Figure 11. Human disease predisposition mutation segregates developmental versus regenerative enhancer functions.

Model depicts the +9.5(E-box Ets)^–/– HSC emergence and fetal liver hematopoietic defects, which phenocopy the previously described +9.5^–/– phenotype. Both mutations are embryonically lethal. In contrast, the human disease +9.5 Ets motif mutant is not an embryonically lethal mutation. In adult mice, the mutation impedes HSPC regeneration. We propose that the human mutation renders the hematopoietic system vulnerable to subsequent insults that demand HSPC regeneration to reestablish the steady state. The intimate connection between the predisposition mutation and mechanisms elicited by secondary insults may underlie the variable penetrance of disease onset in GATA-2 deficiency syndrome.