Stop-codon and C-terminal nonsense mutations are associated with a lower risk of cardiac events in patients with long QT syndrome type 1
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Stop-codon and C-terminal nonsense mutations are associated with a lower risk of cardiac events in patients with long QT syndrome type 1. / Ruwald, Martin H; Xu Parks, Xiaorong; Moss, Arthur J; Zareba, Wojciech; Baman, Jayson; McNitt, Scott; Kanters, Jorgen K; Shimizu, Wataru; Wilde, Arthur A; Jons, Christian; Lopes, Coeli M.
In: Heart rhythm : the official journal of the Heart Rhythm Society, Vol. 13, No. 1, 01.2016, p. 122-131.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Stop-codon and C-terminal nonsense mutations are associated with a lower risk of cardiac events in patients with long QT syndrome type 1
AU - Ruwald, Martin H
AU - Xu Parks, Xiaorong
AU - Moss, Arthur J
AU - Zareba, Wojciech
AU - Baman, Jayson
AU - McNitt, Scott
AU - Kanters, Jorgen K
AU - Shimizu, Wataru
AU - Wilde, Arthur A
AU - Jons, Christian
AU - Lopes, Coeli M
N1 - Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
PY - 2016/1
Y1 - 2016/1
N2 - BACKGROUND: In long QT syndrome type 1 (LQT1), the location and type of mutations have been shown to affect the clinical outcome. Although haploinsufficiency, including stop-codon and frameshift mutations, has been associated with a lower risk of cardiac events in patients with LQT1, nonsense mutations have been presumed functionally equivalent.OBJECTIVE: The purpose of this study was to evaluate clinical differences between patients with nonsense mutations.METHODS: The study sample comprised 1090 patients with genetically confirmed mutations. Patients were categorized into 5 groups, depending on mutation type and location: missense not located in the high-risk cytoplasmic loop (c-loop) (n = 698), which is used as reference; missense c-loop (n = 192); stop-codon (n = 67); frameshift (n = 39); and others (n = 94). The primary outcome was a composite end point of syncope, aborted cardiac arrest, and long QT syndrome-related death (cardiac events). Outcomes were evaluated using the multivariate Cox proportional hazards regression analysis. Standard patch clamp techniques were used.RESULTS: Compared to patients with missense non-c-loop mutations, the risk of cardiac events was reduced significantly in patients with stop-codon mutations (hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.34-0.96; P = .035), but not in patients with frameshift mutations (HR 1.01; 95% CI 0.58-1.77; P = .97). Our data suggest that currents of the most common stop-codon mutant channel (Q530X) were larger than those of haploinsufficient channels (wild type: 42 ± 6 pA/pF, n = 20; Q530X+wild type: 79 ± 14 pA/pF, n = 20; P < .05) and voltage dependence of activation was altered.CONCLUSION: Stop-codon mutations are associated with a lower risk of cardiac events in patients with LQT1, while frameshift mutations are associated with the same risk as the majority of the missense mutations. Our data indicate functional differences between these previously considered equivalent mutation subtypes.
AB - BACKGROUND: In long QT syndrome type 1 (LQT1), the location and type of mutations have been shown to affect the clinical outcome. Although haploinsufficiency, including stop-codon and frameshift mutations, has been associated with a lower risk of cardiac events in patients with LQT1, nonsense mutations have been presumed functionally equivalent.OBJECTIVE: The purpose of this study was to evaluate clinical differences between patients with nonsense mutations.METHODS: The study sample comprised 1090 patients with genetically confirmed mutations. Patients were categorized into 5 groups, depending on mutation type and location: missense not located in the high-risk cytoplasmic loop (c-loop) (n = 698), which is used as reference; missense c-loop (n = 192); stop-codon (n = 67); frameshift (n = 39); and others (n = 94). The primary outcome was a composite end point of syncope, aborted cardiac arrest, and long QT syndrome-related death (cardiac events). Outcomes were evaluated using the multivariate Cox proportional hazards regression analysis. Standard patch clamp techniques were used.RESULTS: Compared to patients with missense non-c-loop mutations, the risk of cardiac events was reduced significantly in patients with stop-codon mutations (hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.34-0.96; P = .035), but not in patients with frameshift mutations (HR 1.01; 95% CI 0.58-1.77; P = .97). Our data suggest that currents of the most common stop-codon mutant channel (Q530X) were larger than those of haploinsufficient channels (wild type: 42 ± 6 pA/pF, n = 20; Q530X+wild type: 79 ± 14 pA/pF, n = 20; P < .05) and voltage dependence of activation was altered.CONCLUSION: Stop-codon mutations are associated with a lower risk of cardiac events in patients with LQT1, while frameshift mutations are associated with the same risk as the majority of the missense mutations. Our data indicate functional differences between these previously considered equivalent mutation subtypes.
U2 - 10.1016/j.hrthm.2015.08.033
DO - 10.1016/j.hrthm.2015.08.033
M3 - Journal article
C2 - 26318259
VL - 13
SP - 122
EP - 131
JO - Heart Rhythm
JF - Heart Rhythm
SN - 1547-5271
IS - 1
ER -
ID: 165711719