Inflammatory arthritis is a multifactorial disease that is induced by complex combinations of genetic and environmental influences. Thus, characterization of a single factor triggering spontaneous inflammation is a major challenge in the field. Despite the accumulated evidence regarding systemic inflammatory diseases, only treatments targeting symptoms are available.
In a large-scale N-ethyl-N-nitrosourea mutagenesis project, the Ali14 (Ali for abnormal limb) mutant mouse strain was established because of dominant inheritance of spontaneous swelling and inflammation of the hind paws. In a genetic mapping approach and subsequent candidate gene sequencing the phospholipase Cγ2 gene (Plcg2) was identified as the causative gene. Systematic phenotyping of Ali14/+ mice was performed in the German Mouse Clinic to analyse the phenotype in detail.
The Ali14 mutation causes an amino acid substitution from AT to CG. The tyrosine residue is conserved among various vertebrates. The consequence of the transition is a greater responsiveness to a variety of upstream signals, such as epidermal growth factor (EGF) in vitro. Therefore Dr. Koichiro Abe and his colleagues conclude that Ali14 is a gain-of-function allele of Plcg2 (Plcg2Ali14).
The systemic phenotypic analysis in the GMC revealed the following phenotypic changes compared to wildtype animals:
- An abnormally high T cell to B cell ratio,
- up-regulation of IgG1, IgG2b and IgM,
- significantly reduced bone mineral content and bone mineral density,
- reduced fat mass and significant reduction in body weight in male Plcg2Ali14/+ mice,
- reduction in cholesterol, triglyceride levels and alkaline phosphatase in peripheral blood,
- reduced levels of dehydroepiandrosterone (DHEA) in male Plcg2Ali14/+ mice.
Plcg2 is a subtype of PLC (Phosphoinositide-specific phospholipase C). PLC contributes to the regulation of various biologic functions, such as cell motility, fertilization, and immunity via regulation of signal transduction. The results of the study suggest that the Plcg2-mediated pathways play a crucial role in various metabolic pathways and sperm function, in addition to initiating and maintaining the immune system. These findings may indicate the importance of the Ali14/+ mouse strain as a model for systemic inflammatory diseases and inflammation-related metabolic changes in humans.
A Novel N-ethyl-N-nitrosourea–Induced Mutation in Phospholipase Cγ2 Causes Inflammatory Arthritis, Metabolic Defects, and Male Infertility In Vitro in a Murine Model”, Abe et al., ARTHRITIS & RHEUMATISM, Vol. 63, No. 5, May 2011, pp 1301–1311