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An autoinflammatory syndrome caused by DPP9 deficiency, leading to NLRP1 inflammasome activation! Wonderful collaboration with Zhong lab and @ReversadeLab, led by @CassHarapas @KimSamirah and Kenneth Lay, with Jon Bernstein and Nevin Hatipoglu. 1/5 https://www.medrxiv.org/content/10.1101/2021.01.31.21250067v1
Patients with DPP9 deficiency suffer from immune-associated defects, skin pigmentation abnormalities and neurological deficits. Mutant alleles are loss of function or hypomorphic for enzymatic activity and NLRP1 inhibition. Keratinocytes display spontaneous NLRP1 activation. 2/5
Remarkably, in a model of disease, DPP9 deficiency can be almost completely resolved by heterozygous deletion of NLRP1, ASC, Casp1 or IL-1R, but not IL-18. This suggests that IL-1 blockade could be beneficial for patients. 3/5
Cells with highest expression of NLRP1 in blood seem particularly affected. NLRP1 independent roles of DPP9 may influence stature and lung physiology, consistent with GWAS links for DPP9 in pulmonary fibrosis and COVID19 severity. 4/5
Could NLRP1 inhibitors be useful in the clinic? Certainly this is at least one condition that might benefit! Sincere thanks to our supporters @WEHI_research @nhmrc @EMBO_YIP @wellcometrust @HHMINEWS @veskiorg @VicGovAu 5/5