Alu‐repeat–induced deletions within the NCF2 gene causing p67‐phox–deficient chronic granulomatous disease (CGD) |
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| Authors: | Marcus Gentsch Aneta Kaczmarczyk Karin van Leeuwen Martin de Boer Magdalena Kaus‐Drobek Marie‐Claire Dagher Petra Kaiser Peter D Arkwright Manfred Gahr Angela Rösen‐Wolff Matthias Bochtler Elizabeth Secord Pamela Britto‐Williams Gulam Mustafa Saifi Anne Maddalena Ghassan Dbaibo Jacinta Bustamante Jean‐Laurent Casanova Dirk Roos Joachim Roesler |
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| Institution: | 1. Department of Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany;2. Marcus Gentsch, Aneta Kaczmarczyk, Dirk Roos, and Joachim Roesler contributed equally to this work.;3. Structural Biology Laboratory, International Institute of Molecular and Cell Biology, Warszawa, Poland;4. Sanquin Research, Amsterdam, The Netherlands;5. Karl Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands;6. Max‐Planck‐Institute for Molecular Cell Biology and Genetics, Dresden, Germany;7. Centre Diagnostic et Recherche CGD, TIM‐C Imag, Centre National de la Recherche Scientifique (CNRS), Université Joseph Fourier, Grenoble, France;8. Professor Hess Kinderklinik, Klinikum Bremen‐Mitte, Bremen, Germany;9. Child Health, Division of Translational Medicine, University of Manchester, Manchester, United Kingdom;10. Allergy/Immunology Division, Children's Hospital of Michigan, Wayne State University, Detroit, Michigan;11. GeneDx, Gaithersburg, Maryland;12. Department of Pediatrics, American University of Beirut‐Medical Center, Beirut, Lebanon;13. Department of Biochemistry, American University of Beirut‐Medical Center, Beirut, Lebanon;14. Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, U550, Paris, France;15. Paris René Descartes University, Necker Medical School, Paris, France |
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| Abstract: | Mutations that impair expression or function of the components of the phagocyte NADPH oxidase complex cause chronic granulomatous disease (CGD), which is associated with life‐threatening infections and dysregulated granulomatous inflammation. In five CGD patients from four consanguineous families of two different ethnic backgrounds, we found similar genomic homozygous deletions of 1,380 bp comprising exon 5 of NCF2, which could be traced to Alu‐mediated recombination events. cDNA sequencing showed in‐frame deletions of phase zero exon 5, which encodes one of the tandem repeat motifs in the tetratricopeptide (TPR4) domain of p67‐phox. The resulting shortened protein (p67Δ5) had a 10‐fold reduced intracellular half‐life and was unable to form a functional NADPH oxidase complex. No dominant negative inhibition of oxidase activity by p67Δ5 was observed. We conclude that Alu‐induced deletion of the TPR4 domain of p67‐phox leads to loss of function and accelerated degradation of the protein, and thus represents a new mechanism causing p67‐phox–deficient CGD. Hum Mutat 30:1–8, 2009. © 2009 Wiley‐Liss, Inc. |
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| Keywords: | recombination immunodeficiency phagocyte NCF2 |
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