TREX1 Mutant Mouse Model
TREX1 is a powerful DNA exonuclease. Point mutations in the TREX1 gene cause a spectrum of lupus-like autoimmune diseases in humans. Knock-in mouse models with orthologous mutations express dysfunctional TREX1 enzyme so preventing DNA degradation and recapitulating systemic lupus and other human autoimmune diseases.
Scientists at Wake Forest School of Medicine have developed and validated a mouse model of lupus based on a genetic mutation present in patients with an inherited form of lupus, familial chilblain lupus. These patients have a heterozygous mutation in the TREX1 gene resulting in a dysfunctional TREX1 D18N enzyme that cannot effectively degrade double-stranded DNA. Impaired degradation of double-stranded DNA triggers cGAS and STING (stimulator of interferon genes) proteins, activating a downstream interferon-mediated immune response and systemic lupus. The TREX1 D18N mice exhibit various characteristics of human lupus, including systemic inflammation, lymphoid hyperplasia, vasculitis and kidney disease.
According to The Lupus Foundation of America, approximately 1.5 million Americans have some form of lupus, a chronic, debilitating autoimmune disorder. There are few therapeutics available, due primarily to a lack of understanding of pathways that cause the disease. While the characteristics of lupus are widely known – patients make antibodies to their own DNA that signal activation of the immune system and disease-response – there is a need for validated animal models of the disease to define mechanisms of DNA sensing and to advance effective autoimmune therapeutics.
A genetically defined validated mouse model of human lupus available for non-exclusive licensing
- Fred W. Perrino, PhD, Department of Biochemistry
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