As noted above, CDH and related birth defects occur in random combinations, but the mechanistic basis for this phenotypic variability has remained an enigma. Recent studies suggest that bimodal gene expression, triggered by haploinsufficiency for transcription factors or signaling molecules, may underlie this phenomenon.
Transcriptional regulation is commonly viewed as a “rheostatic” process in which promoter activity increases proportionally in response to rising levels of a particular transcriptional activator (128
). Under the rheostatic model, transcription factor haploinsufficiency leads to uniform reductions in target gene levels in all mesenchymal cells. An alternative to this model is the binary model of transcriptional activation (128
). This model implies that genes exist in either an “on” or an “off” state and that transcription factors regulate the probability of a gene occupying either state. Accordingly, transcription factor haploinsufficiency impacts the bimodal distribution of cells that either express or do not express a target gene.
The accumulation of a separate population of “non-expressing” mesenchymal cells in sensitive areas of a particular organ could trigger a focal structural abnormality, such as a diaphragmatic hernia or valvuloseptal cardiac defect. Alternatively, the presence of expressing and non-expressing cells might impair morphogenesis by disrupting signaling molecules that influence cell migration. Indeed, the bimodal population of expressing and non-expressing cells in EFNB1+/–
) is reminiscent of the situation encountered under the binary model of transcription factor haploinsufficiency. Similarly, bimodal expression of an anti-apoptotic factor could be the direct pathogenic mechanism of CDH and related defects. Gata4
heterozygosity has been associated with a small but significant increase in the number of apoptotic cells in the stressed heart and in the developing diaphragm of the mouse (57
). One can imagine that the increased incidence yield a higher probability of a cluster of cells in the diaphragm or heart that all die, leading to a structural defect.
Another potential cause of bimodal gene expression is somatic mutagenesis. Recently, investigators have detected somatic mutations in GATA4
and other “cardiac” transcription factors in the hearts of patients who died of congenital heart disease (132
). Thus, somatic mutations that arise during cardiogenesis may be a novel molecular cause of congenital heart disease, and it is conceivable that somatic mutations in transcription factor genes contribute to the pathogenesis of CDH.