Homozygous premature truncation of the HERG protein : the human HERG knockout.

Background-In long-QT syndrome (LQTS), heterozygosity for a mutation in 1 of the K(+) channel genes leads to prolongation of the cardiac action potential, because the aberrant protein exhibits "loss of function." HERG, which is involved in LQT2, is the gene encoding the rapid component of the delayed rectifier, I(Kr). Methods and Results-In a consanguineous family, a stillbirth was followed by the premature birth of a child in distress due to ventricular arrhythmia in the presence of QT prolongation. LQTS was diagnosed, beta-blocker therapy was begun, and a pacemaker was implanted. She developed well and remained symptom-free for 1.5 years. In the index patient, we identified a duplication of bp 558 to 600 in exon 4 of HERG on both alleles. This will result in a frameshift and a premature stop codon before the S1 domain of the HERG protein. Because it is present on both alleles, no functional I(Kr) is anticipated. The same mutation was found heterozygously in both parents and homozygously in the stillborn brother. Conclusions-It is concluded that absence of I(Kr) gives rise to a severe cardiac phenotype, with no indication of malfunction of any other organ.