Clinical, genetic, and electrophysiologic characteristics of a new Pas-domain HERG mutation (M124R) causing long QT syndrome

Liat Shushi, Batsheva Kerem, Maya Goldmit, Asher Peretz, Bernard Attali, Aron Medina, Jeffrey Towbin, Junko Kurokawa, Robert S. Kass, Jesaia Benhorin

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Objectives: 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.

Original languageEnglish (US)
Pages (from-to)334-341
Number of pages8
JournalAnnals of Noninvasive Electrocardiology
Volume10
Issue number3
DOIs
StatePublished - Jul 1 2005
Externally publishedYes

Fingerprint

Long QT Syndrome
Mutation
Cricetulus
Tail
Ovary
Penetrance
Electrophysiology
Syncope
Patch-Clamp Techniques
Sudden Death
Heart Arrest
Point Mutation
Phenotype

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Clinical, genetic, and electrophysiologic characteristics of a new Pas-domain HERG mutation (M124R) causing long QT syndrome. / Shushi, Liat; Kerem, Batsheva; Goldmit, Maya; Peretz, Asher; Attali, Bernard; Medina, Aron; Towbin, Jeffrey; Kurokawa, Junko; Kass, Robert S.; Benhorin, Jesaia.

In: Annals of Noninvasive Electrocardiology, Vol. 10, No. 3, 01.07.2005, p. 334-341.

Research output: Contribution to journalArticle

Shushi, Liat ; Kerem, Batsheva ; Goldmit, Maya ; Peretz, Asher ; Attali, Bernard ; Medina, Aron ; Towbin, Jeffrey ; Kurokawa, Junko ; Kass, Robert S. ; Benhorin, Jesaia. / Clinical, genetic, and electrophysiologic characteristics of a new Pas-domain HERG mutation (M124R) causing long QT syndrome. In: Annals of Noninvasive Electrocardiology. 2005 ; Vol. 10, No. 3. pp. 334-341.
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abstract = "Objectives: 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.",
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T1 - Clinical, genetic, and electrophysiologic characteristics of a new Pas-domain HERG mutation (M124R) causing long QT syndrome

AU - Shushi, Liat

AU - Kerem, Batsheva

AU - Goldmit, Maya

AU - Peretz, Asher

AU - Attali, Bernard

AU - Medina, Aron

AU - Towbin, Jeffrey

AU - Kurokawa, Junko

AU - Kass, Robert S.

AU - Benhorin, Jesaia

PY - 2005/7/1

Y1 - 2005/7/1

N2 - Objectives: 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.

AB - Objectives: 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.

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