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Journal Article

Alu-repeat-induced deletions within the NCF2 gene causing p67-phox-deficient chronic granulomatous disease (CGD).

MPS-Authors

Gahr,  Manfred
Max Planck Society;

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Bochtler,  Matthias
Max Planck Institute of Molecular Cell Biology and Genetics, Max Planck Society;

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Citation

Gentsch, M., Kaczmarczyk, A., Leeuwen, K. v., Boer, M. d., Kaus-Drobek, M., Dagher, M.-C., et al. (2010). Alu-repeat-induced deletions within the NCF2 gene causing p67-phox-deficient chronic granulomatous disease (CGD). Human Mutation, 31(2), 151-158.


Cite as: https://hdl.handle.net/21.11116/0000-0001-0B06-D
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.