A new hypothesis to explain disease dominance

The onset and progression of dominant diseases are thought to result from haploinsufficiency or dominant negative effects. Here, we propose transcriptional adaptation (TA), a newly identified response to mRNA decay, as an additional cause of some dominant diseases. TA modulates the expression of so-called adapting genes, likely via mRNA decay products, resulting in genetic compensation or a worsening of the phenotype. Recent studies have challenged the current concepts of haploinsufficiency or poison proteins as the mechanisms underlying certain dominant diseases, including Brugada syndrome, hypertrophic cardiomyopathy, and frontotemporal lobar degeneration. We hypothesize that for these and other dominant diseases, when the underlying mutation leads to mRNA decay, the phenotype is due at least partly to the dysregulation of gene expression via TA.