Sodium channel abnormalities are infrequent in patients with long QT Syndrome: Identification of two novel SCN5A mutations

D Wattanasirichaigoon, MR Vesely… - American journal of …, 1999 - Wiley Online Library
D Wattanasirichaigoon, MR Vesely, P Duggal, JC Levine, ED Blume, GS Wolff, SB Edwards…
American journal of medical genetics, 1999Wiley Online Library
Long QT syndrome (LQTS) is a heterogeneous disorder caused by mutations of at least five
different loci. Three of these, LQT1, LQT2, and LQT5, encode potassium channel subunits.
LQT3 encodes the cardiac‐specific sodium channel, SCN5A. Previously reported LQTS‐
associated mutations of SCN5A include a recurring three amino acid deletion (ΔKPQ1505–
1507) in four different families, and four different missense mutations. We have examined
the SCN5A gene in 88 index cases with LQTS, including four with Jervell and Lange …
Abstract
Long QT syndrome (LQTS) is a heterogeneous disorder caused by mutations of at least five different loci. Three of these, LQT1, LQT2, and LQT5, encode potassium channel subunits. LQT3 encodes the cardiac‐specific sodium channel, SCN5A. Previously reported LQTS‐associated mutations of SCN5A include a recurring three amino acid deletion (ΔKPQ1505–1507) in four different families, and four different missense mutations. We have examined the SCN5A gene in 88 index cases with LQTS, including four with Jervell and Lange‐Nielsen syndrome and the remainder with Romano‐Ward syndrome. Screening portions of DIII–DIV, where mutations have previously been found, showed that none of these patients has the three amino acid deletion, ΔKPQ1505–1507, or the other four known mutations. We identified a novel missense mutation, T1645M, in the DIV; S4 voltage sensor immediately adjacent to the previously reported mutation R1644H. We also examined all of the additional pore‐forming regions and voltage‐sensing regions and discovered another novel mutation, T1304M, at the voltage‐sensing region DIII; S4. Neither T1645M nor T1304M were seen in a panel of unaffected control individuals. Five of six T1304M gene carriers were symptomatic. In contrast to previous studies, QTonset‐c was not a sensitive indicator of SCN5A‐associated LQTS, at least in this family. These data suggest that mutations of SCN5A are responsible for only a small proportion of LQTS cases. Am. J. Med. Genet. 86:470–476, 1999. © 1999 Wiley‐Liss, Inc.
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