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 , hypercholesterolemia [79–82], chronic granulomatous disease , α-thalassaemia [84, 85], diabetes , thrombophilia , hypobetalipoproteinemia , and spastic paraplegia type 11 . "
[Show abstract][Hide abstract] ABSTRACT: Alus, the short interspersed repeated sequences (SINEs), are retrotransposons that litter the human genomes and have long been considered junk DNA. However, recent findings that these mobile elements are transcribed, both as distinct RNA polymerase III transcripts and as a part of RNA polymerase II transcripts, suggest biological functions and refute the notion that Alus are biologically unimportant. Indeed, Alu RNAs have been shown to control mRNA processing at several levels, to have complex regulatory functions such as transcriptional repression and modulating alternative splicing and to cause a host of human genetic diseases. Alu RNAs embedded in Pol II transcripts can promote evolution and proteome diversity, which further indicates that these mobile retroelements are in fact genomic gems rather than genomic junks.
"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]. "
[Show abstract][Hide abstract] ABSTRACT: Different types of human gene mutation may vary in size, from structural variants (SVs) to single base-pair substitutions, but what they all have in common is that their nature, size and location are often determined either by specific characteristics of the local DNA sequence environment or by higher order features of the genomic architecture. The human genome is now recognized to contain "pervasive architectural flaws" in that certain DNA sequences are inherently mutation prone by virtue of their base composition, sequence repetitivity and/or epigenetic modification. Here, we explore how the nature, location and frequency of different types of mutation causing inherited disease are shaped in large part, and often in remarkably predictable ways, by the local DNA sequence environment. The mutability of a given gene or genomic region may also be influenced indirectly by a variety of noncanonical (non-B) secondary structures whose formation is facilitated by the underlying DNA sequence. Since these non-B DNA structures can interfere with subsequent DNA replication and repair and may serve to increase mutation frequencies in generalized fashion (i.e., both in the context of subtle mutations and SVs), they have the potential to serve as a unifying concept in studies of mutational mechanisms underlying human inherited disease.
Human Mutation 10/2011; 32(10):1075-99. DOI:10.1002/humu.21557 · 5.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chronic granulomatous Disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. The disease is caused by mutations in the genes encoding the components of the leukocyte NADPH oxidase. This enzyme produces superoxide, which is essential in the process of intracellular pathogen killing by phagocytic leukocytes. Four of the five genes involved in CGD are autosomal; these are CYBA, encoding p22-phox, NCF2, encoding p67-phox, NCF1, encoding p47-phox, and NCF4, encoding p40-phox. This article lists all mutations identified in these genes in the autosomal forms of CGD. Moreover, polymorphisms in these genes are also given, which should facilitate the recognition of future disease-causing mutations.