Sodium channel abnormalities are infrequent in patients with long QT syndrome: identification of two novel SCN5A mutations.
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 (DeltaKPQ1505-1507) 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, DeltaKPQ1505-1507, 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, QT(onset-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.
Wattanasirichaigoon
D
D
Division of Genetics, Children's Hospital, Boston, Massachusetts 02115, USA.
Vesely
M R
MR
Duggal
P
P
Levine
J C
JC
Blume
E D
ED
Wolff
G S
GS
Edwards
S B
SB
Beggs
A H
AH
D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D002874:Chromosome Mapping; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010375:Pedigree; D017433:Protein Structure, Secondary; D017384:Sequence Deletion; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics*
D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels