title: The role of CAV3 in long-QT syndrome: clinical and functional assessment of a caveolin-3/Kv11.1 double heterozygote versus caveolin-3 single heterozygote.
abstract: BACKGROUND
  Mutations in CAV3, coding for caveolin-3, the major constituent scaffolding protein of cardiac caveolae, have been associated with skeletal muscle disease, cardiomyopathy, and most recently long-QT syndrome (LQTS) and sudden infant death syndrome. We examined the occurrence of CAV3 mutations in a large cohort of patients with LQTS.
  
  
  RESULTS
  Probands with LQTS (n=167) were screened for mutations in CAV3 using direct DNA sequencing. A single proband (0.6%) was found to be a heterozygous carrier of a previously described missense mutation, caveolin-3:p.T78M. The proband was also a heterozygous carrier of the trafficking-deficient Kv11.1:p.I400N mutation. The caveolin-3:p.T78M mutation was found isolated in 3 family members, none of whom had a prolonged QTc interval. Coimmunoprecipitations of caveolin-3 and the voltage-gated potassium channel subunit (Kv11.1) were performed, and the electrophysiological classification of the Kv11.1 mutant was carried out by patch-clamp technique in human embryonic kidney 293 cells. Furthermore, the T-wave morphology was assessed in mutation carriers, double mutation carriers, and nonmutation carriers by applying a morphology combination score. The morphology combination score was normal for isolated caveolin-3:p.T78M carriers and of LQT2 type in double heterozygotes.
  
  
  CONCLUSIONS
  Mutations in CAV3 are rare in LQTS. Furthermore, caveolin-3:p.T78M did not exhibit a LQTS phenotype. Because no association has ever been found between LQTS and isolated CAV3 mutations, we suggest that LQTS9 is considered a provisional entity.
authors.affiliation: Department of Clinical Biochemistry, Immunology, and Genetics, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Paula L
authors.initials: PL
authors.lastname: Hedley
authors.forename: Jørgen K
authors.initials: JK
authors.lastname: Kanters
authors.forename: Maja
authors.initials: M
authors.lastname: Dembic
authors.forename: Thomas
authors.initials: T
authors.lastname: Jespersen
authors.forename: Lasse
authors.initials: L
authors.lastname: Skibsbye
authors.forename: Frederik H
authors.initials: FH
authors.lastname: Aidt
authors.forename: Ole
authors.initials: O
authors.lastname: Eschen
authors.forename: Claus
authors.initials: C
authors.lastname: Graff
authors.forename: Elijah R
authors.initials: ER
authors.lastname: Behr
authors.forename: Sarah
authors.initials: S
authors.lastname: Schlamowitz
authors.forename: Valerie
authors.initials: V
authors.lastname: Corfield
authors.forename: William J
authors.initials: WJ
authors.lastname: McKenna
authors.forename: Michael
authors.initials: M
authors.lastname: Christiansen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D051244:Caveolin 3 / Q000235:genetics* / Q000378:metabolism; D002648:Child; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics* / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D018408:Patch-Clamp Techniques; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: D051244:Caveolin 3; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human
keywords: arrhythmias, cardiac; genetics; ion channel; long–QT syndrome; molecular biology