Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism

Corey L. Anderson, Brian P. Delisle, Blake D. Anson, Jennifer A. Kilby, Melissa L. Will, David J. Tester, Qiuming Gong, Zhengfeng Zhou, Michael J. Ackerman, Craig T. January

    Research output: Contribution to journalArticle

    286 Citations (Scopus)

    Abstract

    BACKGROUND-: The KCNH2 or human ether-a-go-go related gene (hERG) encodes the Kv11.1 α-subunit of the rapidly activating delayed rectifier K + current (IKr) in the heart. Type 2 congenital long-QT syndrome (LQT2) results from KCNH2 mutations that cause loss of Kv11.1 channel function. Several mechanisms have been identified, including disruption of Kv11.1 channel synthesis (class 1), protein trafficking (class 2), gating (class 3), or permeation (class 4). For a few class 2 LQT2-Kv11.1 channels, it is possible to increase surface membrane expression of Kv11.1 current (I Kv11.1). We tested the hypotheses that (1) most LQT2 missense mutations generate trafficking-deficient Kv11.1 channels, and (2) their trafficking-deficient phenotype can be corrected. METHODS AND RESULTS-: Wild-type (WT)-Kv11.1 channels and 34 missense LQT2-Kv11.1 channels were expressed in HEK293 cells. With Western blot analyses, 28 LQT2-Kv11.1 channels had a trafficking-deficient (class 2) phenotype. For the majority of these mutations, the class 2 phenotype could be corrected when cells were incubated for 24 hours at reduced temperature (27°C) or in the drugs E4031 or thapsigargin. Four of the 6 LQT2-Kv11.1 channels that had a wild-type-like trafficking phenotype did not cause loss of Kv11.1 function, which suggests that these channels are uncommon sequence variants. CONCLUSIONS-: This is the first study to identify a dominant mechanism, class 2, for the loss of Kv11.1 channel function in LQT2 and to report that the class 2 phenotype for many of these mutant channels can be corrected. This suggests that if therapeutic strategies to correct protein trafficking abnormalities can be developed, it may offer clinical benefits for LQT2 patients.

    Original languageEnglish (US)
    Pages (from-to)365-373
    Number of pages9
    JournalCirculation
    Volume113
    Issue number3
    DOIs
    StatePublished - Jan 2006

    Fingerprint

    Ether
    Phenotype
    Mutation
    Genes
    Protein Transport
    Long QT Syndrome
    Thapsigargin
    HEK293 Cells
    Missense Mutation
    Western Blotting
    Temperature
    Membranes
    Pharmaceutical Preparations
    Therapeutics

    Keywords

    • Arrhythmia
    • hERG
    • Ion channels
    • Long-QT syndrome
    • Protein trafficking

    ASJC Scopus subject areas

    • Physiology
    • Cardiology and Cardiovascular Medicine

    Cite this

    Anderson, C. L., Delisle, B. P., Anson, B. D., Kilby, J. A., Will, M. L., Tester, D. J., ... January, C. T. (2006). Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism. Circulation, 113(3), 365-373. https://doi.org/10.1161/CIRCULATIONAHA.105.570200

    Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism. / Anderson, Corey L.; Delisle, Brian P.; Anson, Blake D.; Kilby, Jennifer A.; Will, Melissa L.; Tester, David J.; Gong, Qiuming; Zhou, Zhengfeng; Ackerman, Michael J.; January, Craig T.

    In: Circulation, Vol. 113, No. 3, 01.2006, p. 365-373.

    Research output: Contribution to journalArticle

    Anderson, CL, Delisle, BP, Anson, BD, Kilby, JA, Will, ML, Tester, DJ, Gong, Q, Zhou, Z, Ackerman, MJ & January, CT 2006, 'Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism', Circulation, vol. 113, no. 3, pp. 365-373. https://doi.org/10.1161/CIRCULATIONAHA.105.570200
    Anderson, Corey L. ; Delisle, Brian P. ; Anson, Blake D. ; Kilby, Jennifer A. ; Will, Melissa L. ; Tester, David J. ; Gong, Qiuming ; Zhou, Zhengfeng ; Ackerman, Michael J. ; January, Craig T. / Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism. In: Circulation. 2006 ; Vol. 113, No. 3. pp. 365-373.
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    abstract = "BACKGROUND-: The KCNH2 or human ether-a-go-go related gene (hERG) encodes the Kv11.1 α-subunit of the rapidly activating delayed rectifier K + current (IKr) in the heart. Type 2 congenital long-QT syndrome (LQT2) results from KCNH2 mutations that cause loss of Kv11.1 channel function. Several mechanisms have been identified, including disruption of Kv11.1 channel synthesis (class 1), protein trafficking (class 2), gating (class 3), or permeation (class 4). For a few class 2 LQT2-Kv11.1 channels, it is possible to increase surface membrane expression of Kv11.1 current (I Kv11.1). We tested the hypotheses that (1) most LQT2 missense mutations generate trafficking-deficient Kv11.1 channels, and (2) their trafficking-deficient phenotype can be corrected. METHODS AND RESULTS-: Wild-type (WT)-Kv11.1 channels and 34 missense LQT2-Kv11.1 channels were expressed in HEK293 cells. With Western blot analyses, 28 LQT2-Kv11.1 channels had a trafficking-deficient (class 2) phenotype. For the majority of these mutations, the class 2 phenotype could be corrected when cells were incubated for 24 hours at reduced temperature (27°C) or in the drugs E4031 or thapsigargin. Four of the 6 LQT2-Kv11.1 channels that had a wild-type-like trafficking phenotype did not cause loss of Kv11.1 function, which suggests that these channels are uncommon sequence variants. CONCLUSIONS-: This is the first study to identify a dominant mechanism, class 2, for the loss of Kv11.1 channel function in LQT2 and to report that the class 2 phenotype for many of these mutant channels can be corrected. This suggests that if therapeutic strategies to correct protein trafficking abnormalities can be developed, it may offer clinical benefits for LQT2 patients.",
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    AU - Anderson, Corey L.

