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902 Loss-of-function variants in SAT1 cause X-linked Childhood-onset Systemic Lupus Erythematosus
  1. Lingxiao Xu1,2†,
  2. Jian Zhao1†,
  3. Qing Sun1†,
  4. Xue Xu1,
  5. Lei Wang1,
  6. Ting Liu10,
  7. Yunjuan Wu2,
  8. Jingfeng Zhu11,
  9. Linyu Geng1,
  10. Yun Deng1,
  11. Alexander Awgulewitsch12,
  12. Diane L Kamen1,
  13. Jim C Oates1,8,
  14. Prithvi Raj3,
  15. Edward K Wakeland3,
  16. R Hal Scofield4,5,
  17. Joel M Guthridge4,6,
  18. Judith A James4,6,
  19. Bevra H Hahn13,
  20. Deborah K McCurdy7,
  21. Fang Wang9,
  22. Miaojia Zhang2,
  23. Wenfeng Tan2,
  24. Gary S Gilkeson1,8 and
  25. Betty P Tsao1*
  1. 1Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
  2. 2Department of Rheumatology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
  3. 3Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
  4. 4Arthritis & Clinical Immunology Research Program, Division of Genomics and Data Sciences, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
  5. 5Veterans Affairs Medical Center, Oklahoma City, OK, USA
  6. 6Oklahoma Clinical and Translational Science Institute, University of Oklahoma Health Sciences Center, 920 NE Stanton L. Young, Oklahoma City, OK, USA
  7. 7Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, 90095, USA
  8. 8Ralph H. Johnson VA Medical Center, Medical Service, Charleston, SC, USA
  9. 9Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
  10. 10Department of Rheumatology and Immunology, Wuxi People’s Hospital, Wuxi, Jiangsu, China
  11. 11Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
  12. 12Cardiovascular Developmental Biology Center, Department of Regenerative Medicine and Cell Biology, College of Medicine, Children’s Research Institute, Medical University of South Carolina, Charleston, South Carolina, USA
  13. 13Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
  14. *Presenter.


Objectives Families that contain multiple siblings affected with childhood-onset of systemic lupus erythematosus (SLE) likely have strong genetic predispositions. We performed whole-exome sequencing (WES) to identify familial rare risk variants and to assess their effects in lupus.

Methods Sanger sequencing validated the two ultra-rare, predicted pathogenic risk variants discovered by WES and identified additional variants in 562 additional SLE patients. Effects of a splice site variant and a frameshift variant were assessed using a Minigene assay and CRISPR/Cas9-mediated knock-in (KI) mice, respectively.

Results The two familial ultra-rare, predicted loss-of-function (LOF) SAT1 variants exhibited X-linked recessive Mendelian inheritance in two unrelated African-American families. Each LOF variant was transmitted from the heterozygous unaffected mother to her two sons with childhood-onset SLE. The p.Asp40Tyr variant affected a splice donor site causing deleterious transcripts. The young hemizygous male and homozygous female Sat1p.Glu92Leufs*6 KI mice spontaneously developed splenomegaly, enlarged glomeruli with leukocyte infiltration, proteinuria and elevated expression of type I interferon inducible genes. SAT1 is highly expressed in neutrophils and encodes spermidine/spermine-N1-acetyltransferase 1 (SSAT1), a rate-limiting enzyme in polyamine catabolism. Young male KI mice exhibited neutrophil defects and decreased proportions of Foxp3+CD4+ T-cell subsets. Circulating neutrophil counts and proportions of Foxp3+CD4+ T cells correlated with decreased plasma levels of spermine in treatment naïve, incipient SLE patients.

Conclusions We identified two novel SAT1 loss-of-function variants, showed the ability of the frameshift variant to confer murine lupus, highlighted the pathogenic role of dysregulated polyamine catabolism, and identified SAT1 LOF variants as new monogenic causes for SLE.

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