title: Deletions of SCN1A 5' genomic region with promoter activity in Dravet syndrome.
abstract: Mutations involving the voltage-gated sodium channel alpha(I) gene SCN1A are major genetic causes of childhood epileptic disorders, as typified by Dravet syndrome. Here we investigated the upstream regions of the SCN1A 5' noncoding exons and found two major regions with promoter activity. These two major promoters were simultaneously active in various brain regions and in most neurons. Using multiplex ligation-dependent probe amplification (MLPA) assays with probes for the 5' noncoding exons, their upstream regions, and all coding exons of SCN1A, we investigated 130 epileptic patients who did not show any SCN1A mutations by sequence analysis of all coding exons and exon-intron boundaries. Among 71 Dravet syndrome patients, we found two patients with heterozygous microdeletions removing the 5' noncoding exons and regions with promoter activity but not affecting the coding exons. We also identified four patients with deletions/duplication in the coding region. One patient with symptomatic focal epilepsy also showed a deletion in the coding region. This study provides the first case of microdeletion limited to the SCN1A 5' promoter region with the coding sequence preserved, and indicates the critical involvement of this upstream region in the molecular pathology of Dravet syndrome.
authors.affiliation: Laboratory for Neurogenetics, RIKEN Brain Science Institute, Wako, Saitama, Japan.
authors.forename: Tojo
authors.initials: T
authors.lastname: Nakayama
authors.forename: Ikuo
authors.initials: I
authors.lastname: Ogiwara
authors.forename: Koichi
authors.initials: K
authors.lastname: Ito
authors.forename: Makoto
authors.initials: M
authors.lastname: Kaneda
authors.forename: Emi
authors.initials: E
authors.lastname: Mazaki
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Osaka
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ohtani
authors.forename: Yushi
authors.initials: Y
authors.lastname: Inoue
authors.forename: Tateki
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Uematsu
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Haginoya
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tsuchiya
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamakawa
mesh_terms: D024506:5' Flanking Region / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D004831:Epilepsies, Myoclonic / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D020440:Gene Duplication; D020869:Gene Expression Profiling; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011689:Purkinje Cells / Q000166:cytology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D015222:Sodium Channels / Q000235:genetics*; D013577:Syndrome; D024363:Transcription Initiation Site
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; C568249:Scn1a protein, mouse; D015222:Sodium Channels