Novel missense mutation found in a Japanese patient with myeloperoxidase deficiency

Ohashi, Yuko; Kameoka, Yosuke; Persad, Amanda S.; Koi, Fumikazu; Yamagoe, Satoshi; Hashimoto, Katsuyuki; Suzuki, Kazuo

doi:10.1016/j.gene.2003.11.023

Cited by 13 publications

(10 citation statements)

References 23 publications

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“…Among these deficient individuals were two with missense mutations in MPO, G501S, and R499C, that had not been reported previously. In both cases, the individuals were asymptomatic and had not suffered from frequent or severe infectious complications, as described in the detailed clinical reports (21,22,42).…”

Section: Resultsmentioning

confidence: 77%

“…To date, none of the previously characterized genotypes has directly involved the region around the heme group of MPO. However, missense mutations at residue 501 3 (glycine to serine, G501S) and residue 499 (arginine to cysteine, R499C) have been identified in two unrelated Japanese individuals with inherited MPO deficiency (21,22). We describe here the structural and functional consequences caused by G501S and R499C, two mutations adjacent to the critical histidine 502 on the proximal side of the heme in MPO.…”

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confidence: 96%

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Impact of Two Novel Mutations on the Structure and Function of Human Myeloperoxidase

Goedken

McCormick

Leidal

et al. 2007

Journal of Biological Chemistry

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The heme protein myeloperoxidase (MPO) contributes critically to O 2 -dependent neutrophil antimicrobial activity. Two Japanese adults were identified with inherited MPO deficiency because of mutations at Arg-499 or Gly-501, conserved residues near the proximal histidine in the heme pocket. Because of the proximity of these residues to a critical histidine in the heme pocket, we examined the biosynthesis, function, and spectral properties of the peroxidase stably expressed in human embryonic kidney cells. Biosynthesis of normal MPO by human embryonic kidney cells faithfully mirrored events previously identified in cells expressing endogenous MPO. Mutant apopro-MPO was 90 kDa and interacted normally with the molecular chaperones ERp57, calreticulin, and calnexin in the endoplasmic reticulum. However, mutant precursors were not proteolytically processed into subunits of MPO, although secretion of the unprocessed precursors occurred normally. Although ␦-[14 C]aminolevulinic acid incorporation demonstrated formation of pro-MPO in both mutants, neither protein was enzymatically active. The Soret band for each mutant was shifted from the normal 430 to ϳ412 nm, confirming that heme was incorporated but suggesting that the number of covalent bonds or other structural aspects of the heme pocket were disrupted by the mutations. These studies demonstrate that despite heme incorporation, mutations in the heme environs compromised the oxidizing potential of MPO.

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Section: Resultsmentioning

confidence: 77%

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confidence: 96%

Impact of Two Novel Mutations on the Structure and Function of Human Myeloperoxidase

Goedken

McCormick

Leidal

et al. 2007

Journal of Biological Chemistry

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“…However, there is a geographic heterogeneity between the frequencies of hereditary MPO deficiency in different populations. For example, these findings are compared to the reported 1 in 55,000 in Japan [ 200 , 201 , 202 ]. Generally, MPO deficiency results in a modest increase of either inflammatory problems or infectious complications [ 203 ].…”

Section: Myeloperoxidase Deficiencymentioning

confidence: 96%

Myeloperoxidase as an Active Disease Biomarker: Recent Biochemical and Pathological Perspectives

2018

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Myeloperoxidase (MPO) belongs to the family of heme-containing peroxidases, produced mostly from polymorphonuclear neutrophils. The active enzyme (150 kDa) is the product of the MPO gene located on long arm of chromosome 17. The primary gene product undergoes several modifications, such as the removal of introns and signal peptides, and leads to the formation of enzymatically inactive glycosylated apoproMPO which complexes with chaperons, producing inactive proMPO by the insertion of a heme moiety. The active enzyme is a homodimer of heavy and light chain protomers. This enzyme is released into the extracellular fluid after oxidative stress and different inflammatory responses. Myeloperoxidase is the only type of peroxidase that uses H2O2 to oxidize several halides and pseudohalides to form different hypohalous acids. So, the antibacterial activities of MPO involve the production of reactive oxygen and reactive nitrogen species. Controlled MPO release at the site of infection is of prime importance for its efficient activities. Any uncontrolled degranulation exaggerates the inflammation and can also lead to tissue damage even in absence of inflammation. Several types of tissue injuries and the pathogenesis of several other major chronic diseases such as rheumatoid arthritis, cardiovascular diseases, liver diseases, diabetes, and cancer have been reported to be linked with MPO-derived oxidants. Thus, the enhanced level of MPO activity is one of the best diagnostic tools of inflammatory and oxidative stress biomarkers among these commonly-occurring diseases.

