PMID- 17698727
OWN - NLM
STAT- MEDLINE
DCOM- 20071011
LR  - 20220129
IS  - 1524-4539 (Electronic)
IS  - 0009-7322 (Linking)
VI  - 116
IP  - 10
DP  - 2007 Sep 4
TI  - Gating properties of SCN5A mutations and the response to mexiletine in long-QT 
      syndrome type 3 patients.
PG  - 1137-44
AB  - BACKGROUND: Mexiletine (Mex) has been proposed as a gene-specific therapy for 
      patients with long-QT syndrome type 3 (LQT3) caused by mutations in the cardiac 
      sodium channel gene (SCN5A). The degree of QT shortening and the protection from 
      arrhythmias vary among patients harboring different mutations. We tested whether 
      the clinical response to Mex in LQT3 could be predicted by the biophysical 
      properties of the different mutations. METHODS AND RESULTS: We identified 4 SCN5A 
      mutations in 5 symptomatic LQT3 patients with different responses to Mex (6 to 8 
      mg . kg(-1) . d(-1)). We classified the mutations as sensitive to Mex (P1332L, 
      R1626P; >/=10% of QTc shortening and QTc <500 ms or no arrhythmias) or 
      insensitive to Mex (S941N, M1652R; negligible or no QTc shortening and sudden 
      death). We measured Na(+) current from HEK 293 cells transfected with wild-type 
      (WT) or mutant Nav1.5. All mutations showed impaired inactivation of Na(+) 
      current, but the mutations identified in patient responders to Mex (P1332L, 
      R1626P) showed a hyperpolarizing shift of V(1/2) of steady-state inactivation. 
      Furthermore, Mex produced use-dependent block with the order 
      R1626P=P1332L>S941N=WT>M1652R, suggesting that Mex-sensitive mutants present 
      prolonged recovery from Mex block. CONCLUSIONS: We propose that voltage 
      dependence of channel availability and shifts of V(1/2) of steady-state 
      inactivation correlate with the clinical response observed in LQT3 patients. This 
      supports the view that the response to Mex is mutation specific and that in vitro 
      testing may help to predict the response to therapy in LQT3.
FAU - Ruan, Yanfei
AU  - Ruan Y
AD  - Molecular Cardiology, Fondazione Salvatore Maugeri, Via Maugeri 10/10A, 27100 
      Pavia, Italy.
FAU - Liu, Nian
AU  - Liu N
FAU - Bloise, Raffaella
AU  - Bloise R
FAU - Napolitano, Carlo
AU  - Napolitano C
FAU - Priori, Silvia G
AU  - Priori SG
LA  - eng
GR  - GGP04066/TI_/Telethon/Italy
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070813
PL  - United States
TA  - Circulation
JT  - Circulation
JID - 0147763
RN  - 0 (Muscle Proteins)
RN  - 0 (NAV1.5 Voltage-Gated Sodium Channel)
RN  - 0 (SCN5A protein, human)
RN  - 0 (Sodium Channels)
RN  - 1U511HHV4Z (Mexiletine)
SB  - IM
MH  - Adult
MH  - Child
MH  - Child, Preschool
MH  - Genetic Therapy/trends
MH  - Humans
MH  - Infant
MH  - Ion Channel Gating/*drug effects/physiology
MH  - Long QT Syndrome/classification/*drug therapy/*genetics/metabolism
MH  - Mexiletine/pharmacology/*therapeutic use
MH  - Muscle Proteins/*genetics/metabolism
MH  - *Mutation
MH  - NAV1.5 Voltage-Gated Sodium Channel
MH  - Sodium Channels/*genetics/metabolism
EDAT- 2007/08/19 09:00
MHDA- 2007/10/12 09:00
CRDT- 2007/08/19 09:00
PHST- 2007/08/19 09:00 [pubmed]
PHST- 2007/10/12 09:00 [medline]
PHST- 2007/08/19 09:00 [entrez]
AID - CIRCULATIONAHA.107.707877 [pii]
AID - 10.1161/CIRCULATIONAHA.107.707877 [doi]
PST - ppublish
SO  - Circulation. 2007 Sep 4;116(10):1137-44. doi: 10.1161/CIRCULATIONAHA.107.707877. 
      Epub 2007 Aug 13.