Heterozygous missense variant of the proteasome subunit β-type 9 causes neonatal-onset autoinflammation and immunodeficiency PMID: 34819510

Target-related Cytokines

2026-09-23

Heterozygous missense variant of the proteasome subunit β-type 9 causes neonatal-onset autoinflammation and immunodeficiency

Nat Commun. 2021 Nov 24;12(1):6819. doi: 10.1038/s41467-021-27085-y.

Nobuo Kanazawa ^# ¹ ² , Hiroaki Hemmi ^# ³ ⁴ , Noriko Kinjo ⁵ , Hidenori Ohnishi ⁶ , Jun Hamazaki ⁷ , Hiroyuki Mishima ⁸ , Akira Kinoshita ⁸ , Tsunehiro Mizushima ⁹ , Satoru Hamada ⁵ , Kazuya Hamada ⁵ , Norio Kawamoto ⁶ , Saori Kadowaki ⁶ , Yoshitaka Honda ¹⁰ , Kazushi Izawa ¹⁰ , Ryuta Nishikomori ¹¹ , Miyuki Tsumura ¹² , Yusuke Yamashita ¹³ , Shinobu Tamura ¹³ , Takashi Orimo ³ ¹⁴ , Toshiya Ozasa ³ , Takashi Kato ³ , Izumi Sasaki ³ , Yuri Fukuda-Ohta ³ , Naoko Wakaki-Nishiyama ³ , Yutaka Inaba ¹⁵ , Kayo Kunimoto ¹⁵ , Satoshi Okada ¹² , Takeshi Taketani ¹⁶ , Koichi Nakanishi ⁵ , Shigeo Murata ⁷ , Koh-Ichiro Yoshiura ⁸ ¹⁷ , Tsuneyasu Kaisho ¹⁸

Affiliations

1. Department of Dermatology, Wakayama Medical University, Wakayama, Japan. [email protected].
2. Department of Dermatology, Hyogo College of Medicine, Nishinomiya, Japan. [email protected].
3. Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan.
4. Laboratory of Immunology, Faculty of Veterinary Medicine, Okayama University of Science, Imabari, Japan.
5. Department of Child Health and Welfare (Pediatrics), Graduate School of Medicine, University of the Ryukyus, Nishibara, Japan.
6. Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan.
7. Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
8. Department of Human Genetics, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
9. Graduate School of Science, University of Hyogo, Himeji, Japan.
10. Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
11. Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan.
12. Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
13. Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan.
14. Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Japan.
15. Department of Dermatology, Wakayama Medical University, Wakayama, Japan.
16. Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Japan.
17. Division of Advanced Preventive Medical Sciences and Leading Medical Research Core Unit, Nagasaki Univeristy Graduate School of Biomedical Sciences, Nagasaki, Japan.
18. Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan. [email protected].
# Contributed equally.

Abstract

Impaired Proteasome activity due to genetic variants of certain subunits might lead to proteasome-associated autoinflammatory syndromes (PRAAS). Here we report a de novo heterozygous missense variant of the PSMB9 Proteasome subunit gene in two unrelated Japanese infants resulting in amino acid substitution of the glycine (G) by aspartic acid (D) at position 156 of the encoded protein β1i. In addition to PRAAS-like manifestations, these individuals suffer from Pulmonary Hypertension and immunodeficiency, which are distinct from typical PRAAS symptoms. The missense variant results in impaired immunoproteasome maturation and activity, yet ubiquitin accumulation is hardly detectable in the patients. A mouse model of the heterozygous human genetic variant (Psmb9^G156D/+) recapitulates the Proteasome defects and the immunodeficiency phenotype of patients. Structurally, PSMB9 G156D interferes with the β-ring-βring interaction of the wild type protein that is necessary for 20S Proteasome formation. We propose the term, proteasome-associated autoinflammatory syndrome with immunodeficiency (PRAAS-ID), to indicate a separate category of autoinflammatory diseases, similar to, but distinct from PRAAS, that describes the patients in this study.