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Alu‐repeat–induced deletions within the NCF2 gene causing p67‐ phox –deficient chronic granulomatous disease (CGD)
Author(s) -
Gentsch Marcus,
Kaczmarczyk Aneta,
van Leeuwen Karin,
de Boer Martin,
KausDrobek Magdalena,
Dagher MarieClaire,
Kaiser Petra,
Arkwright Peter D.,
Gahr Manfred,
RösenWolff Angela,
Bochtler Matthias,
Secord Elizabeth,
BrittoWilliams Pamela,
Saifi Gulam Mustafa,
Maddalena Anne,
Dbaibo Ghassan,
Bustamante Jacinta,
Casanova JeanLaurent,
Roos Dirk,
Roesler Joachim
Publication year - 2010
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21156
Subject(s) - chronic granulomatous disease , biology , nadph oxidase , exon , genetics , alu element , p22phox , gene , microbiology and biotechnology , genome , reactive oxygen species , human genome
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 (p67Δ5) 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 p67Δ5 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. Hum Mutat 30:1–8, 2009. © 2009 Wiley‐Liss, Inc.