KCNH2 Membrane Protein Introduction

Introduction of KCNH2

KCNH2, also known as potassium voltage-gated channel subfamily H (eag-related) member 2, potassium channel voltage gated eag related subfamily H member 2, ether-a-go-go-related potassium channel protein, HERG1, HERG-1, ERG1, HERG, Kv11.1, SQT1, LQT2, or ERG, is a membrane protein of 126.7 kDa that comprises 1159 amino acids. In humans, it is encoded by the KCNH2 gene which is mapped to the chromosome 17q36.1. The full-length KCNH2 contains an N-terminal Per-Arnt-Sim (PAS) domain that regulates the channel function. KCNH2 gene codes for a voltage-activated potassium channel, which is a member of the ether-a-go-go (eag) family, sharing sequence similarity with the Drosophila eag gene. Initially, KCNH2 is determined to contain 16 exons, ranging from 100-553 bp.

Function of KCNH2 Membrane Protein

KCNH2 provides instruction for making a pore-forming subunit of the rapidly activating delayed rectifier potassium channel and plays an important role in the final repolarization of the ventricular action potential. Channels formed by KCNH2 proteins are active in the cardiac muscle. They participate in recharging the cardiac muscle after each heartbeat to sustain a regular rhythm. The KCNH2 proteins are also generated in nerve cells and several immune cells in the brain and spinal cord. Further, the KCNH2 gene can interact with the KCNE2 gene that forms a functional potassium channel. Four alpha subunits, each derived from KCNH2, form the structure of each channel, while one beta subunit from KCNE2 attaches to the channel and modulates its activity. Loss of function mutations in KCNH2 probably induce long QT syndrome (LQT2), and gain of function mutations may cause short QT syndrome 1 (SQT1). These clinical disorders all stem from ion channel dysfunction that results in the risk of potentially fatal cardiac arrhythmias.

Fig.1 Protein structure of KCNH2.

Application of KCNH2 Membrane Protein in Literature

1. Fukumoto D., et al. Novel intracellular transport-refractory mutations in KCNH2 identified in patients with symptomatic long QT syndrome. J Cardiol. 2018, 71(4):401-408. PubMed ID: 29146210
   
   

   There are two new KCNH2 mutations disrupting the intracellular transport of Kv11.1. Low-temperature incubation could rescue the plasma membrane expression of Kv11.1-T826I but not G785D. These two mutations exert loss-of-function effects on Kv11.1 and explain the phenotypes of mutation carriers.

2. Yin C., et al. Unique ECG presentations and clinical management of a symptomatic LQT2 female carrying a novel de novo KCNH2 mutation. J Electrocardiol. 2018, 51(1):111-116. PubMed ID: 29037423
   
   

   This case report is about a 26-year-old woman, 12 days in postpartum, who develops recurrent syncope and cardiac arrest. Her ECG shows QT-prolongation correlated with LQT2-specific T-U wave patterns, long QT-dependent torsade de pointes (TdP), T wave alternans, and ventricular fibrillation (VF).

3. Smith J.L., et al. Functional invalidation of putative sudden infant death syndrome-associated variants in the KCNH2-encoded Kv11.1 channel. Circ Arrhythm Electrophysiol. 2018, 11(5):e005859. PubMed ID: 29752375
   
   

   The purpose of the study is to illustrate the pathological potential for rare nonsynonymous KCNH2 variants. Authors conclude that rare Kv11.1 missense variants are not long-QT syndrome subtype 2-causative variants and thus do not on behalf of the pathogenic substrate for the sudden infant death syndrome in variant-positive infants.

4. Jia P.L., et al. Postmortem analysis of 4 mutation hotspots of KCNQ1, KCNH2,and SCN5A genes in sudden unexplained death in southwest of China. Am J Forensic Med Pathol. 2018, 39(3):218-222. PubMed ID: 29851656
   
   

   Long QT syndrome (LQTS) is involved in several sudden unexplained death (SUD) cases. To elucidate whether pathogenic genes of LQTS participate in SUD in Yunnan province, China, 4 mutation hotspot segments of KCNQ1, KCNH2, and SCN5A genes are examined in 83 SUD cases by using PCR and direct DNA sequencing.

5. Seo S.H., et al. Application of multigene panel sequencing in patients with prolonged rate-corrected QT interval and no pathogenic variants detected in KCNQ1, KCNH2, and SCN5A. Ann Lab Med. 2018, 38(1):54-58. PubMed ID: 29071820
   
   

   This review investigates genetic causes in patients with prolonged heart rate-corrected QT (QTc) intervals who are negative for pathogenic variants in three major long QT syndrome (LQTS)-related genes, KCNQ1, KCNH2, and SCN5A. Later, the molecular genetic test is performed by a panel containing 13 LQTS-related genes and 67 additional genes.

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