P67-phox (NCF2) Lacking Exons 11 and 12 Is Functionally Active and Leads to an Extremely Late Diagnosis of Chronic Granulomatous Disease (CGD)

Abstract

Two brothers in their fifties presented with a medical history of suspected fungal allergy, allergic bronchopulmonary aspergillosis, alveolitis, and invasive aspergillosis and pulmonary fistula, respectively. Eventually, after a delay of 50 years, chronic granulomatous disease (CGD) was diagnosed in the index patient. We found a new splice mutation in the NCF2 (p67-phox) gene, c.1000+2T→G, that led to several splice products one of which lacked exons 11 and 12. This deletion was in frame and allowed for remarkable residual NADPH oxidase activity as determined by transduction experiments using a retroviral vector. We conclude that p67-phox which lacks the 34 amino acids encoded by the two exons can still exert considerable functional activity. This activity can partially explain the long-term survival of the patients without adequate diagnosis and treatment, but could not prevent progressing lung damage.

Human CD40 ligand deficiency dysregulates the macrophage transcriptome causing functional defects that are improved by exogenous IFN-γ

“…Patients with CGD face life-threatening infections, even when oxidative burst is only slightly reduced or partially inhibited. 17,60,61 Therefore the partially defective oxidative burst observed in macrophages from CD40L-deficient patients might contribute to the abnormal microbicidal activity that we demonstrated in our experiments and might be a risk factor for the increased susceptibility to opportunistic fungal and intracellular bacterial infections. However, it seems unlikely that defective fungicidal activity in macrophages from CD40L-deficient patients is solely due to reduced reactive oxygen species production because additional nonoxidative killing mechanisms might also be affected.…”

Newly diagnosed chronic granulomatous disease in a 44 year old male presenting with recurrent groin cellulitis and colitis

“…The mean age of diagnosis for the x-linked recessive form is 3 years of age while the autosomal recessive forms are diagnosed at 7.8 years of age [1]. A small number of CGD cases have been diagnosed in adulthood beyond the fourth decade [7-10]; the oldest case report identified in the English language literature was of a male diagnosed at 69 years of age [11]. …”

Novel molecular genetic defects and immunopathological mechanisms in Brazilian patients with mycobacterial diseases.

“…Correlation between molecular defects and severity of CGD is attributed to the type of mutation and its effect on the capacity of the NADPH to trigger ROS production, irrespective of the affected gene (Kuhns et al, 2010;Roesler et al, 2012). Usually, patients with partial defect of oxidative burst, whose phagocytes are able to produce residual amounts of ROS, show a much milder phenotype, develop infections later in life, and have better prognoses compared with those with complete absence of an oxidative burst response.…”