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

Bunki Natsumoto; Hirofumi Shoda; Yasuo Nagafuchi; Mineto Ota; Takashi Okumura; Yumi Horie; Tomohisa Okamura; Kazuhiko Yamamoto; Motonori Tsuji; Makoto Otsu; Hideki Taniguchi; Keishi Fujio

doi:10.1016/j.jaut.2023.103085

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

J Autoimmun. 2023 Sep:139:103085. doi: 10.1016/j.jaut.2023.103085. Epub 2023 Jun 22.

Authors

Affiliations

¹ Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8654, Japan. Electronic address: natsumotobunki@gmail.com.
² Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8654, Japan. Electronic address: SHODAH-INT@h.u-tokyo.ac.jp.
³ Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8654, Japan; Department of Functional Genomics and Immunological Diseases, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8654, Japan.
⁴ Division of Stem Cell Processing/Stem Cell Bank, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, 108-8639, Japan.
⁵ Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Tsurumi-ku, Yokohama, 230-0045, Japan.
⁶ Institute of Molecular Function, Misato-shi Saitama, 341-0037, Japan.
⁷ Department of Transfusion and Cell Transplantation, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara Kanagawa, 252-0374, Japan.
⁸ Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8654, Japan. Electronic address: FUJIOK-INT@h.u-tokyo.ac.jp.

PMID: 37354689
DOI: 10.1016/j.jaut.2023.103085

Abstract

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 patients 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 between 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 information to unveil the heritability of the pathogenesis of autoimmune diseases.

Keywords: 2′-5′-oligoadenylate synthetase like (OASL); Dendritic cell (DC); Induced pluripotent stem cell (iPSC); Interferon induced with helicase C domain 1 (IFIH1); Interferon signature gene (ISG); Rare variant; Retinoic acid-inducible gene-I (RIGI); Systemic lupus erythematosus (SLE); Type 1 IFN.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenine Nucleotides
Humans
Induced Pluripotent Stem Cells*
Interferons
Lupus Erythematosus, Systemic* / genetics

Substances

2',5'-oligoadenylate
Interferons
Adenine Nucleotides