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

Nobuo Kanazawa (), Hiroaki Hemmi, Noriko Kinjo, Hidenori Ohnishi, Jun Hamazaki, Hiroyuki Mishima, Akira Kinoshita, Tsunehiro Mizushima, Satoru Hamada, Kazuya Hamada, Norio Kawamoto, Saori Kadowaki, Yoshitaka Honda, Kazushi Izawa, Ryuta Nishikomori, Miyuki Tsumura, Yusuke Yamashita, Shinobu Tamura, Takashi Orimo, Toshiya Ozasa, Takashi Kato, Izumi Sasaki, Yuri Fukuda-Ohta, Naoko Wakaki-Nishiyama, Yutaka Inaba, Kayo Kunimoto, Satoshi Okada, Takeshi Taketani, Koichi Nakanishi, Shigeo Murata, Koh-ichiro Yoshiura and Tsuneyasu Kaisho ()
Additional contact information
Nobuo Kanazawa: Wakayama Medical University
Hiroaki Hemmi: Wakayama Medical University
Noriko Kinjo: University of the Ryukyus
Hidenori Ohnishi: Gifu University
Jun Hamazaki: The University of Tokyo
Hiroyuki Mishima: Nagasaki University
Akira Kinoshita: Nagasaki University
Tsunehiro Mizushima: University of Hyogo
Satoru Hamada: University of the Ryukyus
Kazuya Hamada: University of the Ryukyus
Norio Kawamoto: Gifu University
Saori Kadowaki: Gifu University
Yoshitaka Honda: Kyoto University Graduate School of Medicine
Kazushi Izawa: Kyoto University Graduate School of Medicine
Ryuta Nishikomori: Kurume University School of Medicine
Miyuki Tsumura: Hiroshima University Graduate School of Biomedical and Health Sciences
Yusuke Yamashita: Wakayama Medical University
Shinobu Tamura: Wakayama Medical University
Takashi Orimo: Wakayama Medical University
Toshiya Ozasa: Wakayama Medical University
Takashi Kato: Wakayama Medical University
Izumi Sasaki: Wakayama Medical University
Yuri Fukuda-Ohta: Wakayama Medical University
Naoko Wakaki-Nishiyama: Wakayama Medical University
Yutaka Inaba: Wakayama Medical University
Kayo Kunimoto: Wakayama Medical University
Satoshi Okada: Hiroshima University Graduate School of Biomedical and Health Sciences
Takeshi Taketani: Shimane University Faculty of Medicine
Koichi Nakanishi: University of the Ryukyus
Shigeo Murata: The University of Tokyo
Koh-ichiro Yoshiura: Nagasaki University
Tsuneyasu Kaisho: Wakayama Medical University

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: 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 (Psmb9G156D/+) 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27085-y

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DOI: 10.1038/s41467-021-27085-y

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