A knockout may not always be a knockout.

نویسنده

  • B London
چکیده

To the Editor: In a recent issue of Circulation, Hoorntje et al1 presented data on a family with a duplication in exon 4 of HERG. A consanguineous marriage resulted in 2 homozygous offspring: one died before birth and the other had a severe cardiac phenotype characterized by arrhythmias and conduction defects. The importance of these findings regarding the role of HERG in the heart is clear. The authors conclude that these homozygous individuals will lack functional IKr and that HERG likely plays no critical roles in other organs. Various laboratories have reported the existence of alternate HERG isoforms.2,3 One isoform, HERGb, begins at an alternate transcription start site between exons 5 and 6, is expressed in the heart, and encodes channels with deactivation kinetics more rapid than those of the longer HERGa isoform. A duplication in exon 4 of HERG would probably not affect HERGb, and homozygotes would probably have an isoformspecific “knockout” of HERGa. In addition, HERGb expression could be upregulated in response to the absence of HERGa, and the mutation could lead to altered splicing and some functional HERGa protein. When a gene is knocked out in an animal model, investigators design the targeting construct to abolish protein expression and/or function. In channels, a transmembrane domain is usually disrupted. The absence of RNA, protein, and protein activity is then confirmed. This is often not possible in humans homozygous for a cardiac mutation because cardiac tissue and cells are rarely available. Given these difficulties, the conclusions from patients with homozygous HERG mutations are necessarily limited, especially regarding the potential role of HERG in other organs. In addition, the term “knockout” should be restricted to animal models in which the absence of channel function is directly proven.

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عنوان ژورنال:
  • Circulation

دوره 102 18  شماره 

صفحات  -

تاریخ انتشار 2000