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Long QT syndrome type 3 caused by a PY‐motif mutation leading to altered ubiquitylation and increased expression of Nav1.5 in knock‐in mice
Author(s) -
ROUGIER Jean-Sébastien,
Albesa Maxime,
Remme Carol Ann,
Ogrodnik Jakob,
Petitprez Séverine,
Bankston John,
Kass Robert S.,
Bezzina Connie R.,
Chung Wendy,
Abriel Hugues
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1067.3
Subject(s) - nav1.5 , ubiquitin ligase , ubiquitin , sodium channel , hek 293 cells , mutant , nav1 , knockout mouse , immunoprecipitation , long qt syndrome , microbiology and biotechnology , nedd4 , gene knockdown , gene knockin , mutation , wild type , phenotype , chemistry , biology , genetics , gene , medicine , qt interval , sodium , organic chemistry
Background Congenital long QT syndrome type 3 (LQT3) is a cardiac arrhythmias caused by gain‐of‐function mutations in SCN5A, the gene encoding the sodium channel Nav1.5. This channel can be regulated via the ubiquitin ligase Nedd4‐2 which binds to the PY‐motif of Nav1.5. Aim We have investigated the mechanisms underlying the phenotype of a LQT3 family harboring a SCN5A mutation located in the PY‐motif (p.Y1981N) of Nav1.5. Results In HEK cell, co‐immunoprecipitation experiments revealed that the interaction of Nav1.5 with Nedd4‐2 was abolished by the mutation. While the WT protein was ubiquitylated and the sodium current (INa) down‐regulated upon Nedd4‐2 co‐expression, no such regulation was observed with the mutant channel. In vivo relevance of this mechanism was assessed by generating a knock‐in (KI) mouse line bearing the p.Y1981N mutation. Ubiquitylation of the mutant channel expressed in KI hearts mice was reduced, and the total level of Nav1.5 protein was increased compared to WT littermates. INa and action potential duration were increased in KI cardiomyocytes compare to WT. Conclusions These results demonstrate a central role for Nav1.5 ubiquitylation in the regulation of sodium channel density in cardiomyocytes. Funding from the European Community's Seventh Framework Programme, EUTrigTreat, the Swiss National Science Foundation, and the Swiss Heart Foundation.