Loss-of-function myeloperoxidase mutations are associated with increased neutrophil counts and pustular skin disease

Vergnano, M. et al. (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. 32758448. (doi: 10.1016/j.ajhg.2020.06.020) (PMID:PMC7477255)

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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.

Item Type:Articles
Additional Information:We acknowledge support from the Department of Health via a National Institute of Health Research (NIHR) Biomedical Research Centre award to Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust (guysbrc-2012-1). We also acknowledge support from the Newcastle NIHR Biomedical Research Centre. The APRICOT trial is funded by the Efficacy and Mechanism Evaluation Programme (grant EME 13/50/17). This work has been partly funded by a European Academy of Dermatology and Venereology (EADV) award to J.N.B. and F.C. (grant PPRC-2018-25). U.H. is funded by the DFG (CRC1181, Project A05). M.V. is supported by a Medical Research Council (MRC) PhD studentship, N.B.-O. by a NIHR pre-doctoral fellowship (NIHR300473), and S.K.M. by an MRC Clinical Academic Research Partnership award (MR/T02383X/1).
Keywords:AGEP, GPP, MPO, acute generalized exanthematous pustulosis, generalized pustular psoriasis, myeloperoxidase, myeloperoxidase deficiency, neutrophils
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Burden, Professor David
Authors: Vergnano, M., Mockenhaupt, M., Benzian-Olsson, N., Paulmann, M., Grys, K., Mahil, S. K., Chaloner, C., Barbosa, I. A., August, S., Burden, A. D., Choon, S.-E., Cooper, H., Navarini, A. A., Reynolds, N. J., Wahie, S., Warren, R. B., Wright, A., Huffmeier, U., Baum, P., Visvanathan, S., Barker, J. N., Smith, C. H., and Capon, F.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:American Journal of Human Genetics
Publisher:Cell Press
ISSN:0002-9297
ISSN (Online):1537-6605
Published Online:05 August 2020
Copyright Holders:Copyright © 2020 The Author(s)
First Published:First published in American Journal of Human Genetics 107(3): 539-543
Publisher Policy:Reproduced under a Creative Commons License
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