alexa Two CGD Families with a Hypomorphic Mutation in the Activation Domain of p67phox
ISSN: 2155-9899

Journal of Clinical & Cellular Immunology
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Research Article

Two CGD Families with a Hypomorphic Mutation in the Activation Domain of p67phox

Dirk Roos1*, Jaap D van Buul1, Anton TJ Tool1, Juan D Matute2, Christophe M Marchal2, Bu’Hussain Hayee3, M Yavuz Köker4, Martin de Boer1, Karin van Leeuwen1, Anthony W Segal3, Edgar Pick5 and Mary C Dinauer2
1Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
2Departments of Pediatrics (Hematology/Oncology), Microbiology/Immunology, and Medical and Molecular Genetics, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA
3Department of Medicine, University College London, London, United Kingdom
4Department of Immunology and Immunology Laboratory, Faculty of Medicine, University of Erciyes, Kayseri, Turkey
5Julius Friedrich Cohnheim Laboratory of Phagocyte Research, Sackler School of Medicine, Tel Aviv University, Israel
Corresponding Author : Dr. Dirk Roos
Sanquin Research, Plesmanlaan 125
1066 CX Amsterdam, The Netherlands
Tel: 00-31-20-5123317
Fax: 00-31-20-5123310
E-mail: [email protected]
Received May 14, 2014; Accepted June 28, 2014; Published June 30, 2014
Citation: Roos D, van Buul JD, Tool ATJ, Matute JD, Marchal CM, et al. (2014) Two CGD Families with a Hypomorphic Mutation in the Activation Domain of p67phox. J Clin Cell Immunol 5:231. doi:10.4172/2155-9899.1000231
Copyright: © 2014 Roos D, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Abstract

Study background: Chronic granulomatous Disease (CGD) is a rare immunodeficiency caused by a defect in the leukocyte NADPH oxidase. This enzyme generates superoxide, which is needed for the killing of bacteria and fungi by phagocytic leukocytes. Most CGD patients have mutations in CYBB, the X-linked gene that encodes gp91phox, the catalytic subunit of the leukocyte NADPH oxidase. We report here three autosomal recessive CGD patients from two families with a homozygous mutation in NCF2, the gene that encodes p67phox, the activator subunit of the NADPH oxidase.

Methods: Leukocyte NADPH oxidase activity, expression of oxidase components and gene sequences were measured with standard methods. The mutation found in the patients’ NCF2 gene was expressed as Ala202Valp67phox in K562 cells to measure its effect on NADPH oxidase activity. Translocation of the mutated p67phox from the cytosol of the patients’ neutrophils to the plasma membrane was measured by confocal microscopy and by Western blotting after membrane purification.

Results: The exceptional feature of the A67 CGD patients reported here is that the p.Ala202Val mutation in the activation domain of p67phox was clearly hypomorphic: substantial expression of p67phox protein was noted and the NADPH oxidase activity in the neutrophils of the patients was 20-70% of normal, dependent on the stimulus used to activate the cells. The extent of Ala202Val-p67phox translocation to the plasma membrane during cell activation was also stimulus dependent. Ala202Val-p67phox in K562 cells mediated only about 3% of normal oxidase activity compared to cells transfected with the wild-type p67phox.

Conclusion: The mutation found in NCF2 is the cause of the decreased NADPH oxidase activity and the (mild) clinical problems of the patients. We propose that the p.Ala202Val mutation has changed the conformation of the activation domain of p67phox, resulting in reduced activation of gp91phox.

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