Cellular dysfunction of LQT5-minK mutants

Abnormalities of I(Ks), I(Kr) and trafficking in long QT syndrome

Laura Bianchi, Zhijun Shen, Adrienne T. Dennis, Silvia G. Priori, Carlo Napolitano, Elena Ronchetti, Robert Bryskin, Peter J. Schwartz, Arthur M. Brown

Research output: Contribution to journalArticle

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Abstract

Mutations in the minK gene KCNE1 have been linked to the LQT5 variant of human long QT syndrome. MinK assembles with KvLQT1 to produce the slow delayed rectifier K+ current I(Ks) and may assemble with HERG to modulate the rapid delayed rectifier I(Kr). We used electrophysiological and immunocytochemical methods to compare the cellular phenotypes of wild-type minK and four LQT5 mutants co-expressed with KvLQT1 in Xenopus oocytes and HERG in HEK293 cells. We found that three mutants, V47F, W87R and D76N, were expressed at the cell surface, while one mutant, L51H, was not. Coexpression of V47F and W87R with KvLQT1 produced I(Ks) currents having altered gating and reduced amplitudes compared with WT-minK, co-expression with L51H produced KvLQT1 current rather than I(Ks) and coexpression with D76N suppressed KvLQT1 current. V47F increased HERG current but to a lesser extent than WT-minK, while L51H and W87R had no effect and D76N suppressed HERG current markedly. Thus, V47F interacts with both KvLQT1 and HERG, W87R interacts functionally with KvLQT1 but not with HERG, D76N suppresses both KvLQT1 and HERG, and L51H is processed improperly and interacts with neither channel. We conclude that minK is a co-factor in the expression of both I(Ks) and I(Kr) and propose that clinical manifestations of LQT5 may be complicated by differing effects of minK mutations on KvLQT1 and HERG.

Original languageEnglish
Pages (from-to)1499-1507
Number of pages9
JournalHuman Molecular Genetics
Volume8
Issue number8
DOIs
StatePublished - Aug 18 1999
Externally publishedYes

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Mink
Long QT Syndrome
Mutation
HEK293 Cells
Xenopus
Oocytes
Phenotype
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Cellular dysfunction of LQT5-minK mutants : Abnormalities of I(Ks), I(Kr) and trafficking in long QT syndrome. / Bianchi, Laura; Shen, Zhijun; Dennis, Adrienne T.; Priori, Silvia G.; Napolitano, Carlo; Ronchetti, Elena; Bryskin, Robert; Schwartz, Peter J.; Brown, Arthur M.

In: Human Molecular Genetics, Vol. 8, No. 8, 18.08.1999, p. 1499-1507.

Research output: Contribution to journalArticle

Bianchi, L, Shen, Z, Dennis, AT, Priori, SG, Napolitano, C, Ronchetti, E, Bryskin, R, Schwartz, PJ & Brown, AM 1999, 'Cellular dysfunction of LQT5-minK mutants: Abnormalities of I(Ks), I(Kr) and trafficking in long QT syndrome', Human Molecular Genetics, vol. 8, no. 8, pp. 1499-1507. https://doi.org/10.1093/hmg/8.8.1499
Bianchi, Laura ; Shen, Zhijun ; Dennis, Adrienne T. ; Priori, Silvia G. ; Napolitano, Carlo ; Ronchetti, Elena ; Bryskin, Robert ; Schwartz, Peter J. ; Brown, Arthur M. / Cellular dysfunction of LQT5-minK mutants : Abnormalities of I(Ks), I(Kr) and trafficking in long QT syndrome. In: Human Molecular Genetics. 1999 ; Vol. 8, No. 8. pp. 1499-1507.
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abstract = "Mutations in the minK gene KCNE1 have been linked to the LQT5 variant of human long QT syndrome. MinK assembles with KvLQT1 to produce the slow delayed rectifier K+ current I(Ks) and may assemble with HERG to modulate the rapid delayed rectifier I(Kr). We used electrophysiological and immunocytochemical methods to compare the cellular phenotypes of wild-type minK and four LQT5 mutants co-expressed with KvLQT1 in Xenopus oocytes and HERG in HEK293 cells. We found that three mutants, V47F, W87R and D76N, were expressed at the cell surface, while one mutant, L51H, was not. Coexpression of V47F and W87R with KvLQT1 produced I(Ks) currents having altered gating and reduced amplitudes compared with WT-minK, co-expression with L51H produced KvLQT1 current rather than I(Ks) and coexpression with D76N suppressed KvLQT1 current. V47F increased HERG current but to a lesser extent than WT-minK, while L51H and W87R had no effect and D76N suppressed HERG current markedly. Thus, V47F interacts with both KvLQT1 and HERG, W87R interacts functionally with KvLQT1 but not with HERG, D76N suppresses both KvLQT1 and HERG, and L51H is processed improperly and interacts with neither channel. We conclude that minK is a co-factor in the expression of both I(Ks) and I(Kr) and propose that clinical manifestations of LQT5 may be complicated by differing effects of minK mutations on KvLQT1 and HERG.",
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T2 - Abnormalities of I(Ks), I(Kr) and trafficking in long QT syndrome

