Spontaneous mutant mice that showed high levels of serum
IgE and an
atopic dermatitis (AD)-like
skin disease were found in a colony of the KOR inbred strain that was derived from Japanese wild mice. No segregation was observed between hyper-
IgE-emia and
dermatitis in (BALB/c x KOR mutant) N(2) mice, suggesting that the mutation can be attributed to a single recessive locus, which we designated adjm (
atopic dermatitis from Japanese mice). All four adjm congenic strains in different genetic backgrounds showed both hyper-
IgE-emia and
dermatitis, although the disease severity varied among strains. Linkage analysis using (BALB/c x KOR-adjm/adjm) N(2) mice restricted the potential adjm locus to the 940 kb between D10Stm216 and D10Stm238 on chromosome 10. Sequence analysis of genes located in this region revealed that the gene AI429613, which encodes the mouse homologue of the human TNFR-associated factor 3-interacting
protein 2 (TRAF3IP2)
protein (formerly known as
NF-kappaB activator 1/connection to
IkappaB kinase and stress-activated
protein kinase/Jun
kinase), carried a single point mutation leading to the substitution of a stop
codon for
glutamine at
amino acid position 214. TRAF3IP2 has been shown to function as an adaptor
protein in signaling pathways mediated by the TNFR superfamily members CD40 and
B cell-activating factor in epithelial cells and B cells as well as in the IL-17-mediated signaling pathway. Our results suggest that malfunction of the TRAF3IP2
protein causes hyper-
IgE-emia through the CD40- and
B cell-activating factor-mediated pathway in B cells and causes skin
inflammation through the IL-17-mediated pathway. This study demonstrates that the TRAF3IP2
protein plays an important role in AD and suggests the
protein as a therapeutic target to treat AD.