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

Abstract

Mucopolysaccharidosis type II (MPS II) is caused by mutations in the IDS gene, which encodes the lysosomal enzyme iduronate-2-sulfatase. In B20% of MPS II patients the disorder is caused by gross IDS structural rearrangements. We identified two male cases harboring complex rearrangements involving the IDS gene and the nearby pseudogene, IDSP1, which has been annotated as a low-copy repeat (LCR). In both cases the rearrangement included a partial deletion of IDS and an inverted insertion of the neighboring region. In silico analyses revealed the presence of repetitive elements as well as LCRs at the junctions of rearrangements. Our models illustrate two alternative consequences of rearrangements initiated by non-allelic homologous recombination of LCRs: resolution by a second recombination event (that is, Alu-mediated recombination), or resolution by non-homologous end joining repair. These complex rearrangements have the potential to be recurrent and may be present among those MSP II cases with previously uncharacterized aberrations involving IDS.

High incidence of BSCL2 intragenic recombinational mutation in Peruvian type 2 Berardinelli–Seip syndrome

“…Our breakpoint analysis suggests that Alu‐mediated intragenic recombination can be a mechanism of deletional mutation in CGL2, as reported in other loci that undergo non‐allelic homologous recombination (NAHR) following the ectopic cross‐over of repeat sequences [Oshima et al, , ; Liu et al, ]. Alignments of breakpoint sequences revealed two interesting features, raising additional mechanistic possibilities.…”

A New Mutation in IDS Gene Causing Hunter Syndrome: A Case Report

“…In another study with Israeli families (Simon-Schiff et al, 1994), the authors identified two patients with deletions of the exons 5, 6, and 7. Oshima et al in 2011, identified two cases of rearrangements that included a partial deletion of IDS gene and an inverted insertion of the pseudogene IDSP1, probably mediated by an Alu element (Oshima et al, 2011).…”

Detection of Structural Variants by NGS: Revealing Missing Alleles in Lysosomal Storage Diseases

“…A pseudogene ( IDSP1 —also known as IDS2 ), located telomeric to the functional IDS gene, contains sequences homologous to exon 2, intron 2, exon 3 and a chimerical fragment of intron 3–intron 7, making this region prone to the occurrence of non-allelic homologous recombination events [ 41 ]. Indeed, whole IDS gene deletion (with or without the involvement of further neighboring genes) and partial IDS exon deletions have been reported in multiple studies, mainly in patients with a severe Hunter syndrome presentation [ 41 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ]. Furthermore, IDS exons duplications, IDS1/IDS2 inversions, chimeric IDS-IDS2 allele and other large complex rearrangements have been described [ 41 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ], as well as deletions in the promoter region in patients with a mild phenotype [ 72 ].…”