| Title: | Loss-of-Function Myeloperoxidase Mutations Are Associated with Increased Neutrophil Counts and Pustular Skin Disease |
| Journal: | American Journal of Human Genetics |
| Published: | 5 Aug 2020 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/32758448/ |
| DOI: | https://doi.org/10.1016/j.ajhg.2020.06.020 |
| URL: | http://www.cell.com/article/S0002929720302299/pdf |
Publication 5342
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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.</p>
44 Authors
- Marta Vergnano
- Maja Mockenhaupt
- Natashia Benzian-Olsson
- Maren Paulmann
- Katarzyna Grys
- Satveer K. Mahil
- Charlotte Chaloner
- Ines A. Barbosa
- Suzannah August
- A. David Burden
- Siew-Eng Choon
- Hywel Cooper
- Alex A. Navarini
- Nick J. Reynolds
- Shyamal Wahie
- Richard B. Warren
- Andrew Wright
- The APRICOT and PLUM study team
- Thamir Abraham
- Mahmud Ali
- Suzannah August
- David Baudry
- Anthony Bewley
- Hywel Cooper
- John Ingram
- Susan Kelly
- Mohsen Korshid
- Effie Ladoyanni
- John McKenna
- Freya Meynell
- Richard Parslew
- Prakash Patel
- Angela Pushparajah
- Nick Reynolds
- Catherine Smith
- Shyamal Wahie
- Richard Warren
- Andrew Wright
- Ulrike Huffmeier
- Patrick Baum
- Sudha Visvanathan
- Jonathan N. Barker
- Catherine H. Smith
- Francesca Capon
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