B6-huC3*R102G Mouse

Complement component C3 plays a central role in activating the complement system and is the most abundant complement protein in human plasma, primarily synthesized in the liver. As part of the innate immune system, the complement system is activated during tissue damage and pathogen invasion, playing a crucial role in the inflammatory response, host homeostasis, and pathogen defense. The complement cascade is activated through the classical pathway, alternative pathway, and lectin pathway, all of which generate C3 convertase, which cleaves C3 into C3a and C3b. C3a is a potent anaphylatoxin with pro-inflammatory activity, while C3b is a regulator that induces C5 cleavage, thereby participating in the dissolution and clearance of immune complexes. Mutations in this gene are associated with atypical hemolytic uremic syndrome (aHUS) and age-related macular degeneration (AMD). Deficiencies in C3 and C3-derived peptides can lead to autoimmune diseases (such as rheumatoid arthritis, systemic lupus erythematosus, and vasculitis) and make individuals susceptible to recurrent respiratory infections and infections caused by encapsulated organisms. Conversely, excessive activation of C3 and related complement components is associated with kidney diseases (immune complex glomerulonephritis, hemolytic uremic syndrome, lupus nephritis, membranous nephropathy, and immune-mediated nephropathy) ^[1-2]. Specifically, the C3*R102G mutation involves a substitution of the amino acid arginine (R) with glycine (G) at position 102 of the mature C3 protein, often leading to a gain-of-function that results in the protein being more susceptible to cleavage and thus causing uncontrolled complement activation ^[3].

The B6-huC3*R102G mouse is a humanized disease model constructed by gene-editing technology. The sequences from upstream of exon 1 to the TGA stop codon of mouse C3 were replaced with the sequences from upstream of exon 1 to downstream of exon 41 of human C3. The p.R102G (CGC to GGC) mutation was introduced into human C3 exon 3. This model is suitable for the mechanistic study of immune-related diseases caused by uncontrolled activation of the complement system (such as age-related macular degeneration (AMD), etc.) and the development of therapies targeting C3 R102G.