AU - Bianchi, Laura

AU - Shen, Zhijun

AU - Dennis, Adrienne T.

AU - Priori, Silvia G.

AU - Napolitano, Carlo

AU - Ronchetti, Elena

AU - Bryskin, Robert

AU - Schwartz, Peter J.

AU - Brown, Arthur M.

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N2 - Mutations in the minK gene KCNE1 have been linked to the LQT5 variant of human long QT syndrome. MinK assembles with KvLQT1 to produce the slow delayed rectifier K+ current I(Ks) and may assemble with HERG to modulate the rapid delayed rectifier I(Kr). We used electrophysiological and immunocytochemical methods to compare the cellular phenotypes of wild-type minK and four LQT5 mutants co-expressed with KvLQT1 in Xenopus oocytes and HERG in HEK293 cells. We found that three mutants, V47F, W87R and D76N, were expressed at the cell surface, while one mutant, L51H, was not. Coexpression of V47F and W87R with KvLQT1 produced I(Ks) currents having altered gating and reduced amplitudes compared with WT-minK, co-expression with L51H produced KvLQT1 current rather than I(Ks) and coexpression with D76N suppressed KvLQT1 current. V47F increased HERG current but to a lesser extent than WT-minK, while L51H and W87R had no effect and D76N suppressed HERG current markedly. Thus, V47F interacts with both KvLQT1 and HERG, W87R interacts functionally with KvLQT1 but not with HERG, D76N suppresses both KvLQT1 and HERG, and L51H is processed improperly and interacts with neither channel. We conclude that minK is a co-factor in the expression of both I(Ks) and I(Kr) and propose that clinical manifestations of LQT5 may be complicated by differing effects of minK mutations on KvLQT1 and HERG.

AB - Mutations in the minK gene KCNE1 have been linked to the LQT5 variant of human long QT syndrome. MinK assembles with KvLQT1 to produce the slow delayed rectifier K+ current I(Ks) and may assemble with HERG to modulate the rapid delayed rectifier I(Kr). We used electrophysiological and immunocytochemical methods to compare the cellular phenotypes of wild-type minK and four LQT5 mutants co-expressed with KvLQT1 in Xenopus oocytes and HERG in HEK293 cells. We found that three mutants, V47F, W87R and D76N, were expressed at the cell surface, while one mutant, L51H, was not. Coexpression of V47F and W87R with KvLQT1 produced I(Ks) currents having altered gating and reduced amplitudes compared with WT-minK, co-expression with L51H produced KvLQT1 current rather than I(Ks) and coexpression with D76N suppressed KvLQT1 current. V47F increased HERG current but to a lesser extent than WT-minK, while L51H and W87R had no effect and D76N suppressed HERG current markedly. Thus, V47F interacts with both KvLQT1 and HERG, W87R interacts functionally with KvLQT1 but not with HERG, D76N suppresses both KvLQT1 and HERG, and L51H is processed improperly and interacts with neither channel. We conclude that minK is a co-factor in the expression of both I(Ks) and I(Kr) and propose that clinical manifestations of LQT5 may be complicated by differing effects of minK mutations on KvLQT1 and HERG.

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