Alu-repeat-induced deletions within the NCF2 gene causing p67-phox-deficient chronic granulomatous disease (CGD).
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.
Gentsch
Marcus
M
Department of Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany.
Kaczmarczyk
Aneta
A
van Leeuwen
Karin
K
de Boer
Martin
M
Kaus-Drobek
Magdalena
M
Dagher
Marie-Claire
MC
Kaiser
Petra
P
Arkwright
Peter D
PD
Gahr
Manfred
M
Rösen-Wolff
Angela
A
Bochtler
Matthias
M
Secord
Elizabeth
E
Britto-Williams
Pamela
P
Saifi
Gulam Mustafa
GM
Maddalena
Anne
A
Dbaibo
Ghassan
G
Bustamante
Jacinta
J
Casanova
Jean-Laurent
JL
Roos
Dirk
D
Roesler
Joachim
J
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*
D050505:Mutant Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C079789:neutrophil cytosol factor 67K; D019255:NADPH Oxidases; C527764:NCF2 protein, human