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

Vergnano, Marta and Mockenhaupt, Maja and Benzian-Olsson, Natashia and Paulmann, Maren and Grys, Katarzyna and Mahil, Satveer K. and Chaloner, Charlotte and Barbosa, Ines A. and August, Suzannah and Burden, A. David and Choon, Siew-Eng and Cooper, Hywel and Navarini, Alex A. and Reynolds, Nick J. and Wahie, Shyamal and Warren, Richard B. and Wright, Andrew and APRICOT and PLUM study team, and Huffmeier, Ulrike and Baum, Patrick and Visvanathan, Sudha and Barker, Jonathan N. and Smith, Catherine H. and Capon, Francesca. (2020) Loss-of-Function Myeloperoxidase Mutations Are Associated with Increased Neutrophil Counts and Pustular Skin Disease. American Journal of Human Genetics, 107 (3). pp. 539-543.

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Official URL: https://edoc.unibas.ch/80434/

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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.
Faculties and Departments:03 Faculty of Medicine > Bereich Spezialfächer (Klinik) > Dermatologie USB > Dermatologie (Navarini)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Spezialfächer (Klinik) > Dermatologie USB > Dermatologie (Navarini)
UniBasel Contributors:Navarini, Alexander
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:14 Apr 2021 12:41
Deposited On:14 Apr 2021 12:41

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