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Human Molecular Genetics Advance Access published online on January 13, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi055
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Human Molecular Genetics © Oxford University Press 2005; all rights reserved

Article

Common arterial trunk associated with a homeodomain mutation of NKX2.6

Kirsten Heathcote 1, Claire Braybrook 2, Lulu Abushaban 3, Michelle Guy 1, Maher E. Khetyar 1, Michael A. Patton 1, Nicholas D. Carter 1, Peter J. Scambler 2*, and Petros Syrris 1

1 Department of Clinical Developmental Science, St George's Hospital Medical School, London, SW17 ORE, UK
2 Molecular Medicine Unit, Institute of Child Health, London WC1N 1EH, UK
3 Department of Cardiology, The Chest Hospital, Kuwait City, 13041 Safat, Kuwait

* To whom correspondence should be addressed.
Peter J. Scambler, E-mail: p.scambler{at}ich.ucl.ac.uk


  Abstract

Persistent truncus arteriosus (PTA) is a failure of septation of the cardiac outflow tract into the pulmonary artery and the aorta. A common arterial trunk (CAT) is often diagnosed as PTA in absence of evidence of embryological mechanism. We have used autozygosity mapping of a large consanguineous family segregating CAT to map the causative locus to chromosome 8p21. An F151L mutation was identified in the homeodomain of NKX2.6, a transcription factor expressed in murine pharyngeal endoderm and embryonic outflow tract myocardium. While expression of Nkx2.6 during murine embryogenesis is strongly suggestive of a role for this gene in heart development, mice homozygous for a targeted mutation of Nkx2.6 are normal. However, in these mice it has been shown that Nkx2.5 expression expands into regions lacking Nkx2.6 suggesting functional complementation. As transcriptional targets of NKX2.6 are unknown, we investigated functional effects of the mutation in transcriptional and protein interaction assays using NKX2.5 as a surrogate. Introduction of F157L into human NKX2.5 substantially reduced its transcription activating function, its synergism with partners at the atrial natriuretic factor (ANF) and connexin-40 (Cx40) promoters, and its specific DNA binding. We tested NKX2.5 target promoters for NKX2.6 activity. NKX2.6 was inactive at ANF but weakly activated transcription of a Cx40 promoter, whereas the F151L mutant lacked this activity. These findings indicate a previously unsuspected role for NKX2.6 in heart development which should be re-evaluated in more sophisticated model systems.


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