A homozygous loss-of-function mutation leading to CYBC1 deficiency causes chronic granulomatous disease

Abstract

Mutations in genes encoding subunits of the phagocyte NADPH oxidase complex are recognized to cause chronic granulomatous disease (CGD), a severe primary immunodeficiency. Here we describe how deficiency of CYBC1, a previously uncharacterized protein in humans (C17orf62), leads to reduced expression of NADPH oxidase’s main subunit (gp91phox) and results in CGD. Analyzing two brothers diagnosed with CGD we identify a homozygous loss-of-function mutation, p.Tyr2Ter, in CYBC1. Imputation of p.Tyr2Ter into 155K chip-genotyped Icelanders reveals six additional homozygotes, all with signs of CGD, manifesting as colitis, rare infections, or a severely impaired PMA-induced neutrophil oxidative burst. Homozygosity for p.Tyr2Ter consequently associates with inflammatory bowel disease (IBD) in Iceland (P = 8.3 × 10−8; OR = 67.6), as well as reduced height (P = 3.3 × 10−4; −8.5 cm). Overall, we find that CYBC1 deficiency results in CGD characterized by colitis and a distinct profile of infections indicative of macrophage dysfunction.

Next generation sequencing analysis of consecutive Russian patients with clinical suspicion of inborn errors of immunity

“…The list of genes implicated in the pathogenesis of immunerelated disease is constantly growing, so some of the very recently identified gene candidates (eg, RIPK1, ICOSLG, CYBC1) could not be considered in our NGS panel. [30][31][32][33] Furthermore, our NGS test could not reliably identify copy number variations (CNVs), as the adaptation of NGS to CNV testing requires additional bioinformatics and analytical efforts. 34 It is relevant to mention that CNVs appear to be uncommon for PID patients.…”

A novel variant in the neutrophil cytosolic factor 2 (NCF2) gene results in severe disseminated BCG infectious disease: A clinical report and literature review

“…Variants in the CYBA , CYBB , NCF1 , NCF2 (OMIM *608,515), NCF4, and CYBC1 genes, which code for the six components of this enzyme complex, lead to CGD (Roos et al, 2010). Hemizygous variants in the CYBB gene, which encodes the gp91 phox subunit of the NADPH oxidase complex, lead to X‐linked recessive (XL) CGD, while bi‐allelic variants in the CYBA , NCF1 , NCF2 , NCF4, and CYBC1 genes, which encode the p22 phox , p47 phox , p67 phox , p40 phox , and EROS subunits, respectively, lead to different forms of autosomal recessive (AR) disease (Arnadottir et al, 2018; Chiriaco, Salfa, Di Matteo, Rossi, & Finocchi, 2016; Roos et al, 2010; Thomas et al, 2017). CGD is characterized by recurrent bacterial, including mycobacterial, and fungal infections, resulting in granulomas, episodes of fever, rash, and other symptoms, such as colitis (Roos et al, 2010).…”

Inflammatory consequences of inherited disorders affecting neutrophil function

“…16,17 Autosomal-recessive null mutations in NCF4 or CYBC1 have only recently been described. [18][19][20][21] In contrast to the "classic" forms of CGD that lack or have profoundly reduced NADPH oxidase activity, the respiratory burst defects are more nuanced. NCF4 (p40 phox ) is a specialized subunit that stimulates phagosome oxidase activity via a regulatory domain that binds to phosphatidylinositol 3-phosphate, a membrane lipid present in high concentrations on phagosome and other intracellular membranes.…”

“…14 Nine patients are reported, including 8 from Iceland homozygous for the same founder mutation and 1 patient from Saudi Arabia. 20,21 Detailed studies are still limited but suggest that defects in human monocyte and macrophage flavocytochrome b 558 expression and NADPH oxidase activity are more substantial that those in neutrophils. Of note, phorbol ester-induced dihydrorhodamine-1,2,3 oxidation in neutrophils, a widely used diagnostic test for CGD, may not be abnormal in NCF4 or CYBC1 deficiency.…”