Human Molecular Genetics Advance Access originally published online on January 13, 2005
Human Molecular Genetics 2005 14(5):585-593; doi:10.1093/hmg/ddi055
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Human Molecular Genetics, Vol. 14, No. 5 © Oxford University Press 2005; all rights reserved
Common arterial trunk associated with a homeodomain mutation of NKX2.6
1Department of Clinical Developmental Science, St George's Hospital Medical School, London, SW17 ORE, UK, 2Molecular Medicine Unit, Institute of Child Health, London WC1N 1EH, UK and 3Department of Cardiology, The Chest Hospital, Kuwait City, 13041 Safat, Kuwait
* To whom correspondence should be addressed. Tel: +44 2079052635; Fax: +44 2079052609; Email: p.scambler{at}ich.ucl.ac.uk
Received October 19, 2004; Revised December 10, 2004; Accepted January 4, 2005
Persistent truncus arteriosus (PTA) is a failure of septation of the cardiac outflow tract (OFT) into the pulmonary artery and the aorta. A common arterial trunk (CAT) is often diagnosed as PTA in the 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 OFT myocardium. Although 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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  G. Piacentini, B. Marino, and M. C. Digilio Familial recurrence of discrete membranous subaortic stenosis J. Thorac. Cardiovasc. Surg., September 1, 2007; 134(3): 818 - 819. [Full Text] [PDF]
|
|
|
|
 |
|
 S M Reamon-Buettner and J Borlak Somatic mutations in cardiac malformations. J. Med. Genet., August 1, 2006; 43(8): e45 - e45. [Full Text] [PDF]
|
|
|
|
 |
|
 A. Inga, S. M. Reamon-Buettner, J. Borlak, and M. A. Resnick Functional dissection of sequence-specific NKX2-5 DNA binding domain mutations associated with human heart septation defects using a yeast-based system Hum. Mol. Genet., July 15, 2005; 14(14): 1965 - 1975. [Abstract] [Full Text] [PDF]
|
|