Supplementary MaterialsSupplemental data jci-128-97116-s113. condition, resembling a mild, atypical form of CGD. [and p67deficiencies appear to be as severe as XR CGD (18, 19). Patients are routinely placed on prophylactic antimicrobial therapy, and the only curative treatment widely available is allogeneic hematopoietic stem cell transplantation (HSCT) (20). The NADPH oxidase in human phagocytes P7C3-A20 price is a complex of at least 5 subunits. The membrane-bound component is a heterodimer consisting of gp91and p22gene and the autosomal gene, respectively. This heterodimer is known as flavocytochrome underlie the XR form of CGD, whereas LOF mutations of underlie the AR forms. Hypomorphic mutations of some of these genes have been shown to underlie variant CGD, in which residual activity does not differ between cell types (24). Hypomorphic mutations, which are more deleterious in monocyte-derived macrophages (MDMs) than in peripheral phagocytes, have been shown to underlie Mendelian susceptibility to mycobacterial disease (MSMD) (25). Much less is known about the fifth component, p40have only been described once before in a young boy with severe colitis (26). p40has 3 domains: PX, PB1, and SH3 (27, 28). During phagocytosis, upregulation of the membrane phospholipid phosphatidylinositol 3-phosphate [PI(3)P] and subsequent high-affinity binding of the p40PX domain enhance NADPH oxidase activity (21, 29). The p40is impaired in the patients neutrophils, and killing is also defective (20, 26, 30). However, in this patient, unlike in classic CGD patients, the production of O2C by neutrophils in response to stimulation with PMA or formyl-methionyl-leucyl-phenylalanine (fMLF) is normal (26). The killing of by neutrophils is impaired in p40deficiency and classic CGD are mainly unfamiliar also. Here, we explain the features of 24 patients from 12 families in 8 countries with biallelic mutations of gene in patients from 11 families: 2 variants affecting essential splice sites (c.118-1G A in kindreds A, E, and K and c.32+2T G in kindred F); 3 missense variants (c.314G A in kindred B, resulting in p.R105Q; c.172C T in kindreds G and L, resulting in p.R58C; and c.430C A in kindred H, resulting in p.P144T); 1 nonsense variant (c.716G A in kindred I, resulting in p.W239X); and 1 in-frame deletion (c.120_134del in kindreds C and J). Finally, we detected compound heterozygous splice-site variants in 1 family (c.118-1G A and c.759-1G C in kindred D). All variants were verified by Sanger sequencing. In 11 kindreds, the familial segregation of the alleles was consistent with an AR trait. Kindred J displayed uniparental isodisomy (UPD), as both copies of chromosome 22 were inherited from the father (Physique 1A and ref. 38). Four asymptomatic individuals were shown to carry biallelic mutations (kindreds E and G) (Physique 1A). None of the variants, other than p.R58C (minor allele frequency [MAF] = 0.001), P7C3-A20 price was found in public P7C3-A20 price databases (Exome Aggregation Consortium [ExAC], Human Gene Mutation Database [HGMD], gnomAD, and Biomarker Recognition and Validation Online [BRAVO]) or in our in-house WES database (~4,500 WES). Furthermore, combined annotation-dependent depletion (CADD) scores predicted all mutations to be deleterious, as these scores were above or close to the mutation significance cutoff (MSC) (ref. 24 and Supplemental Physique 1A; supplemental material Plxna1 available online with this article; https://doi.org/10.1172/JCI97116DS1). The 3 missense mutations P7C3-A20 price affect residues located in the PX domain name of the p40protein (Physique 1B). These residues are highly conserved in other species, suggesting that they have an important function in the p40protein.