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Abstract Number: 2810

Does Loss-of-function Variants in SAT1 Cause X-linked Pediatric Lupus?

Ling-Xiao Xu 1, Jian Zhao 2, Qing Sun 2, Lin-Yu Geng 2, Yun Deng 2, Diane Kamen 2, Jim Oates 3, Prithvi Raj 4, Edward Wakeland 4, R.Hal Scofield 5, Joel Guthridge 6, Judith James 6, Deborah McCurdy 7 and Betty Tsao8, 1Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA., Charelston, SC, 2Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA., Charleston, SC, 3Division of Rheumatology & Immunology/Medical University of South Carolina, Charleston, SC, 4Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA., Dallas, 5Arthritis & Clinical Immunology Research Program, Division of Genomics and Data Sciences, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA, Los Angeles, 6Oklahoma Medical Research Foundation, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 7University of California, MDCC 12-430, 10833 Le Conte Ave, Los Angeles, 90095, CA, USA, Los Angeles, 8Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA., Charleston

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: Loss of function, Rare variants, SAT1, X-linked and Pediatric lupus

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Session Information

Date: Tuesday, November 12, 2019

Title: 5T115: SLE – Etiology & Pathogenesis I: Signaling Pathways (2810–2815)

Session Type: ACR Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: Mendelian inheritances of highly penetrant single gene variants have been reported as monogenic forms of SLE. To explore novel risk variants, we carried out whole-exome sequencing to identify underlying monogenic causes in two multiplex families that each contains unaffected parents and two sons with pediatric-onset SLE, and assessed candidate rare variants for Mendelian inheritance and functional consequences.

Methods: Whole-exome sequencing, variant calling and annotation were conducted using Illumina Hiseq2000, the Genome Analysis Toolkit GATK and ANNOVAR, respectively. Variants in the gene of interest were confirmed by Sanger sequencing.  Functions of candidate variants were tested using Minigene assay for differential splicing, and CRISPR/Cas9 mediated knock-in (KI) mice for the frameshift variant.

Results: In each family, we identified a putative loss-of-function variant in the SAT1 gene that co-segregated with lupus in an X-linked recessive pattern. This variant is extremely rare in the population (absent in > 200,000 individuals), and is not in previously known SLE-associated genes. In one family, a SAT1 frameshift mutation, which is expected to trigger nonsense-mediated mRNA decay, was transmitted from the mother to the two sons affected with SLE, but not to the unaffected son. Using CRISPR/Cas9, we have 5 founders of frameshift mutation KI mice and are establishing a colony for lupus-like phenotype studies. In the other family, we found a missense variant on exon 2 that was predicted to be deleterious by altering transcript splicing. Using the Minigene assay, we confirmed that the mutant construct resulted in aberrantly spliced transcripts, including ~30% intron 2 containing, ~20% exon 2 skipping and 50% normal transcripts, in transiently transfected 293T or HeLa cell lines. We further extended Sanger sequencing of SAT1 in 566 SLE patients enriched in multiplex male lupus and pediatric patients, found 4 common variants and 12 additional rare variants, but none had robust evidence for functions based on HaploReg v4.1 and Regulome database.

Conclusion: We identified two rare SAT1 loss-of-function variants on the X chromosome that segregate with SLE phenotype in two families that each contained two sons with pediatric-onset SLE. The exon 2 variant disrupted the splice donor site, and the frameshift variant created a premature stop codon. SAT1 encodes spermidine/spermine-N1-acetyltransferase, a rate-limiting enzyme that regulates polyamine catabolism. The low or absent function of SAT1 might perturb polyamine catabolism, predisposing to SLE, especially in boys.


Disclosure: L. Xu, None; J. Zhao, None; Q. Sun, None; L. Geng, None; Y. Deng, None; D. Kamen, None; J. Oates, None; P. Raj, None; E. Wakeland, None; R. Scofield, None; J. Guthridge, DxTerity, 2; J. James, Abbvie, 5, Janssen, 5, Progentec, 2, Progentec Diagnostics, Inc., 2, Xencor, 2, Xencor, Inc., 2; D. McCurdy, None; B. Tsao, None.

To cite this abstract in AMA style:

Xu L, Zhao J, Sun Q, Geng L, Deng Y, Kamen D, Oates J, Raj P, Wakeland E, Scofield R, Guthridge J, James J, McCurdy D, Tsao B. Does Loss-of-function Variants in SAT1 Cause X-linked Pediatric Lupus? [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/does-loss-of-function-variants-in-sat1-cause-x-linked-pediatric-lupus/. Accessed .
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