Mechanisms of I(Ks) suppression in LQT1 mutants

Laura Bianchi, Silvia G. Priori, Carlo Napolitano, Krystyna A. Surewicz, Adrienne T. Dennis, Mirella Memmi, Peter J. Schwartz, Arthur M. Brown

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Mutations in the cardiac potassium ion channel gene KCNQ1 (voltage-gated K+ channel subtype KvLQT1) cause LQT1, the most common type of hereditary long Q-T syndrome. KvLQT1 mutations prolong Q-T by reducing the repolarizing cardiac current [slow delayed rectifier K+ current (I(Ks))], but, for reasons that are not well understood, the clinical phenotypes may vary considerably even for carriers of the same mutation, perhaps explaining the mode of inheritance. At present, only currents expressed by LQT1 mutants have been studied, and it is unknown whether abnormal subunits are transported to the cell surface. Here, we have examined for the first time trafficking of KvLQT1 mutations and correlated the results with the I(Ks) currents that were expressed. Two missense mutations, S225L and A300T, produced abnormal currents, and two others, Y281C and Y315C, produced no currents. However, all four KvLQT1 mutations were detected at the cell surface. S225L, Y281C, and Y315C produced dominant negative effects on wild-type I(Ks) current, whereas the mutant with the mildest dysfunction, A300T, did not. We examined trafficking of a severe insertion deletion mutant Δ544 and detected this protein at the cell surface as well. We compared the cellular and clinical phenotypes and found a poor correlation for the severely dysfunctional mutations.

Original languageEnglish
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume279
Issue number6 48-6
StatePublished - Dec 1 2000
Externally publishedYes

Fingerprint

Mutation
KCNQ1 Potassium Channel
Phenotype
Potassium Channels
Missense Mutation
Membrane Proteins
Genes

Keywords

  • Cellular phenotype
  • Cellular processing
  • Clinical phenotype
  • KvLQT1 mutations
  • Long Q-T syndrome
  • Slow delayed rectifier potassium current

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Bianchi, L., Priori, S. G., Napolitano, C., Surewicz, K. A., Dennis, A. T., Memmi, M., ... Brown, A. M. (2000). Mechanisms of I(Ks) suppression in LQT1 mutants. American Journal of Physiology - Heart and Circulatory Physiology, 279(6 48-6).

Mechanisms of I(Ks) suppression in LQT1 mutants. / Bianchi, Laura; Priori, Silvia G.; Napolitano, Carlo; Surewicz, Krystyna A.; Dennis, Adrienne T.; Memmi, Mirella; Schwartz, Peter J.; Brown, Arthur M.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 279, No. 6 48-6, 01.12.2000.

Research output: Contribution to journalArticle

Bianchi, L, Priori, SG, Napolitano, C, Surewicz, KA, Dennis, AT, Memmi, M, Schwartz, PJ & Brown, AM 2000, 'Mechanisms of I(Ks) suppression in LQT1 mutants', American Journal of Physiology - Heart and Circulatory Physiology, vol. 279, no. 6 48-6.
Bianchi L, Priori SG, Napolitano C, Surewicz KA, Dennis AT, Memmi M et al. Mechanisms of I(Ks) suppression in LQT1 mutants. American Journal of Physiology - Heart and Circulatory Physiology. 2000 Dec 1;279(6 48-6).
Bianchi, Laura ; Priori, Silvia G. ; Napolitano, Carlo ; Surewicz, Krystyna A. ; Dennis, Adrienne T. ; Memmi, Mirella ; Schwartz, Peter J. ; Brown, Arthur M. / Mechanisms of I(Ks) suppression in LQT1 mutants. In: American Journal of Physiology - Heart and Circulatory Physiology. 2000 ; Vol. 279, No. 6 48-6.
@article{e18c9683cc2f4413b7061dd137464853,
title = "Mechanisms of I(Ks) suppression in LQT1 mutants",
abstract = "Mutations in the cardiac potassium ion channel gene KCNQ1 (voltage-gated K+ channel subtype KvLQT1) cause LQT1, the most common type of hereditary long Q-T syndrome. KvLQT1 mutations prolong Q-T by reducing the repolarizing cardiac current [slow delayed rectifier K+ current (I(Ks))], but, for reasons that are not well understood, the clinical phenotypes may vary considerably even for carriers of the same mutation, perhaps explaining the mode of inheritance. At present, only currents expressed by LQT1 mutants have been studied, and it is unknown whether abnormal subunits are transported to the cell surface. Here, we have examined for the first time trafficking of KvLQT1 mutations and correlated the results with the I(Ks) currents that were expressed. Two missense mutations, S225L and A300T, produced abnormal currents, and two others, Y281C and Y315C, produced no currents. However, all four KvLQT1 mutations were detected at the cell surface. S225L, Y281C, and Y315C produced dominant negative effects on wild-type I(Ks) current, whereas the mutant with the mildest dysfunction, A300T, did not. We examined trafficking of a severe insertion deletion mutant Δ544 and detected this protein at the cell surface as well. We compared the cellular and clinical phenotypes and found a poor correlation for the severely dysfunctional mutations.",
keywords = "Cellular phenotype, Cellular processing, Clinical phenotype, KvLQT1 mutations, Long Q-T syndrome, Slow delayed rectifier potassium current",
author = "Laura Bianchi and Priori, {Silvia G.} and Carlo Napolitano and Surewicz, {Krystyna A.} and Dennis, {Adrienne T.} and Mirella Memmi and Schwartz, {Peter J.} and Brown, {Arthur M.}",
year = "2000",
month = "12",
day = "1",
language = "English",
volume = "279",
journal = "American Journal of Physiology - Cell Physiology",
issn = "0363-6143",
publisher = "American Physiological Society",
number = "6 48-6",

