The human Δ1261 mutation of the HERG potassium channel results in a truncated protein that contains a subunit interaction domain and decreases the channel expression

HERG (human eag-related gene) encodes an inward-rectifier potassium channel formed by the assembly of four subunits. Since the truncated HERG protein in patients with long QT syndrome induces a dominant phenotype, that is, cardiac sudden death, the assembly of nonfunctional complexes between wild-type and mutated subunits was implicated in causing the disease. To understand HERG-mediated cardiac sudden death at the molecular level, it is important to determine which regions in the HERG protein participate in subunit interaction. We therefore report the identification of a subunit interaction domain, NAB(HERG), that is localized at the hydrophilic cytoplasmic N terminus and can form a tetramer in the absence of the rest of the HERG protein. Truncated HERG proteins containing NAB(HERG), including one that resulted from the Δ1261 human mutation, inhibit the functional expression of the HERG channel in transfected cells. Together, these results support the notion that the expression of HERG in the human heart may be decreased in the presence of the truncated subunit. Such a decrease of potassium channel expression can contribute to the longer QT intervals observed in the patients with the HERG mutation.