Hereditary myeloperoxidase deficiency due to a missense mutation of arginine 569 to tryptophan.

Nauseef, William M.; Brigham, S.; Cogley, M.

doi:10.1016/s0021-9258(17)42244-7

Cited by 71 publications

(5 citation statements)

References 27 publications

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“…Of note, homozygous c.1705C>T (p.Arg569Trp) mutations have been repeatedly observed in individuals affected by MPOD. 5,6 A c.1555_1568del variant, which overlaps the c.1552_1565del variant described here, has also been documented in an affected-relative pair, where it triggered nonsense-mediated decay in at least one individual 7 (Table S3). Thus, all the MPO alleles observed in our dataset have a well-established impact on protein function.…”

supporting

confidence: 53%

Loss-of-Function Myeloperoxidase Mutations Are Associated with Increased Neutrophil Counts and Pustular Skin Disease

Vergnano

Mockenhaupt

Benzian-Olsson

et al. 2020

The American Journal of Human Genetics

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The identification of disease alleles underlying human autoinflammatory diseases can provide important insights into the mechanisms that maintain neutrophil homeostasis. Here, we focused our attention on generalized pustular psoriasis (GPP), a potentially life-threatening disorder presenting with cutaneous and systemic neutrophilia. Following the whole-exome sequencing of 19 unrelated affected individuals, we identified a subject harboring a homozygous splice-site mutation (c.2031−2A>C) in MPO . This encodes myeloperoxidase, an essential component of neutrophil azurophil granules. MPO screening in conditions phenotypically related to GPP uncovered further disease alleles in one subject with acral pustular psoriasis (c.2031−2A>C;c.2031−2A>C) and in two individuals with acute generalized exanthematous pustulosis (c.1705C>T;c.2031−2A>C and c.1552_1565del;c.1552_1565del). A subsequent analysis of UK Biobank data demonstrated that the c.2031−2A>C and c.1705C>T (p.Arg569Trp) disease alleles were also associated with increased neutrophil abundance in the general population (p = 5.1 × 10 −6 and p = 3.6 × 10 −5 , respectively). The same applied to three further deleterious variants that had been genotyped in the cohort, with two alleles (c.995C>T [p.Ala332Val] and c.752T>C [p.Met251Thr]) yielding p values < 10 −10 . Finally, treatment of healthy neutrophils with an MPO inhibitor (4-Aminobenzoic acid hydrazide) increased cell viability and delayed apoptosis, highlighting a mechanism whereby MPO mutations affect granulocyte numbers. These findings identify MPO as a genetic determinant of pustular skin disease and neutrophil abundance. Given the recent interest in the development of MPO antagonists for the treatment of neurodegenerative disease, our results also suggest that the pro-inflammatory effects of these agents should be closely monitored.

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supporting

confidence: 53%

Loss-of-Function Myeloperoxidase Mutations Are Associated with Increased Neutrophil Counts and Pustular Skin Disease

Vergnano

Mockenhaupt

Benzian-Olsson

et al. 2020

The American Journal of Human Genetics

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“…For four of these mutations, the functional consequences have been studied in more detail and were found to affect MPO biosynthesis. For example, a single-nucleotide mutation in the heavy subunit at codon 569 results in the replacement of an arginine with a tryptophan (R569W) and is the most common cause of MPO deficiency in Europe and the United States (251). Transfection studies of this mutated gene in hematopoietic cell lines showed that the mutation leads to a dysfunctional protein, because MPO biosynthesis stops at the apoproMPO stage without heme incorporation and proteolytic processing.…”

Section: A Microbicidal Effects Of Mpomentioning

confidence: 99%

Myeloperoxidase: Molecular Mechanisms of Action and Their Relevance to Human Health and Disease

Veen

Winther

Heeringa

2009

Antioxidants & Redox Signaling

455

334

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Myeloperoxidase (MPO) is a heme-containing peroxidase abundantly expressed in neutrophils and to a lesser extent in monocytes. Enzymatically active MPO, together with hydrogen peroxide and chloride, produces the powerful oxidant hypochlorous acid and is a key contributor to the oxygen-dependent microbicidal activity of phagocytes. In addition, excessive generation of MPO-derived oxidants has been linked to tissue damage in many diseases, especially those characterized by acute or chronic inflammation. It has become increasingly clear that MPO exerts effects that are beyond its oxidative properties. These properties of MPO are, in many cases, independent of its catalytic activity and affect various processes involved in cell signaling and cell-cell interactions and are, as such, capable of modulating inflammatory responses. Given these diverse effects, an increased interest has emerged in the role of MPO and its downstream products in a wide range of inflammatory diseases. In this article, our knowledge pertaining to the biologic role of MPO and its downstream effects and mechanisms of action in health and disease is reviewed and discussed.

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“…Bi-allelic loss-of-function mutations in the MPO gene have previously been reported to underlie myeloperoxidase deficiency (OMIM 254600), which is mainly characterized by disseminated candidiasis. 19 It is noteworthy that our patient had been treated with oral terbinafine due to cutaneous candidiasis on the face before the onset of GPP. 10 Although it was unclear if the patient had frequently suffered from candidiasis since a young age, there is a high possibility that he has had myeloperoxidase deficiency as an underlying condition.…”

Section: Discussionmentioning

confidence: 81%

“…Therefore, the patient can be considered to be a knock‐out human of the MPO gene. Bi‐allelic loss‐of‐function mutations in the MPO gene have previously been reported to underlie myeloperoxidase deficiency (OMIM 254600), which is mainly characterized by disseminated candidiasis 19 . It is noteworthy that our patient had been treated with oral terbinafine due to cutaneous candidiasis on the face before the onset of GPP 10 .…”

Section: Discussionmentioning

confidence: 86%

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

Murata

Farooq

Iqbal

et al. 2022

The Journal of Dermatology

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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

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Hereditary myeloperoxidase deficiency due to a missense mutation of arginine 569 to tryptophan.

Cited by 71 publications

References 27 publications

Loss-of-Function Myeloperoxidase Mutations Are Associated with Increased Neutrophil Counts and Pustular Skin Disease

Loss-of-Function Myeloperoxidase Mutations Are Associated with Increased Neutrophil Counts and Pustular Skin Disease

Myeloperoxidase: Molecular Mechanisms of Action and Their Relevance to Human Health and Disease

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

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