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PMID:17060380

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Citation

Vatta, M, Ackerman, MJ, Ye, B, Makielski, JC, Ughanze, EE, Taylor, EW, Tester, DJ, Balijepalli, RC, Foell, JD, Li, Z, Kamp, TJ and Towbin, JA (2006) Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation 114:2104-12

Abstract

Congenital long-QT syndrome (LQTS) is a primary arrhythmogenic syndrome stemming from perturbed cardiac repolarization. LQTS, which affects approximately 1 in 3000 persons, is 1 of the most common causes of autopsy-negative sudden death in the young. Since the sentinel discovery of cardiac channel gene mutations in LQTS in 1995, hundreds of mutations in 8 LQTS susceptibility genes have been identified. All 8 LQTS genotypes represent primary cardiac channel defects (ie, ion channelopathy) except LQT4, which is a functional channelopathy because of mutations in ankyrin-B. Approximately 25% of LQTS remains unexplained pathogenetically. We have pursued a "final common pathway" hypothesis to elicit novel LQTS-susceptibility genes. With the recent observation that the LQT3-associated, SCN5A-encoded cardiac sodium channel localizes in caveolae, which are known membrane microdomains whose major component in the striated muscle is caveolin-3, we hypothesized that mutations in caveolin-3 may represent a novel pathogenetic mechanism for LQTS.

Links

PubMed Online version:10.1161/CIRCULATIONAHA.106.635268

Keywords

Amino Acid Sequence; Caveolin 3/genetics; Cell Line; DNA Mutational Analysis; Electric Conductivity; Electrocardiography; Electrophysiology; Female; Humans; Immunoprecipitation; Long QT Syndrome/diagnosis; Long QT Syndrome/genetics; Long QT Syndrome/metabolism; Long QT Syndrome/physiopathology; Male; Molecular Sequence Data; Muscle Proteins/metabolism; Mutation; Myocardium/metabolism; Sodium Channels/metabolism; Time Factors; Transfection

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:KCNA5

colocalizes_with

GO:0005901: caveola

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete

HUMAN:CAV3

enables

GO:0017080: sodium channel regulator activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(UniProtKB:Q14524)

Seeded From UniProt

complete

HUMAN:CAV3

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0002131)

Seeded From UniProt

complete

HUMAN:CAV3

involved_in

GO:2000649: regulation of sodium ion transmembrane transporter activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CAV3

located_in

GO:0042383: sarcolemma

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:CAV3

involved_in

GO:0060373: regulation of ventricular cardiac muscle cell membrane depolarization

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CAV3

involved_in

GO:0098909: regulation of cardiac muscle cell action potential involved in regulation of contraction

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CAV3

involved_in

GO:0060307: regulation of ventricular cardiac muscle cell membrane repolarization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CAV3

involved_in

GO:0002027: regulation of heart rate

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CAV3

enables

GO:0044325: transmembrane transporter binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q14524

F

Seeded From UniProt

complete

HUMAN:CAV3

enables

GO:0060090: molecular adaptor activity

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q14524

F

Seeded From UniProt

complete

HUMAN:SCN5A

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0002131)

Seeded From UniProt

complete

HUMAN:SCN5A

located_in

GO:0042383: sarcolemma

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SCN5A

part_of

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0002131)

Seeded From UniProt

complete

HUMAN:SCN5A

enables

GO:0097110: scaffold protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P56539

F

Seeded From UniProt

complete

HUMAN:SCN5A

part_of

GO:0042383: sarcolemma

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SCN5A

colocalizes_with

GO:0005901: caveola

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete


See also

References

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