title: Alu-repeat-induced deletions within the NCF2 gene causing p67-phox-deficient chronic granulomatous disease (CGD).
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.
authors: Department of Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany.
authors: Marcus
authors: M
authors: Gentsch
authors: Aneta
authors: A
authors: Kaczmarczyk
authors: Karin
authors: K
authors: van Leeuwen
authors: Martin
authors: M
authors: de Boer
authors: Magdalena
authors: M
authors: Kaus-Drobek
authors: Marie-Claire
authors: MC
authors: Dagher
authors: Petra
authors: P
authors: Kaiser
authors: Peter D
authors: PD
authors: Arkwright
authors: Manfred
authors: M
authors: Gahr
authors: Angela
authors: A
authors: Rösen-Wolff
authors: Matthias
authors: M
authors: Bochtler
authors: Elizabeth
authors: E
authors: Secord
authors: Pamela
authors: P
authors: Britto-Williams
authors: Gulam Mustafa
authors: GM
authors: Saifi
authors: Anne
authors: A
authors: Maddalena
authors: Ghassan
authors: G
authors: Dbaibo
authors: Jacinta
authors: J
authors: Bustamante
authors: Jean-Laurent
authors: JL
authors: Casanova
authors: Dirk
authors: D
authors: Roos
authors: Joachim
authors: J
authors: Roesler
mesh_terms: D020087:Alu Elements / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D005091:Exons / Q000235:genetics; D005786:Gene Expression Regulation; D006105:Granulomatous Disease, Chronic / Q000201:enzymology* / Q000235:genetics*; D006207:Half-Life; D006801:Humans; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D019255:NADPH Oxidases / Q000235:genetics*; D010750:Phosphoproteins / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D055550:Protein Stability; D017433:Protein Structure, Secondary; D020871:RNA Stability / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics*
chemical_list: D050505:Mutant Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C079789:neutrophil cytosol factor 67K; D019255:NADPH Oxidases; C527764:NCF2 protein, human