Clinical, genetic, and electrophysiologic characteristics of a new PAS-domain HERG mutation (M124R) causing Long QT syndrome.
OBJECTIVE
To describe the clinical, genetic, and electrophysiologic characteristics of a new PAS-domain HERG mutation (M124R) that has been identified in a single large Jewish family with Long QT syndrome (LQTS).


BACKGROUND
Many previously reported HERG mutations causing LQTS are located either in the C-terminus, or in the pore region. Relatively fewer clinical data are available on N-terminus (PAS-domain) mutation carriers.


METHODS
Clinical data were available in 76 family members (aged 1-93 years, 69 alive) over 18 years of follow-up, while electrocardiographic data were available in 57, and genetic data in 45 family members. Cellular electrophysiology was assessed in transfected Chinese Hamster Ovary (CHO) cells using the whole-cell patch-clamp technique.


RESULTS
Thirty-six family members were phenotypically categorized as nonaffected, 3 as equivocal, and 20 as affected. Mean QTc was 410+/-23, 440+/-10, and 498+/-41 ms, respectively, in these three subgroups. Eight out of 20 affected family members were symptomatic: five had only syncope, two had aborted cardiac arrest, and one sudden death. Genetic analyses identified the M124R point mutation in all affected members tested (n=16), while all those tested with nonaffected (n=26) and equivocal (n=3) phenotype did not carry the mutation. The M124R mutation reduced the HERG tail-current density by 65%, significantly accelerated the deactivation kinetics, and caused a negative shift in the voltage dependence of activation.


CONCLUSIONS
A new PAS-domain HERG mutation (M124R) was identified as causing LQTS in a large Jewish family, with high penetrance and frequent disease-related symptoms. This mutation markedly decreased the tail-current density and accelerated the deactivation kinetics of the HERG channel in transfected CHO cells.
Shushi
Liat
L
Department of Genetics, The Life Sciences Institute, The Hebrew University, Jerusalem, Israel.
Kerem
Batsheva
B
Goldmit
Maya
M
Peretz
Asher
A
Attali
Bernard
B
Medina
Aron
A
Towbin
Jeffrey A
JA
Kurokawa
Junko
J
Kass
Robert S
RS
Benhorin
Jesaia
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007557:Israel; D008133:Long QT Syndrome / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics*; D017421:Sequence Analysis
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D024642:Potassium Channels, Voltage-Gated