COVID-19 research

Gene: PSMB4

I don't know

Although much evidence is not provided, we should put into consideration its relationship with IFN1 levels and the inflammatory state created by that increase auto inflamation

Additive Loss-Of-Function Proteasome Subunit Mutations in CANDLE/PRAAS Patients Promote Type I IFN Production
PMID: 26829627

Here, we identified 8 mutations in 4 proteasome genes, PSMA3 (encodes α7), PSMB4 (encodes β7), PSMB9 (encodes β1i), and proteasome maturation protein (POMP), that have not been previously associated with disease and 1 mutation in PSMB8 that has not been previously reported. One patient was compound heterozygous for PSMB4 mutations, 6 patients from 4 families were heterozygous for a missense mutation in 1 inducible proteasome subunit and a mutation in a constitutive proteasome subunit, and 1 patient was heterozygous for a POMP mutation, thus establishing a digenic and autosomal dominant inheritance pattern of PRAAS. Function evaluation revealed that these mutations variably affect transcription, protein expression, protein folding, proteasome assembly, and, ultimately, proteasome activity. Moreover, defects in proteasome formation and function were recapitulated by siRNA-mediated knockdown of the respective subunits in primary fibroblasts from healthy individuals. Patient-isolated hematopoietic and nonhematopoietic cells exhibited a strong IFN gene-expression signature, irrespective of genotype. Additionally, chemical proteasome inhibition or progressive depletion of proteasome subunit gene transcription with siRNA induced transcription of type I IFN genes in healthy control cells. Our results provide further insight into CANDLE genetics and link global proteasome dysfunction to increased type I IFN production.

Created: 10 Apr 2020, 1:27 p.m. | Last Modified: 10 Apr 2020, 1:27 p.m.

Panel Version: 0.81

Publications

• PMID: 26829627,

I don't know

agree with all the Amber genes

Created: 25 Sep 2019, 1:49 p.m. | Last Modified: 25 Sep 2019, 1:49 p.m.

Panel Version: 1.115

Green List (high evidence)

I think CANDLE should be green these should be covered in the testing

Created: 26 Sep 2019, 12:43 p.m. | Last Modified: 26 Sep 2019, 12:43 p.m.

Panel Version: 1.127

The amber genes are covered on our targeted exome, we feel that these should be covered in the testing

Created: 25 Sep 2019, 1:44 p.m. | Last Modified: 25 Sep 2019, 1:44 p.m.

Panel Version: 1.114

I don't know

Only one patient with compound heterozygous variants reported so far

Created: 29 Jun 2018, 3:11 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
CANDLE syndrome (Autoinflammation, lipodystrophy, and dermatosis syndrome)

Publications

• 26524591

I don't know

Gene was flagged as requiring further clinical input from the Immunology Test Group, but no additional information was submitted to support the Green rating. In view of a lack of clear evidence the current recommendation is Amber.

Created: 12 Nov 2019, 5:04 p.m. | Last Modified: 12 Nov 2019, 5:04 p.m.

Panel Version: 1.137

?Proteasome-associated autoinflammatory syndrome 3, digenic. One patient het for this and another gene (PSMB9) hence ?digenic - amber on association

Created: 26 Sep 2019, 3:58 p.m. | Last Modified: 26 Sep 2019, 3:58 p.m.

Panel Version: 1.130

Comment on list classification: Changed rating from Red to Amber to reflect the agreed rating agreed by the GMS Immunology Specialist Test Group, but flagged for further follow up with the Immunology Test Group due to the subsequent conflicting review. Evidence /opinion needs consensus before upgrading to Green

Created: 26 Sep 2019, 10:36 a.m. | Last Modified: 26 Sep 2019, 1:04 p.m.

Panel Version: 1.127

Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. Although discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 to rate Amber in the confirmed follow up email on 20th June North West GLH reasserted that PSMB4 should be Green

Created: 25 Sep 2019, 3 p.m. | Last Modified: 26 Sep 2019, 1:05 p.m.

Panel Version: 1.127

Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber

Created: 25 Sep 2019, 3 p.m. | Last Modified: 25 Sep 2019, 3 p.m.

Panel Version: 1.116

Review by Tracy Briggs (NWGLH) on behalf of the Specialist Test Group to support inclusion of this gene on the panel and a Green rating. Flagged for further discussion with the Specialist Test Group as conflicts with the Amber rating agreed in the webex 28th March 2019. Added digenic tag - from review comment 'Digenic also reported'.

Created: 15 Aug 2019, 4:12 p.m. | Last Modified: 12 Sep 2019, 3:34 p.m.

Panel Version: 1.55

Comment on phenotypes: Added phenotype from expert review

Created: 5 Jul 2018, 10:01 a.m.

Comment on publications: Added publications suggested from external expert review

Created: 5 Jul 2018, 10 a.m.

Comment on list classification: Changed from Amber to Red until more info to support gene-disease association. Currently only one case reported in literature. Gene not present on any other PID related panels or within ESID or IUIS classifications. Request evidences / immunological association of this gene from Victorian Clinical Genetics Services.

Created: 5 Jul 2018, 9:56 a.m.

Comment on list classification: This gene was absent from the original PanelApp PID panel dataset (review April 2018). However it was listed in external expert immunodeficiency diagnostic gene list from Victorian Clinical Genetics Services. In this combined PID panel, this gene has been rated as AMBER and needs further curational review to assess pertinence prior to v1. No disorder or MOI was listed in the submitted list.

Created: 26 Jun 2018, 12:45 p.m.