Autoinflammatory disorders

Gene: PSMB9

Green List (high evidence)

This gene has been confirmed for this panel by the NHS Genomic Medicine Service and should be rated green.

Created: 16 Feb 2022, 11:44 a.m. | Last Modified: 16 Feb 2022, 11:44 a.m.

Panel Version: 0.36

Comment on mode of inheritance: Updated MOI from biallelic to monoallelic as all cases reported to date have harboured heterozygous variants in this gene (PMID: 26524591; 33727065; 34819510)

Created: 11 Jan 2022, 2:09 p.m. | Last Modified: 11 Jan 2022, 2:09 p.m.

Panel Version: 0.6

PSMB9 is rated Amber on the PID panel (R15, version 2.524) and the OMIM entry for this phenotype (MIM# 617591) is currently set to provisional.

Brehm et al., 2015 (PMID: 26524591) describe a Jamaican family with two affected sibs who harboured digenic heterozygous variants in the PSMB4 (c.44insG/p.P16Sfs*45) and PSMB9 (c.494G>A/p.G165D) genes that were identified by targeted screening of proteasome candidate genes. Both had a clinical phenotype of CANDLE syndrome.

Kataoka et al., 2021 (PMID: 33727065) reported a de novo PSMB9 variant (c.467G>A/p.G156D) in a 1-month old Japanese boy who developed fever, a chilblain-like skin rash, myositis, and severe pulmonary hypertension due to the hyperactivation of IFN-α. In vitro experiments using patient-derived primary cells and cell lines transduced with the mutant gene revealed reduced proteasome activities. The patient responded to treatment with a Janus kinase inhibitor, tofacitinib, and later received stem cell transplantation - following which he no longer required tofacitinib and experienced no disease recurrence.

Kanazawa et al., 2021 (PMID: 34819510) identified a further two unrelated Japanese patients with the same de novo PSMB9 heterozygous missense variant as that identified in the previous study (c.467G>A/p.G156D). Both individuals displayed severe autoinflammatory phenotypes and pulmonary hypertension and later also manifested combined immunodeficiency with periodic inflammatory exacerbation. The variant lead to impaired immunoproteasome maturation and activity, and the proteasome defect and immunodeficient phenotypes were recapitulated in Psmb9(G156D/+) mice.

Created: 11 Jan 2022, 2:06 p.m. | Last Modified: 11 Jan 2022, 2:06 p.m.

Panel Version: 0.4

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Proteasome-associated autoinflammatory syndrome 3, digenic, OMIM:617591

Publications

• 26524591
• 33727065
• 34819510