A novel missense mutation in the NADPH binding domain of CYBB abolishes the NADPH oxidase activity in a male patient with increased susceptibility to infections.
Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the five structural genes (CYBB, CYBA, NCF1, NCF2, and NCF4) that typically results in a decrease in function or inability to generate a respiratory burst, leading to defective killing of pathogens, including fungi and intracellular bacteria. Mutations in CYBB, encoding the gp91phox (also known as NOX2) result in X-linked CGD account for approximately 65% of CGD cases. Here, we aimed the characterization of a novel missense mutation c.1226C > A/p.A409E in the CYBB gene in a patient with X-linked CGD. Relevant clinical data of a male patient whose family was positive for XCGD was reviewed. Oxidative burst and NADPH protein expression was evaluated by flow cytometry, while Genetic analysis was performed by Sanger sequencing. Monocyte-derived macrophages (MDMs) were evaluated for their capacity for phagocytosis and growth suppression of the intracellular Mycobacterium tuberculosis (M. tuberculosis). We thus report the absence of an oxidative burst in the phagocytes of the patient. Flow cytometry evaluation revealed a normal expression of NADPH oxidase components in neutrophils and genetic analysis proved the existence of a novel missense c.1226C > A mutation in the CYBB gene resulting in p.A409E. Further, we have showed that the patient's MDMs were unhindered in their ability to take up mycobacteria normally. Instead, the MDMs failed to control the intracellular proliferation of M. tuberculosis, a phenotype that improved in the presence of recombinant human interferon-gamma (rhIFN-γ). This work expands the genetic spectrum of X-linked CGD and demonstrates improvement in macrophage function in X91+CGD patient by rhIFN-γ.
Department of Microbiology, Kohat University of Science and Technology, Kohat, Pakistan. Electronic address: microbiologist63@yahoo.com.
Taj Ali
TA
Khan
Department of Food Science & Technology, University of Agriculture, Peshawar, Pakistan.
Kalsoom
K
Kalsoom
Laboratory of Biochemistry and Biophysics, Butantan Institute, Sao Paulo, Brazil.
Asif
A
Iqbal
Laboratory of Biochemistry and Biophysics, Butantan Institute, Sao Paulo, Brazil.
Huma
H
Asif
Department of Microbiology, Kohat University of Science and Technology, Kohat, Pakistan.
Hazir
H
Rahman
Khyber Medical University, Institute of Medical Sciences, Kohat, Pakistan.
Syed Omar
SO
Farooq
Department of Microbiology, Kohat University of Science and Technology, Kohat, Pakistan.
Hassan
H
Naveed
Khyber Medical University, Institute of Medical Sciences, Kohat, Pakistan.
Umar
U
Nasir
Khyber Medical University, Institute of Medical Sciences, Kohat, Pakistan.
Muhammad Usman
MU
Amin
Department of Microbiology, Kohat University of Science and Technology, Kohat, Pakistan.
Mubashir
M
Hussain
Department of Immunology, Armed Forces Institute of Pathology, Rawalpindi, Pakistan.
Hamid Nawaz
HN
Tipu
The Department of Chemistry, University of Oxford, Oxford, United Kingdom.
Andrei
A
Florea
D002478:Cells, Cultured; D003141:Communicable Diseases / Q000235:genetics / Q000276:immunology*; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease; D006105:Granulomatous Disease, Chronic / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008264:Macrophages / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D020125:Mutation, Missense; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000276:immunology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000032:analysis* / Q000235:genetics; D010587:Phagocytosis; D016897:Respiratory Burst; D017422:Sequence Analysis, DNA
D008562:Membrane Glycoproteins; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
Chronic granulomatous disease; Immunodeficiency; Monocyte-derived macrophages; Mycobacterium tuberculosis