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

✍ Scribed by 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

• Publisher: John Wiley and Sons
• Year: 2010
• Tongue: English
• Weight: 376 KB
• Volume: 31
• Category: Article
• ISSN: 1059-7794
• DOI: 10.1002/humu.21156

✦ Synopsis

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 (p67D5) 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 p67D5 was observed. We conclude that Aluinduced 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.