}

TY - JOUR

T1 - Mechanisms of I(Ks) suppression in LQT1 mutants

AU - Bianchi, Laura

AU - Priori, Silvia G.

AU - Napolitano, Carlo

AU - Surewicz, Krystyna A.

AU - Dennis, Adrienne T.

AU - Memmi, Mirella

AU - Schwartz, Peter J.

AU - Brown, Arthur M.

PY - 2000/12/1

Y1 - 2000/12/1

N2 - Mutations in the cardiac potassium ion channel gene KCNQ1 (voltage-gated K+ channel subtype KvLQT1) cause LQT1, the most common type of hereditary long Q-T syndrome. KvLQT1 mutations prolong Q-T by reducing the repolarizing cardiac current [slow delayed rectifier K+ current (I(Ks))], but, for reasons that are not well understood, the clinical phenotypes may vary considerably even for carriers of the same mutation, perhaps explaining the mode of inheritance. At present, only currents expressed by LQT1 mutants have been studied, and it is unknown whether abnormal subunits are transported to the cell surface. Here, we have examined for the first time trafficking of KvLQT1 mutations and correlated the results with the I(Ks) currents that were expressed. Two missense mutations, S225L and A300T, produced abnormal currents, and two others, Y281C and Y315C, produced no currents. However, all four KvLQT1 mutations were detected at the cell surface. S225L, Y281C, and Y315C produced dominant negative effects on wild-type I(Ks) current, whereas the mutant with the mildest dysfunction, A300T, did not. We examined trafficking of a severe insertion deletion mutant Δ544 and detected this protein at the cell surface as well. We compared the cellular and clinical phenotypes and found a poor correlation for the severely dysfunctional mutations.

AB - Mutations in the cardiac potassium ion channel gene KCNQ1 (voltage-gated K+ channel subtype KvLQT1) cause LQT1, the most common type of hereditary long Q-T syndrome. KvLQT1 mutations prolong Q-T by reducing the repolarizing cardiac current [slow delayed rectifier K+ current (I(Ks))], but, for reasons that are not well understood, the clinical phenotypes may vary considerably even for carriers of the same mutation, perhaps explaining the mode of inheritance. At present, only currents expressed by LQT1 mutants have been studied, and it is unknown whether abnormal subunits are transported to the cell surface. Here, we have examined for the first time trafficking of KvLQT1 mutations and correlated the results with the I(Ks) currents that were expressed. Two missense mutations, S225L and A300T, produced abnormal currents, and two others, Y281C and Y315C, produced no currents. However, all four KvLQT1 mutations were detected at the cell surface. S225L, Y281C, and Y315C produced dominant negative effects on wild-type I(Ks) current, whereas the mutant with the mildest dysfunction, A300T, did not. We examined trafficking of a severe insertion deletion mutant Δ544 and detected this protein at the cell surface as well. We compared the cellular and clinical phenotypes and found a poor correlation for the severely dysfunctional mutations.

KW - Cellular phenotype

KW - Cellular processing

KW - Clinical phenotype

KW - KvLQT1 mutations

KW - Long Q-T syndrome

KW - Slow delayed rectifier potassium current

UR - http://www.scopus.com/inward/record.url?scp=0034533563&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034533563&partnerID=8YFLogxK

M3 - Article

C2 - 11087258

AN - SCOPUS:0034533563

VL - 279

JO - American Journal of Physiology - Cell Physiology

JF - American Journal of Physiology - Cell Physiology

SN - 0363-6143

IS - 6 48-6

ER -