Neonatal-onset autoinflammation and immunodeficiency caused by heterozygous missense mutation of the proteasome subunit β-type 9

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 Psmb9 G156D/+ 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 Psmb9 G156D/+ 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Supported by Health Labor Sciences Research Grants for Research on Intractable Diseases (grant 20316700 and 20317089 to H. Ohnishi) from the Ministry of Health, Labour and Welfare (MHLW) of Japan; by the Practical Research Project for Rare/Intractable Diseases under Grant Numbers JP15gk0110012 (to K. Yoshiura), JP16ek0109179 and JP19ek0109209 (to S. Okada), JP17ek0109100 (to N. Kanazawa), JP19ek0109199 (to, N. Kanazawa, H. Hemmi, N. Kinjo K. Yoshiura, and T. Kaisho), JP20ek0109480 (to H. Ohnishi and S. Okada), and Advanced Research and Development Programs for Medical Innovation (AMED-CREST) under Grant Number JP20gm1110003 (to S. Murata) from the Japan Agency for Medical Research and Development (AMED); by Grants-in-Aids for Scientific Research (A) (grant JP18H04022 to S. Murata), Scientific Research (B) (grant 16H05355 and JP19H03620 to S. Okada, grant JP17H04088 and JP20H03505 to T. Kaisho), for Scientific Research (C) (grant JP15K09780 and JP19K08798 to N. Kanazawa, grant JP18K07840 to H. Ohnishi, grant JP19K07628 to I. Sasaki, grant JP18K07071 to H. Hemmi, grant JP16K10171 and JP19K08754 to K. Kunimoto), for Young Scientists (grant JP19K17293 to K. Izawa, grant JP20K16289 to T. Orimo, JP18K16096 to Y. Fukuda-Ohta), for Scientific Research on Innovative Areas (grant JP17H05799 and JP19H04813 to T. Kaisho, JP18H05500 to S. Murata), for Exploratory Research (grant JP17K19568 to T. Kaisho), for Young Scientists (B) (grant JP16K19585 to Y. Fukuda-Ohta), Research Activity start-up (grant JP19K23848 to T. Orimo), Promotion of Joint International Research from the Japan Society for the Promotion of Science (JP18KK0228 to S. Okada) from the Japan Society for the Promotion of Science; by the Uehara Memorial Foundation (to I. Sasaki and T. Kaisho); by Takeda Science Foundation (to H. Hemmi, T. Mizushima, I. Sasaki and T. Kaisho); by the Ichiro Kanehara Foundation for the promotion of Medical Sciences and Medical care (to H. Hemmi); by the Inamori Foundation (to I. Sasaki); by the Extramural Collaborative Research Grant of Cancer Research Institute, Kanazawa University; by a Cooperative Research Grant from the Institute for Enzyme Research, Joint Usage/Research Center, Tokushima University; by the Grant for Joint Research Program of the Institute for Genetic Medicine Hokkaido University; by the Grant for Joint Research Project of the Institute of Medical Science, the University of Tokyo; by the Program of the Network type Joint Usage/Research Center for Radiation Disaster Medical Science; by Wakayama Medical University Special Grant-in-Aid for Research Projects. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the Ethics Committee of the University of the Ryukyus for Medical and Health Research Involving Human Subjects, the Ethics Boards of Gifu University, the Ethics Committee on Human Genome / Gene Analysis Research of Nagasaki University, the Research Ethics Committee and the Animal Research Committee of Wakayama Medical University. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. 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