Adenosine deaminase acting on RNA 1 (ADAR1) is a vital protein required to edit endogenous dsRNA. RNA editing by ADAR1 of the cells own RNA in turn prevents inappropriate activation of innate immune pathways in response to any unedited dsRNA. An under- or over-expression of ADAR1 can lead to human pathologies ranging from autoimmune diseases to cancers. Yet, the mechanism and contribution of the distinct ADAR1 isoforms in these diseases remain to be understood. ADAR1p150 is the longest isoform of ADAR1 and specifically responsible for editing RNAs in the cytoplasm. It has been demonstrated that this inhibits inappropriate activation of viral RNA sensors such as MDA5. However, a research gap remains relating to a more detailed understanding of the contribution and interactions of ADAR1p150 in cells and the effect of ADAR1p150 loss on somatic homeostasis. Here, we describe a novel mouse mutant, Adar1L196C, with a point mutation in ADAR1p150 that results in loss of this isoform. This new line enables identification of the mechanisms of ADAR1p150 in vivo, hence, addressing the research gap. The mutant mice lacking expression of ADAR1p150 had: (1) a significant interferon response in the presence of MDA5, consistent with the role of the p150 isoform of ADAR1 in MDA5-dependent immune activation; (2) abnormal haematopoiesis and tissue development. These data suggest important editing roles of ADAR1p150 in vivo; more importantly, establishing this mouse model will pave the way for investigating the mechanism and functions of the ADAR1 p150 isoform and it’s RNA targets in human diseases.