AbstractDipeptidyl peptidase 9 (DPP9) is a direct inhibitor of NLRP1, but how it impacts inflammasome regulation in vivo is not yet established. Here, we report two families with immune-associated defects, skin pigmentation abnormalities and neurological deficits that segregate with biallelic DPP9 rare variants. Using patient-derived primary cells and biochemical assays, these variants are shown to behave as hypomorphic or loss-of-function alleles that fail to repress NLRP1. Remarkably, the removal in mice, of a single copy of either Nlrp1a/b/c, Asc, Gsdmd, Il-1r, but not Il-18, was sufficient to rescue the lethality of Dpp9 mutant neonates. These experiments suggest that the deleterious consequences of DPP9 loss are mainly driven by the aberrant activation of the canonical NLRP1 inflammasome and IL-1β signaling. Collectively, our results delineate a Mendelian disorder of DPP9 deficiency driven by increased NLRP1 activity as demonstrated in patient cells and in a mouse model of the disease.One Sentence SummaryLoss of DPP9 activity in humans and mice results in pathogenic NLRP1 overactivation.
Loss of coordinated expression between ribosomal and mitochondrial genes revealed by comprehensive characterization of a large family with a rare Mendelian disorder