# Pathogenic role of SAT1 variants in monogenic lupus

> **NIH NIH R21** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2020 · $164,450

## Abstract

Abstract: Systemic lupus erythematosus (SLE) is a debilitating autoimmune disease with a multifactorial etiology
contributed by genetic, epigenetic and environmental factors. The pathogenesis of SLE is complex. In most
cases, genetic susceptibility of SLE is attributed to the overall genetic risk of multiple common variants that each
gene confers a small effect. However, in few cases of SLE, especially early-onset pediatric SLE, is caused by
highly penetrant single gene variants. Monogenic forms of SLE are usually associated with strong family history,
early-onset disease and male gender and result in severe clinical manifestations. Identification of monogenic
causes of lupus, although rare, offers important insight into understanding SLE pathogenesis. 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 each family, we identified an exonic variant
in an X-linked gene SAT1. These two variants presumably lead to the loss-of-function of SAT1. Both variants
are inherited in the X-linked recessive pattern and they are extremely rare in the population (absent in > 200,000
individuals). Taken together, we identified SAT1 as a novel gene associated with monogenic lupus. SAT1
encodes the spermidine/spermine-N1-acetyltransferase (SSAT), a rate-limiting enzyme that regulates the
catabolism of polyamine. We hypothesize that loss-of-function SAT1 variants may cause dysregulated polyamine
homeostasis which confers risk of SLE. To further evaluate the causality of STA1 variants in SLE, we propose
to identify additional SAT1 variants by DNA sequencing and investigate the functional impact of these variants
using cell-based assays and pristane-induced mouse model of lupus. We propose to assess the impact of SAT1
variants on mRNA splicing, protein production, SSAT enzyme activity, polyamine levels, reactive oxygen species
(ROS) levels and manifestation of lupus-related phenotypes. Results from these studies will enhance our
understanding of this novel gene and pathway in lupus pathogenesis. The information gained could help develop
drugs to target the pivotal cellular and/ or molecular pathways responsible for SAT1-mediated risk for
consideration of SLE therapies.

## Key facts

- **NIH application ID:** 9920091
- **Project number:** 5R21AR074691-02
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** BETTY P TSAO
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $164,450
- **Award type:** 5
- **Project period:** 2019-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9920091

## Citation

> US National Institutes of Health, RePORTER application 9920091, Pathogenic role of SAT1 variants in monogenic lupus (5R21AR074691-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9920091. Licensed CC0.

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