title: Expanding the clinical and genetic spectrum of G6PD deficiency: The occurrence of BCGitis and novel missense mutation.
abstract: Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme in the pentose phosphate pathway that ensures sufficient production of coenzyme nicotinamide adenine dinucleotide phosphate (NADPH) by catalyzing the reduction of NADP+ to NADPH. Noteworthy, the latter mediates the production of reactive oxygen species (ROS) by phagocytic cells such as neutrophils and monocytes. Therefore, patients with severe forms of G6PD deficiency may present impaired NADPH oxidase activity and become susceptible to recurrent infections. This fact, highlights the importance to characterize the immunopathologic mechanisms underlying the susceptibility to infections in patients with G6PD deficiency. Here we report the first two cases of G6PD deficiency with Bacille Calmette-Guérin (BCG) adverse effect, besides jaundice, hemolytic anemia and recurrent infections caused by Staphylococcus aureus. The qualitative G6PD screening was performed and followed by oxidative burst analysis using flow cytometry. Genetic and in silico analyses were carried out by Sanger sequencing and mutation pathogenicity predicted using bioinformatics tools, respectively. Activated neutrophils and monocytes from patients displayed impaired oxidative burst. The genetic analysis revealed the novel missense mutation c.1157T>A/p.L386Q in G6PD. In addition, in silico analysis indicated that this mutation is pathogenic, thereby hampering the oxidative burst of neutrophils and monocytes from patients. Our data expand the clinical and genetic spectrum of G6PD deficiency, and suggest that impaired oxidative burst in this severe primary immune deficiency is an underlying immunopathologic mechanism that predisposes to mycobacterial infections.
authors.affiliation: Department of Microbiology, Kohat University of Science and Technology, Kohat, Pakistan. Electronic address: microbiologist63@yahoo.com.
authors.forename: Taj Ali
authors.initials: TA
authors.lastname: Khan
authors.affiliation: Department of Microbiology, Kohat University of Science and Technology, Kohat, Pakistan.
authors.forename: Humaira
authors.initials: H
authors.lastname: Mazhar
authors.affiliation: Department of Microbiology, Kohat University of Science and Technology, Kohat, Pakistan.
authors.forename: Mehboob
authors.initials: M
authors.lastname: Nawaz
authors.affiliation: Department of Food Science & Technology, University of Agriculture, Peshawar, Pakistan.
authors.forename: Kalsoom
authors.initials: K
authors.lastname: Kalsoom
authors.affiliation: Basic Science Research Department, Shaukat Khanum Memorial Cancer Hospital & Research Centre, Lahore, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ishfaq
authors.affiliation: Laboratory of Biochemistry and Biophysics, Butantan Institute, Sao Paulo, Brazil.
authors.forename: Huma
authors.initials: H
authors.lastname: Asif
authors.affiliation: Department of Microbiology, Kohat University of Science and Technology, Kohat, Pakistan.
authors.forename: Hazir
authors.initials: H
authors.lastname: Rahman
authors.affiliation: Department of Microbiology, Kohat University of Science and Technology, Kohat, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Qasim
authors.affiliation: District Hospital Kohat, KPK, Pakistan.
authors.forename: Farkhanda
authors.initials: F
authors.lastname: Naz
authors.affiliation: Department of Microbiology, Kohat University of Science and Technology, Kohat, Pakistan.
authors.forename: Mubashir
authors.initials: M
authors.lastname: Hussain
authors.affiliation: Department of Microbiology, Kohat University of Science and Technology, Kohat, Pakistan.
authors.forename: Baharullah
authors.initials: B
authors.lastname: Khattak
authors.affiliation: Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology, Kohat, Pakistan.
authors.forename: Waheed
authors.initials: W
authors.lastname: Ullah
authors.affiliation: Department of Rheumatology, University Lübeck, Lübeck, Germany.
authors.forename: Otavio
authors.initials: O
authors.lastname: Cabral-Marques
authors.affiliation: Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology, Kohat, Pakistan.
authors.forename: Jawad
authors.initials: J
authors.lastname: Butt
authors.affiliation: Laboratory of Biochemistry and Biophysics, Butantan Institute, Sao Paulo, Brazil. Electronic address: asif.iqbal@butatan.gov.br.
authors.forename: Asif
authors.initials: A
authors.lastname: Iqbal
mesh_terms: D019943:Amino Acid Substitution; D001500:BCG Vaccine / Q000009:adverse effects; D004252:DNA Mutational Analysis; D056726:Genetic Association Studies; D005954:Glucosephosphate Dehydrogenase / Q000737:chemistry / Q000235:genetics*; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000150:complications / Q000175:diagnosis* / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D020125:Mutation, Missense; D009163:Mycobacterium bovis; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D018384:Oxidative Stress; D010375:Pedigree; D011487:Protein Conformation; D017382:Reactive Oxygen Species / Q000378:metabolism; D016897:Respiratory Burst
chemical_list: D001500:BCG Vaccine; D017382:Reactive Oxygen Species; D005954:Glucosephosphate Dehydrogenase
keywords: BCG; Coenzyme nicotinamide adenine dinucleotide phosphate; Glucose-6-phosphate dehydrogenase; Mutation; Reactive oxygen species; Vaccine