The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome

Naomasa Makita, Elijah Behr, Wataru Shimizu, Minoru Horie, Akihiko Sunami, Lia Crotti, Eric Schulze-Bahr, Shigetomo Fukuhara, Naoki Mochizuki, Takeru Makiyama, Hideki Itoh, Michael Christiansen, Pascal McKeown, Koji Miyamoto, Shiro Kamakura, Hiroyuki Tsutsui, Peter J. Schwartz, Alfred L. George, Dan M. Roden

Research output: Contribution to journalArticle

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Abstract

Phenotypic overlap of type 3 long QT syndrome (LQT3) with Brugada syndrome (BrS) is observed in some carriers of mutations in the Na channel SCN5A. While this overlap is important for patient management, the clinical features, prevalence, and mechanisms underlying such overlap have not been fully elucidated. To investigate the basis for this overlap, we genotyped a cohort of 44 LQT3 families of multiple ethnicities from 7 referral centers and found a high prevalence of the E1784K mutation in SCN5A. Of 41 E1784K carriers, 93% had LQT3, 22% had BrS, and 39% had sinus node dysfunction. Heterologously expressed E1784K channels showed a 15.0-mV negative shift in the voltage dependence of Na channel inactivation and a 7.5-fold increase in flecainide affinity for resting-state channels, properties also seen with other LQT3 mutations associated with a mixed clinical phenotype. Furthermore, these properties were absent in Na channels harboring the T1304M mutation, which is associated with LQT3 without a mixed clinical phenotype. These results suggest that a negative shift of steady-state Na channel inactivation and enhanced tonic block by class IC drugs represent common biophysical mechanisms underlying the phenotypic overlap of LQT3 and BrS and further indicate that class IC drugs should be avoided in patients with Na channels displaying these behaviors.

Original languageEnglish
Pages (from-to)2219-2229
Number of pages11
JournalJournal of Clinical Investigation
Volume118
Issue number6
DOIs
Publication statusPublished - Jun 2 2008
Externally publishedYes

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Brugada Syndrome
Phenotype
Mutation
Flecainide
Sick Sinus Syndrome
Pharmaceutical Preparations
Referral and Consultation
Long QT syndrome type 3

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Makita, N., Behr, E., Shimizu, W., Horie, M., Sunami, A., Crotti, L., ... Roden, D. M. (2008). The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome. Journal of Clinical Investigation, 118(6), 2219-2229. https://doi.org/10.1172/JCI34057

The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome. / Makita, Naomasa; Behr, Elijah; Shimizu, Wataru; Horie, Minoru; Sunami, Akihiko; Crotti, Lia; Schulze-Bahr, Eric; Fukuhara, Shigetomo; Mochizuki, Naoki; Makiyama, Takeru; Itoh, Hideki; Christiansen, Michael; McKeown, Pascal; Miyamoto, Koji; Kamakura, Shiro; Tsutsui, Hiroyuki; Schwartz, Peter J.; George, Alfred L.; Roden, Dan M.

In: Journal of Clinical Investigation, Vol. 118, No. 6, 02.06.2008, p. 2219-2229.

Research output: Contribution to journalArticle

Makita, N, Behr, E, Shimizu, W, Horie, M, Sunami, A, Crotti, L, Schulze-Bahr, E, Fukuhara, S, Mochizuki, N, Makiyama, T, Itoh, H, Christiansen, M, McKeown, P, Miyamoto, K, Kamakura, S, Tsutsui, H, Schwartz, PJ, George, AL & Roden, DM 2008, 'The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome', Journal of Clinical Investigation, vol. 118, no. 6, pp. 2219-2229. https://doi.org/10.1172/JCI34057
Makita, Naomasa ; Behr, Elijah ; Shimizu, Wataru ; Horie, Minoru ; Sunami, Akihiko ; Crotti, Lia ; Schulze-Bahr, Eric ; Fukuhara, Shigetomo ; Mochizuki, Naoki ; Makiyama, Takeru ; Itoh, Hideki ; Christiansen, Michael ; McKeown, Pascal ; Miyamoto, Koji ; Kamakura, Shiro ; Tsutsui, Hiroyuki ; Schwartz, Peter J. ; George, Alfred L. ; Roden, Dan M. / The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome. In: Journal of Clinical Investigation. 2008 ; Vol. 118, No. 6. pp. 2219-2229.
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AU - Horie, Minoru

AU - Sunami, Akihiko

AU - Crotti, Lia

AU - Schulze-Bahr, Eric

AU - Fukuhara, Shigetomo

AU - Mochizuki, Naoki

AU - Makiyama, Takeru

AU - Itoh, Hideki

AU - Christiansen, Michael

AU - McKeown, Pascal

AU - Miyamoto, Koji

AU - Kamakura, Shiro

AU - Tsutsui, Hiroyuki

AU - Schwartz, Peter J.

AU - George, Alfred L.

AU - Roden, Dan M.

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N2 - Phenotypic overlap of type 3 long QT syndrome (LQT3) with Brugada syndrome (BrS) is observed in some carriers of mutations in the Na channel SCN5A. While this overlap is important for patient management, the clinical features, prevalence, and mechanisms underlying such overlap have not been fully elucidated. To investigate the basis for this overlap, we genotyped a cohort of 44 LQT3 families of multiple ethnicities from 7 referral centers and found a high prevalence of the E1784K mutation in SCN5A. Of 41 E1784K carriers, 93% had LQT3, 22% had BrS, and 39% had sinus node dysfunction. Heterologously expressed E1784K channels showed a 15.0-mV negative shift in the voltage dependence of Na channel inactivation and a 7.5-fold increase in flecainide affinity for resting-state channels, properties also seen with other LQT3 mutations associated with a mixed clinical phenotype. Furthermore, these properties were absent in Na channels harboring the T1304M mutation, which is associated with LQT3 without a mixed clinical phenotype. These results suggest that a negative shift of steady-state Na channel inactivation and enhanced tonic block by class IC drugs represent common biophysical mechanisms underlying the phenotypic overlap of LQT3 and BrS and further indicate that class IC drugs should be avoided in patients with Na channels displaying these behaviors.

AB - Phenotypic overlap of type 3 long QT syndrome (LQT3) with Brugada syndrome (BrS) is observed in some carriers of mutations in the Na channel SCN5A. While this overlap is important for patient management, the clinical features, prevalence, and mechanisms underlying such overlap have not been fully elucidated. To investigate the basis for this overlap, we genotyped a cohort of 44 LQT3 families of multiple ethnicities from 7 referral centers and found a high prevalence of the E1784K mutation in SCN5A. Of 41 E1784K carriers, 93% had LQT3, 22% had BrS, and 39% had sinus node dysfunction. Heterologously expressed E1784K channels showed a 15.0-mV negative shift in the voltage dependence of Na channel inactivation and a 7.5-fold increase in flecainide affinity for resting-state channels, properties also seen with other LQT3 mutations associated with a mixed clinical phenotype. Furthermore, these properties were absent in Na channels harboring the T1304M mutation, which is associated with LQT3 without a mixed clinical phenotype. These results suggest that a negative shift of steady-state Na channel inactivation and enhanced tonic block by class IC drugs represent common biophysical mechanisms underlying the phenotypic overlap of LQT3 and BrS and further indicate that class IC drugs should be avoided in patients with Na channels displaying these behaviors.

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