title: Non-SCN5A related Brugada syndromes: verification of normal splicing and trafficking of SCN5A without exonic mutations.
abstract: Recently, it has been reported that under 20% of Brugada syndrome cases are linked to SCN5A mutations. The purpose of this study was to clarify whether abnormalities other than exonic mutations, such as splicing disorders, decreased mRNA expression levels, or membrane transport abnormalities of SCN5A, play a role in the pathogenesis of Brugada syndrome. We analyzed all SCN5A exons and splice sites using genomic DNA from 23 Brugada syndrome patients. We also analyzed the mRNA obtained from RV cardiomyocytes using real time PCR and sequencing, to study the expression levels and splicing patterns of SCN5A. The localization of SCN5A was examined by immunofluorescence analysis. A de novo heterozygous G to A transversion in a 5' splice junction of the intron between exons 21 and 22 was detected in 1 patient. In the mRNA analysis of Brugada syndrome patients without a mutation of SCN5A no splicing abnormalities were detected, and the SCN5A mRNA levels were similar to those of normal controls. Immunofluorescence analyses revealed that SCN5A is located on the surface membrane not only in the RV cardiomyocytes of normal controls but also in those with Brugada syndrome. We can confirm that some Brugada syndrome patients without exonic mutations in SCN5A had no other SCN5A abnormalities, including any involving the location of the SCN5A protein. These results suggest the involvement of other proteins in the pathogenesis in Brugada syndrome.
authors.affiliation: Department of Medicine and Molecular Science, Graduate School of Biomedical Sciences, Hiroshima University [corrected] Japan. ynakano@xj8.so-net.ne.jp
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Nakano
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tashiro
authors.forename: Eiji
authors.initials: E
authors.lastname: Kinoshita
authors.forename: Emiko
authors.initials: E
authors.lastname: Kinoshita-Kikuta
authors.forename: Sou
authors.initials: S
authors.lastname: Takenaka
authors.forename: Miwa
authors.initials: M
authors.lastname: Miyoshi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ogi
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Sakoda
authors.forename: Noboru
authors.initials: N
authors.lastname: Oda
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Suenari
authors.forename: Yukiji
authors.initials: Y
authors.lastname: Tonouchi
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Okimoto
authors.forename: Yukoh
authors.initials: Y
authors.lastname: Hirai
authors.forename: Fumiharu
authors.initials: F
authors.lastname: Miura
authors.forename: Kazuko
authors.initials: K
authors.lastname: Yamaoka
authors.forename: Tohru
authors.initials: T
authors.lastname: Koike
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
mesh_terms: D000328:Adult; D000368:Aged; D053840:Brugada Syndrome / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D005260:Female; D006801:Humans; D007438:Introns; D008297:Male; D008875:Middle Aged; D009154:Mutation; D032383:Myocytes, Cardiac / Q000737:chemistry; D062554:NAV1.5 Voltage-Gated Sodium Channel; D021381:Protein Transport; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015222:Sodium Channels / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; D012333:RNA, Messenger; C568320:SCN5A protein, human; D015222:Sodium Channels