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

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.