Referenced in: none

Automatically associated channels: Kir2.3 , Kv11.1 , Kv7.1

Title: Clinical, genetic, and electrophysiologic characteristics of a new PAS-domain HERG mutation (M124R) causing Long QT syndrome.

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

Journal, date & volume: Ann Noninvasive Electrocardiol, 2005 Jul , 10, 334-41

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/16029385

Abstract
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).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.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.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.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.