PubMed 17227473

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Title: Non-SCN5A related Brugada syndromes: verification of normal splicing and trafficking of SCN5A without exonic mutations.

Authors: Yukiko Nakano, Satoshi Tashiro, Eiji Kinoshita, Emiko Kinoshita-Kikuta, Sou Takenaka, Miwa Miyoshi, Hiroshi Ogi, Eiichiro Sakoda, Noboru Oda, Kazuyoshi Suenari, Yukiji Tonouchi, Tomokazu Okimoto, Yukoh Hirai, Fumiharu Miura, Kazuko Yamaoka, Tohru Koike, Kazuaki Chayama

Journal, date & volume: Ann. Hum. Genet., 2007 Jan , 71, 8-17

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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.