The KCNH2 gene is located on chromosome 7q36.1, where it gives instructions for making the pore-forming (alpha) subunit of voltage-gated potassium channel (KV). This protein, made up of 1159 amino acids and weighing about 127 kDa, belongs to the 6-TM family of potassium channel. The KCNH2 subunits oligomerize to form a tetramer that inserts into the cell membrane to form the functional K+ channel, which is active in cardiac muscles. These subunits are involved in recharging the cardiac muscle after each heartbeat to maintain a regular rhythm.
Defects in the KCNH2 protein are the cause of long QT syndrome 2, and Short QT syndrome 1. Long QT syndrome is a disorder of the heart's electrical activity, characterized by a prolongation of the QT interval at basal ECG and by a high risk of life-threatening arrhythmias.
The KCNH2 gene consists of 15 coding exons, and spans approximately 33 kb in the genomic DNA. Over 500 mutations have been identified in this gene in patients with long QT syndrome. These mutations lead to a reduction in the rapid component of the delayed rectifier repolarizing current (IKr), which contributes to a lengthening of the QT interval. Also, at least two mutations in the KCNH2 gene have been found to cause short QT syndrome.
Bhuiyan et al. (2009) performed genetic analysis for six Saudi families affected with long QT syndrome; two of them had Long QT syndrome 1 and four had long QT syndrome 2. Entire coding exons of the genes KCNQ1, KCNH2, and SCN5A were sequenced. Three novel mutations in the KCNH2 were found in the probands of the four families with long QT syndrome 2. A heterozygous c.2362 G>A mutation was identified in the first family, resulting in a p.Glu788Lys amino acid substitution. A compound heterozygous mutations were identified in the second family; a c.1609 C>T mutation, resulting in p.Arg537Trp amino acid substitution, and a nucleotide duplication at position 2334, resulting in a premature termination of the protein (p.Ile782fsX22). The father was a carrier for the p.Ile782fsX22 mutation, and the mother was a carrier for the p.Arg537Trp mutation. A homozygous c.3208 C>T mutation was identified in the third and fourth families with recessive LQT syndrome 2. This mutation resulted in a p.Q1070 amino acid substitution. Both families originated from the Assir region, and were not related. In another study, Bhuiyan et al. (2014) conducted exome sequencing on two sisters with conotruncal heart defects. No pathogenic mutations were found in any of the genes known to be involved in cardiogenesis. However, two pathogenic mutations, p.Val172Met and p.Arg293Cys, were identified in the KCNH2 gene. These mutations were unlikely to be the cause of the malformation, since both the normal mother and an unaffected sister carried them too. Bhuiyan et al. (2014) considered whether these mutations would have any impact on the propensity of arrhythmia in these children with conotruncal defects. However, they did not observe any such effect.
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