Homologous nonallelic recombinations between the iduronate-sulfatase gene and pseudogene cause various intragenic deletions and inversions in patients with mucopolysaccharidosis type II

Abstract

About 20% of patients with mucopolysaccharidosis type II (MPS II) have gross structural rearrangements involving the iduronate-sulfatase (IDS) gene in Xq27.3-q28. A nearby IDS pseudogene (IDS-2) promotes nonallelic recombination between highly homologous sequences. Here we describe major rearrangements due to gene/pseudogene recombination. In two unrelated patients, partial IDS gene deletions were found joining introns 3 and 7 of the IDS gene together with gene to pseudogene conversion in the area of breakpoints. In a third patient, a junction between intron 3 of IDS-2 and intron 7 of IDS was seen that was due to a deletion and inversion of the 5' part of the gene. Characterisation of breakpoints in six patients with large inversions revealed that all recombinations of this type occurred in the same area of homology between IDS and IDS-2; they were molecularly balanced, and accompanied by gene conversions in most cases. Apart from diagnostic implications, such naturally occurring recombination 'hot spots' may allow some insight into general features of crossover events in mammals.

LCR-initiated rearrangements at the IDS locus, completed with Alu-mediated recombination or non-homologous end joining

“…11 Also reported are large deletions of the IDS locus ranging from single or multiple exon deletions to deletions of the entire gene, with or without the involvement of neighboring genes. Complex rearrangements reported previously include recombination between the IDS gene and the IDSP1 pseudogene, 8,9 a deletion with an inverted duplication, 12 and an Alu-mediated deletion with an insertion. 13 In particular, two highly homologous regions within IDS and IDSP1 appear to facilitate intrachromosomal recombination events leading to complex rearrangements.…”

“…10 There have been a number of previous reports documenting various rearrangements involving IDS and IDSP1. 8,9 Among them is a common inversion involving low-copy repeats (LCRs) in IDS intron 7 and IDSP1 that has been observed in multiple independent pedigrees. 11 Also reported are large deletions of the IDS locus ranging from single or multiple exon deletions to deletions of the entire gene, with or without the involvement of neighboring genes.…”

“…IDSP1 is highly homologous to a 1.6-kb region within IDS intron 7 ( Figure 1c). 8,9 To date, more than 350 IDS disease-causing mutations have been described (Human Genome Mutation Database), 10 with the majority represented by missense, nonsense, splicing and small deletion mutations. Genomic rearrangements account for B20% of IDS cases.…”

“…13 In particular, two highly homologous regions within IDS and IDSP1 appear to facilitate intrachromosomal recombination events leading to complex rearrangements. 5,8,14 These two regions span B1.6 kb and are designated as LCRs (UCSC Genome Browser, Human March 2006 Assembly (hg18); http://genome.ucsc.edu/). LCRs are thought to mediate non-allelic homologous recombination (NAHR) events resulting in recurrent rearrangements of a various number of loci.…”

Analysis of a 43.6 kb deletion in a patient with Hunter syndrome (MPSII): Identification of a fusion transcript including sequences from the geneW and theIDS gene

“…Analyses of gross structural rearrangement in the IDS region such as inversions and deletions suggest that these rearrangements are the consequence of both homologous and illegitimate (non-homologous) recombination [Bondeson et al, 1995b;Birot et al, 1996;Karsten et al, 1997;Bunge et al, 1998;Lagerstedt et al, unpublished results]. One of the most common rearrangements in the IDS region is a 40 kb inversion which is caused by homologous recombination between closely related sequences which are located in intron 7 of the IDS gene and in the IDS-2 locus [Bondeson et al, 1995b].…”