A homozygous loss‐of‐function variant in the MPO gene is associated with generalized pustular psoriasis

Abstract

Generalized pustular psoriasis (GPP) is the most severe form of psoriasis and is characterized by sudden onset of diffuse skin rushes with sterile pustule formation, high fever, high leukocyte count, and high levels of C reactive protein in the serum. 1,2 These episodic attacks can be induced by several distinct factors, such as pregnancy, infections, or medicines. It is known that psoriasis vulgaris (PV) can eventually progress to GPP.In recent years, the underlying genetic basis for GPP has gradually been disclosed. Firstly, Marrakchi et al. have reported that Tunisian patients with GPP carried bi-allelic loss-of-function mutations in IL36RN gene encoding interleukin (IL)-36 receptor antagonist, and thus, the disease caused by IL36RN gene mutations is also known as deficiency of interleukin 36 receptor antagonist (DITRA;Online Mendelian Inheritance in Man [OMIM] 614 204). 2 Mutations in the IL36RN gene have also been identified in Japanese patients with GPP, who tended to show an early onset and were not preceded by PV. 3 Soon after that, mono-allelic gain-of-function mutations in CARD14 gene have been reported to be a strong risk factor of GPP. 4 In the Japanese population, it has been demonstrated that a mono-allelic CARD14 gene variant c.526G>C (p.Asp176His) showed a significant association with GPP which progressed from PV. 5 Later on, mono-allelic loss-of-function mutations in AP1S3 gene have been identified in affected individuals with GPP (OMIM 616106). 6 Most recently, SERPINA3 and MPO have been reported as additional causative/susceptibility genes for GPP. [7][8][9] Of these, the MPO gene encodes myeloperoxidase (MPO) which is a lysosomal

Generalized pustular psoriasis that developed in a patient with an NFKB2 variant

“…Additionally, a functional test was performed following the methods described previously. 1 The results demonstrated a complete loss of myeloperoxidase activity in the p.R511C-mutant protein (Figure 1i,j).…”

Mild generalised pustular psoriasis patient with a heterozygous hypomorphic MPO variant successfully treated with granulocyte and monocyte adsorption apheresis

“…To assess the function of the myeloperoxidase variant R604C, we measured myeloperoxidase activity using previously described methods, with slight modifications. 3 In brief, the MPO expression vectors carrying wild type, R590L and R604C mutant MPO (2 μg each) were transfected into HEK293T cells seeded on 6-well plates using Lipofectamine 2000 (Life Technologies) according to the manufacturer's instructions. 24 h after transfection, the total cell lysates were collected and expression of the proteins was confirmed by western blotting (WB) (Figure 2E).…”

“…The β–galactosidase activities were assayed using the β–galactosidase Enzyme Assay System (Promega) according to the manufacturer's instructions. 26 h after transfection, MPO activity was measured using previously described methods 3 …”

“…Pathogenic variants in MPO , which encodes the myeloperoxidase, were reported as causative genetic defects in several cases of generalised pustular psoriasis (GPP) in addition to patients with myeloperoxidase deficiency in 2020 1,2 . In 2022, Onitsuka et al published the first report of a Japanese case of GPP associated with a homozygous pathogenic variant in MPO 3 . Recently, Pérez‐Feal et al described a patient with paediatric‐onset GPP caused by compound heterozygous pathogenic variants in MPO 4 .…”

Generalisierte pustulöse Psoriasis, die sich bei einem Patienten mit einer NFKB2‐Variante entwickelte

“…Zusätzlich wurde ein Funktionstest nach den oben beschriebenen Methoden durchgeführt. 1 Die Ergebnisse zeigten einen vollständigen Verlust der Myeloperoxidase-Aktivität im p.R511C-mutierten Protein (Abbildung 1i,j).…”