Neonatal-onset autoinflammation and immunodeficiency caused by heterozygous missense mutation of the proteasome subunit β-type 9
ABSTRACT BACKGROUND Defective proteasome activities due to genetic mutations lead to an autoinflammatory disease, termed as proteasome-associated autoinflammatory syndromes (PRAAS). In PRAAS relapsing inflammations and progressive wasting are common, but immunodeficiency has not been reported.METHODS We studied two unrelated Japanese infants with PRAAS-like manifestations. We have also generated and analyzed the mice carrying the candidate mutation found in the patients.RESULTS Both patients showed neonatal-onset skin rash, myositis and basal ganglia calcification, similar to PRAAS patients. Meanwhile, they manifested distinct phenotypes, including pulmonary hypertension and immunodeficiency without lipoatrophy. We identified a novel de novo heterozygous missense mutation, G156D, in a proteasome subunit gene, PSMB9, encoding β1i, in the two patients. Maturation and activity of the immunoproteasome were impaired, but ubiquitin accumulation was hardly detected not only in patient-derived cells and samples but also in Psmb9G156D/+ mice. As an immunodeficient phenotype, one patient showed decrease of B cells and increase of monocytes, while the other patient showed decrease of CD8 T cells. The proteasome defects and immunodeficient phenotypes were recapitulated in Psmb9G156D/+ mice.CONCLUSIONS The PSMB9 G156D is a unique mutation in proteasome subunits in causing defects by its heterozygosity, affecting two β rings interaction and leading to immunodeficiency. The mutant mice are the first mice model for analyzing proteasome dysfunctions in PRAAS. We here propose the term, proteasome-associated autoinflammation and immunodeficiency disease (PRAID), as an umbrella name for our cases, PRAAS with immunodeficiency, as well as PRAAS described so far..
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Preprint| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
bioRxiv.org - (2022) vom: 25. Mai Zur Gesamtaufnahme - year:2022 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kanazawa, Nobuo [VerfasserIn] |
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| Links: |
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| doi: |
10.1101/2021.02.01.21250077 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
XBI01984266X |
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| 100 | 1 | |a Kanazawa, Nobuo |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Neonatal-onset autoinflammation and immunodeficiency caused by heterozygous missense mutation of the proteasome subunit β-type 9 |
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| 520 | |a ABSTRACT BACKGROUND Defective proteasome activities due to genetic mutations lead to an autoinflammatory disease, termed as proteasome-associated autoinflammatory syndromes (PRAAS). In PRAAS relapsing inflammations and progressive wasting are common, but immunodeficiency has not been reported.METHODS We studied two unrelated Japanese infants with PRAAS-like manifestations. We have also generated and analyzed the mice carrying the candidate mutation found in the patients.RESULTS Both patients showed neonatal-onset skin rash, myositis and basal ganglia calcification, similar to PRAAS patients. Meanwhile, they manifested distinct phenotypes, including pulmonary hypertension and immunodeficiency without lipoatrophy. We identified a novel de novo heterozygous missense mutation, G156D, in a proteasome subunit gene, PSMB9, encoding β1i, in the two patients. Maturation and activity of the immunoproteasome were impaired, but ubiquitin accumulation was hardly detected not only in patient-derived cells and samples but also in Psmb9G156D/+ mice. As an immunodeficient phenotype, one patient showed decrease of B cells and increase of monocytes, while the other patient showed decrease of CD8 T cells. The proteasome defects and immunodeficient phenotypes were recapitulated in Psmb9G156D/+ mice.CONCLUSIONS The PSMB9 G156D is a unique mutation in proteasome subunits in causing defects by its heterozygosity, affecting two β rings interaction and leading to immunodeficiency. The mutant mice are the first mice model for analyzing proteasome dysfunctions in PRAAS. We here propose the term, proteasome-associated autoinflammation and immunodeficiency disease (PRAID), as an umbrella name for our cases, PRAAS with immunodeficiency, as well as PRAAS described so far. | ||
| 700 | 1 | |a Hemmi, Hiroaki |e verfasserin |4 aut | |
| 700 | 1 | |a Kinjo, Noriko |e verfasserin |4 aut | |
| 700 | 1 | |a Ohnishi, Hidenori |e verfasserin |4 aut | |
| 700 | 1 | |a Hamazaki, Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Mishima, Hiroyuki |e verfasserin |4 aut | |
| 700 | 1 | |a Kinoshita, Akira |e verfasserin |4 aut | |
| 700 | 1 | |a Mizushima, Tsunehiro |e verfasserin |4 aut | |
| 700 | 1 | |a Hamada, Satoru |e verfasserin |4 aut | |
| 700 | 1 | |a Hamada, Kazuya |e verfasserin |4 aut | |
| 700 | 1 | |a Kawamoto, Norio |e verfasserin |4 aut | |
| 700 | 1 | |a Kadowaki, Saori |e verfasserin |4 aut | |
| 700 | 1 | |a Honda, Yoshitaka |e verfasserin |4 aut | |
| 700 | 1 | |a Izawa, Kazushi |e verfasserin |4 aut | |
| 700 | 1 | |a Nishikomori, Ryuta |e verfasserin |4 aut | |
| 700 | 1 | |a Tsumura, Miyuki |e verfasserin |4 aut | |
| 700 | 1 | |a Yamashita, Yusuke |e verfasserin |4 aut | |
| 700 | 1 | |a Tamura, Shinobu |e verfasserin |4 aut | |
| 700 | 1 | |a Orimo, Takashi |e verfasserin |4 aut | |
| 700 | 1 | |a Ozasa, Toshiya |e verfasserin |4 aut | |
| 700 | 1 | |a Kato, Takashi |e verfasserin |4 aut | |
| 700 | 1 | |a Sasaki, Izumi |e verfasserin |4 aut | |
| 700 | 1 | |a Fukuda-Ohta, Yuri |e verfasserin |4 aut | |
| 700 | 1 | |a Wakaki-Nishiyama, Naoko |e verfasserin |4 aut | |
| 700 | 1 | |a Inaba, Yutaka |e verfasserin |4 aut | |
| 700 | 1 | |a Kunimoto, Kayo |e verfasserin |4 aut | |
| 700 | 1 | |a Okada, Satoshi |e verfasserin |4 aut | |
| 700 | 1 | |a Taketani, Takeshi |e verfasserin |4 aut | |
| 700 | 1 | |a Nakanishi, Koichi |e verfasserin |4 aut | |
| 700 | 1 | |a Murata, Shigeo |e verfasserin |4 aut | |
| 700 | 1 | |a Yoshiura, Koh-ichiro |e verfasserin |4 aut | |
| 700 | 1 | |a Kaisho, Tsuneyasu |e verfasserin |4 aut | |
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