RAG1 or RAG2 mutations are associated with defects in V(D)J recombination activity, causing severe immunodeficiency with a wide spectrum of clinical phenotypes. A R229Q mutation of RAG2 was identified in patients with severe combined immunodeficiency (SCID) or Omenn syndrome (OS). Although some factors determining the clinical features between SCID and OS were not clear, the molecular mechanism of OS was studied in a mouse model in which an EGFP tag is fused to Rag2 with the R229Q mutation. To design the human disease model mimicking severe immunodeficiency, we generated Rag2-R229Q knock-in mice without an epitope tag. Mutant mice showed impaired T and B cell differentiation with reduced V(D)J recombination activity; however, the extent to which the R229Q mutation affects severe immunodeficiency was not severe. While Rag2-R229Q mutation under some conditions may cause severe immunological and clinical phenotypes similar to human SCID or OS, R229Q mutation per se did not cause severe immunodeficiency in mice, suggesting that additional factors other than R229Q mutation are required to induce severe immunodeficiency. Thus, our report implies that the effects of genetic background and/or a tagged protein sequence may alter the mouse immune system, revealing the mechanism of phenotypic heterogeneity arising from an identical mutation.

Colorectal cancer is the second most lethal cancer type across all ages and sexes, the many mechanisms of which are still currently being further elucidated. PIERCE1 has been known to be involved in the cell cycle and proliferation, the expression of which is regulated by stress conditions in a p53-dependent manner. Through a database search, we found that PIERCE1 was significantly augmented in patients with colorectal carcinoma compared to normal samples, suggesting its possible role in tumor regulation. Recently, PIERCE1 has also been reported to increase proliferation of a liver cancer cell line, indicating its possible role as an oncogene. To examine its relevance to tumorigenesis, such as whether it has either oncogenic or tumor suppressive function, PIERCE1 was knocked down and overexpressed in several colorectal cancer cell lines and mice, respectively. To evaluate the roles of Pierce1 in vivo , we established a Pierce1 transgenic (TG) mouse model and then administered azoxymethane with dextran sodium sulfate (DSS) to induce colorectal carcinogenesis via promoting mutations in Apc and Kras . Nonetheless, PIERCE1 depletion in these cell lines showed no significant change in cell growth. AOM/DSS-treated Pierce1 TG mice were comparable with respect to colon lengths, the number of polyps, and tumor sizes to those of the control mice. These results implicate that PIERCE1 does not play an oncogenic or tumor suppressive role in AOM/DSS-induced colorectal cancer.