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.

Tako-tsubo syndrome encompasses heterogeneous patient populations and it is likely that different pathogenic mechanisms may operate in different patients. Treatment of the condition is at present empirical and aimed at preserving ventricular function.

Mutations in the gene encoding the TFAP2B transcription factor can cause Char syndrome with cardiac, craniofacial, and hand abnormalities. However, TFAP2B mutations result in great phenotypic variability, which is believed to reflect different expression patterns of tissue-specific TFAP2 coactivators. We investigated a consanguineous family with isolated patent ductus arteriosus (PDA) for mutations in TFAP2B. Our study suggests that a novel splicing mutation in TFAP2B can cause isolated PDA without other clinical features.

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