Original-clinical geneticRecurrent intrauterine fetal loss due to near absence of HERG: Clinical and functional characterization of a homozygous nonsense HERG Q1070X mutation
Introduction
Congenital long QT syndrome is an inherited disorder defined by prolongation of the QT interval. Patients with long QT syndrome are predisposed to the ventricular tachyarrhythmia torsade de pointes, which leads to recurrent syncope or sudden cardiac death. Long QT syndrome affects an estimated one in 2000 people worldwide.1 The molecular basis of long QT syndrome is heterogeneous. It is caused by mutations in one of several genes, including KCNQ1, HERG, KCNJ2, KCNE1, and KCNE2 encoding potassium channel subunits, the cardiac sodium channel gene SCN5A, L-type calcium channel gene CACNA1C, and ANK2, a membrane-anchoring gene.2 Mutations involving the gene HERG are responsible for long QT syndrome type 2 (LQT2).2, 3 In cellular expression studies, HERG mutations are associated with reduction in the rapid component of the delayed rectifier repolarizing current IKr.4 Diminution in the repolarizing IKr current contributes to lengthening of the QT interval, the ECG hallmark of LQT2.
Cardiac IKr channels are composed of HERGa and HERGb subunits,5 which differ in their amino terminal sequence. Functional HERG channels result from coassembly of four HERG subunits (HERGa and HERGb) into a tetrameric protein. Proposed molecular mechanisms that may account for reduced IKr current in patients with HERG mutations are disruption of protein synthesis, protein trafficking, gating, or permeation, and degradation of mutant mRNA by the nonsense-mediated mRNA decay (NMD) pathway.6, 7, 8 Homozygous missense mutations in HERG are associated with a severe form of long QT syndrome,9, 10 with symptoms appearing in the early years of life. Natural human knockout of HERGa, the larger isoform, has more severe effects, with intrauterine fetal death and severe fetal arrhythmias in newborns diagnosed in utero with tachyarrhythmias.11 Biallelic nonsense mutations affecting both HERG isoforms (HERGa and HERGb) have not been described.
We studied a family with recurrent stillbirths and neonatal/intrauterine long QT syndrome in whom the disease locus was mapped to HERG and a HERG mutation segregating with disease was identified, but cell surface expression and electrophysiology were normal. Because the mutation truncated the distal C-terminus of the protein, we examined whether loss of interaction with the HERG C-terminus interacting protein 14-3-3ϵ contributed to the phenotype. We also investigated the hypothesis that Q1070X results in accelerated mRNA degradation and thus failure of protein translation, the phenomenon of “nonsense-mediated decay” recently implicated as a mechanism for loss of function in ion channel and other diseases.
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Clinical data
The study was performed according to a protocol approved by the local ethics committee. The patients studied were the offspring of asymptomatic, consanguineous, Arabian parents (see Figure 1A). The mother had two miscarriages at 8 (II:1) weeks and 10 (II:2) weeks of pregnancy, followed by delivery of a stillborn (II:3) hydropic baby with reported irregular heartbeat at week 29 of pregnancy. Autopsy, complete workup of the stillbirth, and chromosome culture were performed. The fourth pregnancy
II:5
Fetal bradycardia with a heart rate of approximately 90 bpm without fetal hydrops was noted at 22 weeks, and the patient (I:2) was referred to a tertiary fetal medicine unit. Fetal echocardiography performed at 23+2 weeks of gestation showed persistent ventricular tachycardia and hydrops with mild ascites, pericardial and pleural effusions, and skin edema. Ventricular rates were 210–220 bpm, and atrial rates were 120–130 bpm. The fetal heart was structurally normal; however, important
Discussion
TheHERG gene encodes IKr, the rapid component of the delayed rectifier current. Heterozygous missense mutations and mutations giving rise to premature truncations are causally involved in LQT2. The HERG nonsense mutation Q1070X described in this study is expected to lead to a premature termination codon at the C-terminal region of HERG channels. The parents in this study are consanguineous, and both are heterozygous for the same mutation. The heterozygous carriers display virtually no clinical
Conclusion
This study, which was based on homozygosity for the nonsense Q1070X mutant, demonstrates that degradation of the mutant HERG mRNA by NMD causes almost complete loss of HERG, leading to a severe exclusively cardiac phenotype that presumably includes miscarriages and stillbirth. Because our data show that the Q1070X mutant can form HERG channels with near-normal function, interventions to prevent degradation of mutant mRNA transcripts might be a therapeutic approach for homozygous HERG Q1070X
Acknowledgments
We thank Dr. Abdulraouf Al Saeedi and Dr. Saad Alyousef, Prince Sultan Cardiac Center, Riyadh, Saudi Arabia, for expert consultations and F. Hossenia-Salehi for laboratory assistance.
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Dr. Wilde was supported by the Netherlands Heart Foundation (NHS 2003T302). Dr. Zhou is supported by National Institutes of Health Grant HL68854.