    AU - Delisle, Brian P.

    AU - Anson, Blake D.

    AU - Kilby, Jennifer A.

    AU - Will, Melissa L.

    AU - Tester, David J.

    AU - Gong, Qiuming

    AU - Zhou, Zhengfeng

    AU - Ackerman, Michael J.

    AU - January, Craig T.

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    N2 - BACKGROUND-: The KCNH2 or human ether-a-go-go related gene (hERG) encodes the Kv11.1 α-subunit of the rapidly activating delayed rectifier K + current (IKr) in the heart. Type 2 congenital long-QT syndrome (LQT2) results from KCNH2 mutations that cause loss of Kv11.1 channel function. Several mechanisms have been identified, including disruption of Kv11.1 channel synthesis (class 1), protein trafficking (class 2), gating (class 3), or permeation (class 4). For a few class 2 LQT2-Kv11.1 channels, it is possible to increase surface membrane expression of Kv11.1 current (I Kv11.1). We tested the hypotheses that (1) most LQT2 missense mutations generate trafficking-deficient Kv11.1 channels, and (2) their trafficking-deficient phenotype can be corrected. METHODS AND RESULTS-: Wild-type (WT)-Kv11.1 channels and 34 missense LQT2-Kv11.1 channels were expressed in HEK293 cells. With Western blot analyses, 28 LQT2-Kv11.1 channels had a trafficking-deficient (class 2) phenotype. For the majority of these mutations, the class 2 phenotype could be corrected when cells were incubated for 24 hours at reduced temperature (27°C) or in the drugs E4031 or thapsigargin. Four of the 6 LQT2-Kv11.1 channels that had a wild-type-like trafficking phenotype did not cause loss of Kv11.1 function, which suggests that these channels are uncommon sequence variants. CONCLUSIONS-: This is the first study to identify a dominant mechanism, class 2, for the loss of Kv11.1 channel function in LQT2 and to report that the class 2 phenotype for many of these mutant channels can be corrected. This suggests that if therapeutic strategies to correct protein trafficking abnormalities can be developed, it may offer clinical benefits for LQT2 patients.

    AB - BACKGROUND-: The KCNH2 or human ether-a-go-go related gene (hERG) encodes the Kv11.1 α-subunit of the rapidly activating delayed rectifier K + current (IKr) in the heart. Type 2 congenital long-QT syndrome (LQT2) results from KCNH2 mutations that cause loss of Kv11.1 channel function. Several mechanisms have been identified, including disruption of Kv11.1 channel synthesis (class 1), protein trafficking (class 2), gating (class 3), or permeation (class 4). For a few class 2 LQT2-Kv11.1 channels, it is possible to increase surface membrane expression of Kv11.1 current (I Kv11.1). We tested the hypotheses that (1) most LQT2 missense mutations generate trafficking-deficient Kv11.1 channels, and (2) their trafficking-deficient phenotype can be corrected. METHODS AND RESULTS-: Wild-type (WT)-Kv11.1 channels and 34 missense LQT2-Kv11.1 channels were expressed in HEK293 cells. With Western blot analyses, 28 LQT2-Kv11.1 channels had a trafficking-deficient (class 2) phenotype. For the majority of these mutations, the class 2 phenotype could be corrected when cells were incubated for 24 hours at reduced temperature (27°C) or in the drugs E4031 or thapsigargin. Four of the 6 LQT2-Kv11.1 channels that had a wild-type-like trafficking phenotype did not cause loss of Kv11.1 function, which suggests that these channels are uncommon sequence variants. CONCLUSIONS-: This is the first study to identify a dominant mechanism, class 2, for the loss of Kv11.1 channel function in LQT2 and to report that the class 2 phenotype for many of these mutant channels can be corrected. This suggests that if therapeutic strategies to correct protein trafficking abnormalities can be developed, it may offer clinical benefits for LQT2 patients.

    KW - Arrhythmia

    KW - hERG

    KW - Ion channels

    KW - Long-QT syndrome

    KW - Protein trafficking

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