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- DOI: 10.1002/humu.21156
- PMID: 19953534
- UKPMCID: 19953534
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Alu-repeat-induced deletions within the NCF2 gene causing p67-phox-deficient chronic granulomatous disease (CGD).
Gentsch, Marcus; Kaczmarczyk, Aneta; van Leeuwen, Karin; de Boer, Martin; Kaus-Drobek, Magdalena; Dagher, Marie-Claire; Kaiser, Petra; Arkwright, Peter D; Gahr, Manfred; Rösen-Wolff, Angela; Bochtler, Matthias; Secord, Elizabeth; Britto-Williams, Pamela; Saifi, Gulam Mustafa; Maddalena, Anne; Dbaibo, Ghassan; Bustamante, Jacinta; Casanova, Jean-Laurent; Roos, Dirk; Roesler, Joachim
Human Mutation. 2010;31(2):151-8.
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Full-text held externally
- DOI: 10.1002/humu.21156
- PMID: 19953534
- UKPMCID: 19953534
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 (p67Delta5) 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 p67Delta5 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.
Bibliographic metadata
- Gentsch, Marcus
- Kaczmarczyk, Aneta
- van Leeuwen, Karin
- de Boer, Martin
- Kaus-Drobek, Magdalena
- Dagher, Marie-Claire
- Kaiser, Petra
- Arkwright, Peter D
- Gahr, Manfred
- Rösen-Wolff, Angela
- Bochtler, Matthias
- Secord, Elizabeth
- Britto-Williams, Pamela
- Saifi, Gulam Mustafa
- Maddalena, Anne
- Dbaibo, Ghassan
- Bustamante, Jacinta
- Casanova, Jean-Laurent
- Roos, Dirk
- Roesler, Joachim