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“…8 MPO deficiency is reported to have an incidence of 1 in 2000-4000 in the United States and Europe and 1 in 55 000 in Japan. [9][10][11][12][13] Candida infections are common in MPO-deficient patients, especially in those that also develop diabetes. 9,[14][15][16][17][18] Occasionally, serious infectious or inflammatory complications have been observed in completely MPOdeficient patients as well.…”

Section: Introductionmentioning

confidence: 99%

Myeloperoxidase is required for neutrophil extracellular trap formation: implications for innate immunity

Metzler

Fuchs

Nauseef

et al. 2011

Blood

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533

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IntroductionMyeloperoxidase (MPO) is one of the most abundant proteins in neutrophils, accounting for 5% of the dry weight of the cell. 1 Stored in the azurophilic granules and released when neutrophils are stimulated, MPO catalyzes the oxidation of chloride and other halide ions in the presence of hydrogen peroxide 2,3 to generate hypochlorous acid and other highly reactive products that mediate efficient antimicrobial action. 4,5 Several inherited mutations and deletions in the gene encoding MPO result in decreased enzyme production and activity. 6,7 Using automated hematological devices, clinicians can distinguish between partial and complete MPO deficiencies. 8 MPO deficiency is reported to have an incidence of 1 in 2000-4000 in the United States and Europe and 1 in 55 000 in Japan. 9-13 Candida infections are common in MPO-deficient patients, especially in those that also develop diabetes. 9,14-18 Occasionally, serious infectious or inflammatory complications have been observed in completely MPOdeficient patients as well. 8 Consistently, MPO knockout mice are susceptible to particular bacterial and fungal infections. 19 Neutrophil extracellular traps (NETs) are part of the neutrophil response to microbes. Activated neutrophils die and release these structures composed of decondensed chromatin and antimicrobial proteins 20,21 that trap and inhibit a broad range of microbes. 22 Little is known about the molecular mechanism that regulates NET formation, making the antimicrobial role of NETs in vivo difficult to assess.Interestingly, neutrophils from chronic granulomatous disease (CGD) patients fail to make NETs. 20 CGD is caused by mutations that disrupt the ability of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to generate superoxide, which dismutates to hydrogen peroxide, the substrate of MPO. CGD patients are prone to recurrent and severe infections, as well as to persistent inflammation that can occur independently of infection. [23][24][25] NET formation by CGD neutrophils is restored by the addition of exogenous hydrogen peroxide, indicating that reactive oxygen species are required for NET formation. 20 Here we show that MPO is necessary for making NETs and suggest that defective NET formation may undermine host defense in patients lacking MPO. Methods Donor consentAll donors gave consent to blood drawing in accordance with the Declaration of Helsinki and to functional and genetic analysis. Samples were collected with approval from the ethical committees at each institution. Neutrophil isolationNeutrophils were isolated by centrifuging heparinized venous blood over Histopaque 1119 (Sigma-Aldrich) and subsequently over a discontinuous Percoll (Amersham Biosciences) gradient as described previously. 20 Cells were stored in Hank buffered salt solution (-) or Dulbecco phosphatebuffered saline (-), without calcium or magnesium, before experiments. NET formation and visualizationNeutrophils (5 ϫ 10 4 ) were seeded per well in 24-well tissue culture plates, in Hanks buffered salt solution (...

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Novel missense mutation found in a Japanese patient with myeloperoxidase deficiency

Cited by 13 publications

References 23 publications

Impact of Two Novel Mutations on the Structure and Function of Human Myeloperoxidase

Impact of Two Novel Mutations on the Structure and Function of Human Myeloperoxidase

Myeloperoxidase as an Active Disease Biomarker: Recent Biochemical and Pathological Perspectives

Myeloperoxidase is required for neutrophil extracellular trap formation: implications for innate immunity

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