A truncating variant in SERPINA3, skin pustules and adult‐onset immunodeficiency

Abstract

Dear Editor, A 78yearold Thai woman presented with disseminated nontuberculous mycobacterial infection, herpes zoster, and generalized sterile nonfollicular pustules on her trunk and extremities (Figure 1a,b). Lesional skin histology revealed subcorneal and intraepidermal collections of neutrophils (Figure 1c). Serum IFNγ autoantibody level was 192.44 arbitary units/mL (cutoff level <3) and HIV1 antibody testing was negative. A diagnosis of adultonset immunodeficiency disorder (AOID) with pustular reaction was made. The sterile pustules responded well to oral acitretin. Adultonset immunodeficiency disorder is characterized by an AIDSlike illness with disruptive IFNγ signaling. The clinical manifestations of AOID resemble those in patients with inborn deficiencies of IFNγ production or IFNγresponse.1,2 The majority of cases have skin involvement which are mostly neutrophilic dermatoses.1 AOID shares skin manifestations with generalized pustular psoriasis (GPP; MIM 614204), although a mechanistic link between the two disorders is currently lacking.2 Following ethics committee approval and informed consent, and in full accordance with the Declaration of Helsinki, whole exome sequencing was performed on the patient s DNA. A heterozygous truncating variant (c.121C>T; p.Arg41Ter; rs373526796) in SERPINA3 was identified (Figure 1d). This variant is very rare in the general population (allele frequency = 0.00004245) with no regional specificity. Moreover, we have not observed it previously in our inhouse exome database of >600 Thai individuals. The p.Arg41Ter truncation is likely to result in haploinsufficiency from nonsensemediated RNA decay given the 5′ location of the mutation. The key issue in our case is whether the reduced expression of SERPINA3 at gene/protein level might have clinical relevance. In other words, could the heterozygous nonsense mutation in SERPINA3 we identified be contributing to the etiology of the AOID, the pustular rash, or possibly both disorders? Functionally, SERPINA3 is a protease inhibitor that inhibits neutrophil cathepsin G. Previously lossoffunction mutations in SERPINA3 have been demonstrated in some cases of GPP.3 In AOID, we hypothesize that reduced SERPINA3 expression leads to overactivation of proinflammatory cytokines, including IFNγ, IL17, IL22, and TGFβ, which then results in overactivation of KRT17 via IL1β and JAK/STAT1/3 signaling pathways, leading to amplification of inflammatory reactions with neutrophil recruitment3,4 (Figure S1). In common with GPP, increased expression of IL17 activates expression of IL36 cytokines, increases neutrophil chemotaxis, drives neutrophil recruitment, and promotes subsequent severe inflammation (Figure S1). Providing the link between AOID and GPP, IL36γ expression is regulated by cathepsin G and cathepsin G is regulated