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

Department of Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany.
Human Mutation (Impact Factor: 5.14). 02/2010; 31(2):151-8. DOI: 10.1002/humu.21156
Source: PubMed


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.

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    • "When the recombination occurs on different chromosomes, it leads to chromosomal translocations or rearrangements. Several human diseases have been reported to be associated with Alu recombination events such as Gaucher's disease [78], hypercholesterolemia [79–82], chronic granulomatous disease [83], α-thalassaemia [84, 85], diabetes [86], thrombophilia [87], hypobetalipoproteinemia [88], and spastic paraplegia type 11 [89]. "
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    • "Owing to the high frequency (>1 million copies) of complete or partial Alu elements in the human reference genome (∼10.6% of the genome sequence) [Lander et al., 2001], they serve as a huge reservoir of sequences for homology-based recombination. AMR between nonallelic sequences is also a frequent cause of human genetic disease as evidenced by the many recently described examples [e.g., Abo-Dalo et al., 2010; Champion et al., 2010; Cozar et al., 2011; Gentsch et al., 2010; Goldmann et al., 2010; Franke et al., 2009; Resta et al., 2010; Shlien et al., 2010; Tuohy et al., 2010; Yang et al., 2010; Zhang et al., 2010]. "
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