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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 Liu3,
  7. Yunjuan Wu2,
  8. Jingfeng Zhu4,
  9. Linyu Geng1,
  10. Yun Deng1,
  11. Alexander Awgulewitsch5,
  12. Diane L Kamen1,
  13. Jim C Oates1,6,
  14. Prithvi Raj7,
  15. Edward K Wakeland7,
  16. R Hal Scofield8,9,10,
  17. Joel M Guthridge8,11,
  18. Judith A James8,9,
  19. Bevra H Hahn12,
  20. Deborah K McCurdy13,
  21. Fang Wang14,
  22. Miaojia Zhang2,
  23. Wenfeng Tan2,
  24. Gary S Gilkeson1,6,
  25. Betty P Tsao1
  1. 1 Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
  2. 2 Department of Rheumatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
  3. 3 Department of Rheumatology and Immunology, Wuxi People’s Hospital, Wuxi, Jiangsu, People's Republic of China
  4. 4 Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
  5. 5 Department of Regenerative Medicine and Cell Biology, Transgenic and Gene Function Core, Medical University of South Carolina, Charleston, South Carolina, USA
  6. 6 Ralph H. Johnson VA Medical Center, Medical University of South Carolina, Charleston, South Carolina, USA
  7. 7 Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
  8. 8 Arthritis & Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
  9. 9 Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
  10. 10 US Department of Veterans Affairs Medical Center, Oklahoma City, OK, USA
  11. 11 Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
  12. 12 Division of Rheumatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
  13. 13 Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA
  14. 14 Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
  1. Correspondence to Dr Betty P Tsao, Division of Rheumatology and Immunology, Department of Medicine, Medical Universisty of South Carolina, Charleston 29425, South Carolina, USA; tsaob{at}musc.edu

Abstract

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 patients with SLE. 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 Sat1 p.Glu92Leufs*6 KI mice spontaneously developed splenomegaly, enlarged glomeruli with leucocyte 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-naive, incipient SLE patients.

Conclusions We identified two novel SAT1 LOF 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.

  • Lupus Erythematosus, Systemic
  • Autoimmune Diseases
  • Immune System Diseases

Data availability statement

Data are available upon reasonable request.

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Data availability statement

Data are available upon reasonable request.

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Footnotes

  • Handling editor Josef S Smolen

  • LX, JZ and QS contributed equally.

  • Contributors BPT, LX and JZhao designed the study; DLK, JO, GG, PR, EKW, RHAS, JMG, JJ, BH and DKMC provided DNA samples, clinical and demographic information of patients with SLE; JZhao analysed whole exome sequencing data and identified SAT1 as the SLE-risk gene; LX and LG performed mouse breeding, apoptotic cell induction and sample preparation; AA performed CRISPR/Cas9-mediated genome editing of mice; LX conducted most of the mouse and human in vitro assays; XX and LW performed ELISA and spleen index assay; QS performed Western blot and autophagy assay; FW, MZ, WT and TL conducted patient data and serum sample collection as well as medical evaluation and analysis; LX, YD and JZhao performed Sanger sequencing analyses; LX performed minigene assay; LX and JZhao analysed data and performed statistical analyses; YW and LX performed ANA score assessment of mice; JZhu performed renal assessment of mice; BPT and LX drafted the manuscript; BPT is responsible for the overall content as the guarantor; all authors edited and reviewed the manuscript.

  • Funding This work was supported by the following grants: NIH R21074691 (grant to BPT).

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.