TY - JOUR AU - Soukup, Alexandra A. AU - Zheng, Ye AU - Mehta, Charu AU - Wu, Jun AU - Liu, Peng AU - Cao, Miao AU - Hofmann, Inga AU - Zhou, Yun AU - Zhang, Jing AU - Johnson, Kirby D. AU - Choi, Kyunghee AU - Keles, Sunduz AU - Bresnick, Emery H. T1 - Single-nucleotide human disease mutation inactivates a blood-regenerative GATA2 enhancer PY - 2019/03/01/ AB - The development and function of stem and progenitor cells that produce blood cells are vital in physiology. GATA-binding protein 2 (GATA2) mutations cause GATA-2 deficiency syndrome involving immunodeficiency, myelodysplastic syndrome, and acute myeloid leukemia. GATA-2 physiological activities necessitate that it be strictly regulated, and cell type–specific enhancers fulfill this role. The +9.5 intronic enhancer harbors multiple conserved cis-elements, and germline mutations of these cis-elements are pathogenic in humans. Since mechanisms underlying how GATA2 enhancer disease mutations impact hematopoiesis and pathology are unclear, we generated mouse models of the enhancer mutations. While a multi-motif mutant was embryonically lethal, a single-nucleotide Ets motif mutant was viable, and steady-state hematopoiesis was normal. However, the Ets motif mutation abrogated stem/progenitor cell regeneration following stress. These results reveal a new mechanism in human genetics, in which a disease predisposition mutation inactivates enhancer regenerative activity, while sparing developmental activity. Mutational sensitization to stress that instigates hematopoietic failure constitutes a paradigm for GATA-2 deficiency syndrome and other contexts of GATA-2–dependent pathogenesis. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI122694 VL - 129 IS - 3 UR - https://doi.org/10.1172/JCI122694 SP - 1180 EP - 1192 PB - The American Society for Clinical Investigation ER -