Functional evaluation of rare OASL variants by analysis of SLE patient-derived iPSCs

Background: Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by genetic heterogeneity and an interferon (IFN) signature. The overall landscapes of the heritability of SLE remains unclear.Objectives: To identify and elucidate the biological functions of rare variants underlying SLE, we conducted analyses of patient-derived induced pluripotent stem cells (iPSCs) in combination with genetic analysis.Methods: Two familial SLE patient-and two healthy donor (HD)-derived iPSCs were established. Type 1 IFN-secreting dendritic cells (DCs) were differentiated from iPSCs. Genetic analyses of SLE-iPSCs, and 117 SLE pa-tients and 107 HDs in the ImmuNexUT database were performed independently. Genome editing of the variants on iPSCs was performed with the CRISPR/Cas9 system.Results: Type 1 IFN secretion was significantly increased in DCs differentiated from SLE-iPSCs compared to HD-iPSCs. Genetic analyses revealed a rare variant in the 2'-5'-Oligoadenylate Synthetase Like (OASL) shared be-tween SLE-iPSCs and another independent SLE patient, and significant accumulation of OASL variants among SLE patients (HD 0.93%, SLE 6.84%, OR 8.387) in the database. Genome editing of mutated OASL 202Q to wild -type 202 R or wild-type OASL 202 R to mutated 202Q resulted in reduced or enhanced Type 1 IFN secretion of DCs. Three other OASL variants (R60W, T261S and A447V) accumulated in SLE patients had also capacities to enhance Type 1 IFN secretion in response to dsRNA.Conclusions: We established a patient-derived iPSC-based strategy to investigate the linkage of genotype and phenotype in autoimmune diseases. Detailed case-based investigations using patient-derived iPSCs provide in-formation to unveil the heritability of the pathogenesis of autoimmune diseases.

Automated summary

In this study, patient-derived induced pluripotent stem cells (iPSCs) were used in combination with genetic analysis to identify and elucidate the biological functions of rare variants underlying systemic lupus erythematosus (SLE). It was found that a rare variant in the OASL gene was shared between SLE-iPSCs and another independent SLE patient, and there was a significant accumulation of OASL variants among SLE patients. Additionally, genome editing experiments confirmed the impact of these variants on type 1 interferon secretion in immune cells.