The role of polyamine catabolism in the development of lupus
Discovering genetic causes of lupus helps researchers identify new therapies. Dr. Tsao and colleagues identified a defect in the SAT1 gene located on the X chromosome that may be associated with lupus in children, especially in boys. While studying mice with the defective SAT1 gene that codes for a factor that helps control amounts of a nutrient called polyamine, which cells need to remain healthy, Dr. Tsao’s research team found that young male mice, like young boys, developed lupus-like autoimmune disease. Furthermore, the research team discovered that mice with the defective SAT1 gene also have abnormal levels of factors controlling polyamine related nutrients, suggesting that difficulties in maintaining polyamine nutrients at healthy levels could cause lupus. Using this grant, Dr. Tsao will investigate how this disruption in healthy polyamine levels caused by the SAT1 gene defect contributes to lupus in children. She will also test if nutritional supplements such as the naturally occurring nutrient spermidine could help restore the healthy polyamine levels and alleviate lupus symptoms in mice with the SAT1 gene defect.
What this study means for people with lupus
This work may reveal new causes of lupus, particularly childhood-onset lupus. Study findings may also suggest new treatment options for people with lupus caused by this genetic variant.
Monogenic forms of SLE are usually associated with strong family history, early-onset disease, and often result in severe clinical manifestations. Identification of monogenic causes of lupus, although rare, offers important insight into understanding of SLE pathogenesis and may increase the number of targets for treatment development. In our preliminary study, we carried out whole-exome sequencing to identify underlying monogenic causes from two multiplex families that each family has two boys with childhood onset SLE. In the X-linked recessive inheritance pattern, we identified one family has a frameshift mutation and the other has a deleterious missense variant the SAT1 gene. Both variants are extremely rare in the population (absent in > 200,000 individuals). SAT1 encodes the spermidine/spermine-N1-acetyltransferase-1 (SSAT1), a rate-limiting enzyme highly expressed in human neutrophils that regulates the catabolism of polyamine. We hypothesize that loss-of-function SAT1 variants are monogenic causes of SLE in these two families due to dysregulated polyamine homeostasis, and establish the frameshift Sat1 knock in (KI) mutation in C57BL/6J background as a mouse model to test its causality for lupus. Compared to wild type littermates, 5-10-wk-old male KI mice exhibit lupus-like glomerulonephritis, proteinuria, anti-dsDNA, type I interferon signature, multiple neutrophil functional defects and decreased Foxp3+CD4+ T cells that could be aggravated by systemic exposure to dying WT cells. To understand how perturbed polyamine catabolism links to the development of lupus-like autoimmunity, we propose to address: (1) What are key intermediates of polyamine and methionine metabolism in neutrophils associated with their functional defects observed in 5-wk-old KI male mice? (2) What differentially expressed transcripts in bone marrow-derived neutrophil subsets could cause their functional defects in 5-wk-old KI male mice? (3) Could spermidine promote Foxp3+CD4+ T-cell polarization in vitro and ameliorate lupus-like autoimmunity of KI mice in vivo? Our findings will provide novel insights into mechanisms underlying the SAT1 monogenic lupus and may provide new treatment options for SLE patients.