Homozygous premature truncation of the HERG protein - The human HERG knockout

Background-In long-QT syndrome (LQTS), heterozygosity for a mutation in 1 o f the K+ channel genes leads to prolongation of the cardiac action potentia l, 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 b y the premature birth of a child in distress due to ventricular arrhythmia in the presence of QT prolongation. LQTS was diagnosed, beta-blocker therap y 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 duplicat ion 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 p rotein. Because it is present on both alleles, no functional I-Kr is antici pated. The same mutation was found heterozygously in both parents and homoz ygously in the stillborn brother. Conclusions-It is concluded that absence of I-Kr gives rise to a severe car diac phenotype, with no indication of malfunction of any other organ.