has experienced brief afebrile atonic seizures 5 times. The...

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confidence: 99%

A missense mutation of the Na ⁺ channel α _II subunit gene Na _v 1.2 in a patient with febrile and afebrile seizures causes channel dysfunction

Sugawara

Tsurubuchi

Agarwala

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

357

186

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“…In 1999, linkage analysis in 2 large families localized a second GEFS+ locus to an interval of chromosome 2q24 that includes a sodium channel gene cluster (12,13). Sequencing of SCN1A demonstrated that affected individuals are heterozygous for missense mutations in highly evolutionarily conserved amino acid residues, T875M in 1 family and R1648H in the other (14).…”

Section: Inherited and De Novo Mutations Of Scn1a In Gefs+ Severe Myomentioning

confidence: 99%

Sodium channel mutations in epilepsy and other neurological disorders

Meisler

Kearney

2005

Journal of Clinical Investigation

450

367

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Since the first mutations of the neuronal sodium channel SCN1A were identified 5 years ago, more than 150 mutations have been described in patients with epilepsy. Many are sporadic mutations and cause loss of function, which demonstrates haploinsufficiency of SCN1A. Mutations resulting in persistent sodium current are also common. Coding variants of SCN2A, SCN8A, and SCN9A have also been identified in patients with seizures, ataxia, and sensitivity to pain, respectively. The rapid pace of discoveries suggests that sodium channel mutations are significant factors in the etiology of neurological disease and may contribute to psychiatric disorders as well.

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“…A second locus, GEFS+2, was mapped in 1999 to a 20-cM interval of chromosome 2q24 that contained the α subunit genes SCN1A, SCN2A, and SCN3A by analysis of two large families (6,50). Screening affected individuals from both families using conformation sensitive gel electrophoresis of amplified exons identified two missense mutations in the SCN1A gene, R1648H and T875M (27).…”

Section: Generalized Epilepsy With Febrile Seizures Plus-mentioning

confidence: 99%

Identification of Epilepsy Genes in Human and Mouse

et al. 2001

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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.

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Identification of a New Locus for Generalized Epilepsy with Febrile Seizures Plus (GEFS+) on Chromosome 2q24-q33

Cited by 122 publications

References 21 publications

A missense mutation of the Na ⁺ channel α _II subunit gene Na _v 1.2 in a patient with febrile and afebrile seizures causes channel dysfunction

A missense mutation of the Na ⁺ channel α _II subunit gene Na _v 1.2 in a patient with febrile and afebrile seizures causes channel dysfunction

Sodium channel mutations in epilepsy and other neurological disorders

Identification of Epilepsy Genes in Human and Mouse

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Identification of a New Locus for Generalized Epilepsy with Febrile Seizures Plus (GEFS+) on Chromosome 2q24-q33

Cited by 122 publications

References 21 publications

A missense mutation of the Na + channel α II subunit gene Na v 1.2 in a patient with febrile and afebrile seizures causes channel dysfunction

A missense mutation of the Na + channel α II subunit gene Na v 1.2 in a patient with febrile and afebrile seizures causes channel dysfunction

Sodium channel mutations in epilepsy and other neurological disorders

Identification of Epilepsy Genes in Human and Mouse

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Product

Resources

About

A missense mutation of the Na ⁺ channel α _II subunit gene Na _v 1.2 in a patient with febrile and afebrile seizures causes channel dysfunction

A missense mutation of the Na ⁺ channel α _II subunit gene Na _v 1.2 in a patient with febrile and afebrile seizures causes channel dysfunction