PSMB10, the last immunoproteasome gene missing for PRAAS

Sarrabay, Guillaume; Mechin, Déborah; Salhi, Aïcha; Boursier, Guilaine; Rittore, Cécile; Crow, Yanick J.; Rice, Gillian I.; Tran, Tú-Anh; Cezar, Renaud; Duffy, Darragh; Bondet, Vincent; Boudhane, Lakhdar; Broca, Christophe; Kant, Benjamin; VanGijn, Mariëlle; Grandemange, Sylvie; Richard, Eric; Apparailly, Florence; Touitou, Isabelle

doi:10.1016/j.jaci.2019.11.024

Cited by 47 publications

(50 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S6A), which is necessary for both 20S complex and 26S proteasome activities. 5 Thus, PSMB9 G156D is a unique mutation in proteasome subunits which causes proteasome defects by its heterozygosity and affects the interaction of two β rings.…”

Section: Discussionmentioning

confidence: 99%

“…3 Finally, the variants meet the following criteria were selected as “deleterious” mutations: 1) leads stop gain, stop loss, nonsynonymous mutation, or splice site mutation, 2) alternative allele frequencies in databases including Complete Genomics whole genome data, the 1000genome project, NHLBI GO ESP, the human genome variation database of the Japanese population 4 and an in-house database) are all equal or less than 0.5%, 3) not included in Segmental duplication region defined in the UCSC genome browser. 5,6 For target capture sequencing, ubiquitin-proteasome-system, autophagy and interferonopathy-related gene panel was purchased from Integrated DNA Technology (IDT) (Coralville, IA). Gene capture and library construction were performed using Hybridization capture of DNA libraries using xGen Lockdown Probes and Reagents (IDT) according to manufacture’s instructions.…”

Section: Supplementary Methodsmentioning

confidence: 99%

Section: Supplementary Methodsmentioning

confidence: 99%

“…1-4 Subsequently, identification of mostly biallelic mutations of other proteasome subunit and chaperone genes, leading to loss-of-function of the proteasome, has defined a new disease entity as proteasome-associated autoinflammatory syndrome (PRAAS). 5-8…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Kanazawa

Hemmi

Kinjo

et al. 2021

Preprint

View full text Add to dashboard Cite

BACKGROUNDDefective 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.METHODSWe 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.RESULTSBoth 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.CONCLUSIONSThe 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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Supplementary Methodsmentioning

confidence: 99%

Section: Supplementary Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Kanazawa

Hemmi

Kinjo

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Additive depletion of two proteasome subunits by small-interfering RNA (siRNA) was shown to cause more severe assembly defects and decreases in proteolytic function than monogenic inherited PRAAS (24). Recently, Sarrabay et al described a patient exhibiting a PRAAS phenotype due to a homozygous mutation in PSMB10, which led to interferon (IFN) type I dysregulation, PSMB10 maturation defect, and enzymatic impairment (29). Notably, among these mutations, the 5 ′ UTR of PSMB4 variant (c.-9G>A) reduced the expression levels of the mutant transcripts (24).…”

Section: Pomp-related Systemic Autoinflammatory Diseasesmentioning

confidence: 99%

KLICK Syndrome Linked to a POMP Mutation Has Features Suggestive of an Autoinflammatory Keratinization Disease

Takeichi

Akiyama

2020

Front. Immunol.

View full text Add to dashboard Cite

Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome is a rare autosomal recessive skin disorder characterized by palmoplantar keratoderma, linear hyperkeratotic plaques, ichthyosiform scaling, circular constrictions around the fingers, and numerous papules distributed linearly in the arm folds and on the wrists. Histologically, the affected skin shows hypertrophy and hyperplasia of the spinous, granular, and horny epidermal layers with mild infiltration of inflammatory cells in the upper dermis. There are 14 patients with KLICK syndrome described in the literature, and they all carry the same nucleotide deletion. Proteasome maturation protein (POMP), encoded by POMP, is an ubiquitously expressed protein that functions as a chaperone for proteasome maturation. KLICK syndrome is caused by a reduction in POMP levels that leads to proteasome insufficiency in differentiating keratinocytes. It is noteworthy that POMP is also known to be the causative gene for proteasome-associated autoinflammatory syndrome-2 (PRAAS2). It is considered that the disrupted proteasome assembly caused by the POMP mutation might lead to both skin inflammation and then hyperkeratosis in KLICK syndrome. Inflammation caused by the hyperactivation of innate immunity occasionally leads to inflammatory diseases of the skin, recently denoted as autoinflammatory keratinization diseases (AiKDs). We propose that KLICK syndrome caused by the specific 1-bp nucleotide deletion mutation in the regulatory region of POMP might be in a spectrum of proteasome-associated phenotypes.

show abstract

Haploinsufficiency of PSMD12 Causes Proteasome Dysfunction and Subclinical Autoinflammation

Yan

Zhang

Lee

et al. 2022

Arthritis & Rheumatology

View full text Add to dashboard Cite

Objective. Proteasome-associated autoinflammatory syndrome (PRAAS) is caused by mutations affecting components of the proteasome and activation of the type I interferon (IFN) pathway. This study was undertaken to investigate the pathogenic mechanisms of a newly recognized type of PRAAS caused by PSMD12 haploinsufficiency.Methods. Whole-exome sequencing was performed in members of a family with skin rash, congenital uveitis, and developmental delay. We performed functional studies to assess proteasome dysfunction and inflammatory signatures in patients, and single-cell RNA sequencing to further explore the spectrum of immune cell activation.Results. A novel truncated variant in PSMD12 (c.865C>T, p.Arg289*) was identified in 2 family members. The impairment of proteasome function was found in peripheral blood mononuclear cells (PBMCs), as well as in PSMD12-knockdown HEK 293T cell lines. Moreover, we defined the inflammatory signatures in patient PBMCs and found elevated IFN signals, especially in monocytes, by single-cell RNA sequencing.Conclusion. These findings indicate that PSMD12 haploinsufficiency causes a set of inflammation signatures in addition to neurodevelopmental disorders. Our work expands the genotype and phenotype spectrum of PRAAS and suggests a bridge between the almost exclusively inflammatory phenotypes in the majority of PRAAS patients and the almost exclusively neurodevelopmental phenotypes in the previously reported Stankiewicz-Isidor syndrome.

show abstract

PSMB10, the last immunoproteasome gene missing for PRAAS

Abstract: The acute-phase C-reactive protein binds to phosphorylcholine-expressing Neisseria meningitides and increases uptake by human phagocytes.

Cited by 47 publications

References 12 publications

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

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

KLICK Syndrome Linked to a POMP Mutation Has Features Suggestive of an Autoinflammatory Keratinization Disease

Haploinsufficiency of PSMD12 Causes Proteasome Dysfunction and Subclinical Autoinflammation

Contact Info

Product

Resources

About