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

• Published in: Nature communications Vol. 12; no. 1; p. 6819
• Main Authors: Kanazawa, Nobuo, Hemmi, Hiroaki, Kinjo, Noriko, Ohnishi, Hidenori, Hamazaki, Jun, Mishima, Hiroyuki, Kinoshita, Akira, Mizushima, Tsunehiro, Hamada, Satoru, Hamada, Kazuya, Kawamoto, Norio, Kadowaki, Saori, Honda, Yoshitaka, Izawa, Kazushi, Nishikomori, Ryuta, Tsumura, Miyuki, Yamashita, Yusuke, Tamura, Shinobu, Orimo, Takashi, Ozasa, Toshiya, Kato, Takashi, Sasaki, Izumi, Fukuda-Ohta, Yuri, Wakaki-Nishiyama, Naoko, Inaba, Yutaka, Kunimoto, Kayo, Okada, Satoshi, Taketani, Takeshi, Nakanishi, Koichi, Murata, Shigeo, Yoshiura, Koh-ichiro, Kaisho, Tsuneyasu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24-11-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 14; 45; 59; 631/250/248; 631/250/249; 64/60; Amino acid substitution; Amino acids; Animals; Aspartic acid; Cysteine Endopeptidases - genetics; Cysteine Endopeptidases - metabolism; Disease Models, Animal; Female; Genetic diversity; Genetic variance; Glycine; Hereditary Autoinflammatory Diseases - diagnosis; Hereditary Autoinflammatory Diseases - genetics; Hereditary Autoinflammatory Diseases - immunology; Hereditary Autoinflammatory Diseases - pathology; Heterozygote; Humanities and Social Sciences; Humans; Hypertension; Hypertension, Pulmonary - diagnosis; Hypertension, Pulmonary - genetics; Hypertension, Pulmonary - immunology; Immune response; Immune system; Immunodeficiency; Infant, Newborn; Inflammatory diseases; Male; Mice; Mice, Transgenic; multidisciplinary; Mutation, Missense; Neonates; Pedigree; Phenotypes; Primary Immunodeficiency Diseases - diagnosis; Primary Immunodeficiency Diseases - genetics; Primary Immunodeficiency Diseases - immunology; Primary Immunodeficiency Diseases - pathology; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Proteins; Science; Science (multidisciplinary); Signs and symptoms; Syndrome; Ubiquitin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27085-y

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.
Genetic variants of proteasome subunit genes have been shown to associate with perturbed immune function. Here authors show that a heterozygous missense variant of the immunoproteasome subunit β-type 9 causes an autoinflammatory/immune deficiency syndrome in humans and in a mouse model.