Home Publications Research Grants Inventions & Patents Awards Additional Research Activities Faculties & Institutions Research Areas

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

Vergnano M, Mockenhaupt M, Benzian-Olsson N, Paulmann M, Grys K, Mahil SK, Chaloner C, Barbosa IA, August S, Burden AD, Choon SE, Cooper H, Navarini AA, Reynolds NJ, Wahie S, Warren RB, Wright A, Abraham T, Ali M, Baudry D, Bewley A, Ingram J, Kelly S, Korshid M, Ladoyanni E, McKenna J, Meynell F, Parslew R, Patel P, Pushparajah A, Reynolds N, Smith C, Warren R, Hüffmeier U, Baum P, Visvanathan S, Barker JN, Smith CH, Capon F (2020)

---

Publication Type: Journal article

Publication year: 2020

Journal

Book Volume: 107

Pages Range: 539-543

Journal Issue: 3

DOI: 10.1016/j.ajhg.2020.06.020

Abstract

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.

Authors with CRIS profile

Additional Organisation(s)

Involved external institutions

How to cite

APA:

Vergnano, M., Mockenhaupt, M., Benzian-Olsson, N., Paulmann, M., Grys, K., Mahil, S.K.,... Capon, F. (2020). Loss-of-Function Myeloperoxidase Mutations Are Associated with Increased Neutrophil Counts and Pustular Skin Disease. American Journal of Human Genetics, 107(3), 539-543. https://doi.org/10.1016/j.ajhg.2020.06.020

MLA:

Vergnano, Marta, et al. "Loss-of-Function Myeloperoxidase Mutations Are Associated with Increased Neutrophil Counts and Pustular Skin Disease." American Journal of Human Genetics 107.3 (2020): 539-543.

BibTeX: Download