AbstractThe identification of disease alleles underlying human autoinflammatory diseases can provide important insights into the mechanisms that maintain neutrophil homeostasis. Here, we focused on generalized pustular psoriasis (GPP), a potentially life-threatening disorder presenting with cutaneous and systemic neutrophilia. Following the whole exome sequencing of 19 unrelated cases, we identified one affected individual harbouring a homozygous splice-site mutation (c.2031-2A>C) in MPO. The same homozygous change was subsequently identified in a further subject suffering from acral pustular psoriasis, a disease phenotypically related to GPP.MPO encodes myeloperoxidase, an essential component of neutrophil azurophil granules. Of interest, the c.2031-2A>C allele was previously described as a genetic determinant of myeloperoxidase deficiency (MPOD), a condition which can causes recurrent infections. Here, a systematic literature review identified four individuals suffering from MPOD and pustular skin disease, further strengthening the link between MPO and pustular inflammation.A subsequent analysis of the UK Biobank cohort demonstrated that the c.2031-2A>C allele was associated with increased neutrophil abundance in the general population (P=5.1×10−6). The same applied to three further MPOD mutations for which genotype data was available, with two alleles generating p-values <10−10. Finally, treatment of healthy neutrophils with an MPO inhibitor reduced cell apoptosis, highlighting a mechanism whereby MPO mutations affect granulocyte numbers.These findings identify MPO mutations as genetic determinants 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.
Rare Loss-of-Function Mutation in SERPINA3 in Generalized Pustular Psoriasis
