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LCR-Initiated Rearrangements at the IDS Locus, Completed with Alu-Mediated Recombination Or Non-Homologous End Joining

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LCR-Initiated Rearrangements at the IDS Locus, Completed with Alu-Mediated Recombination Or Non-Homologous End Joining Journal of Human Genetics (2011) 56, 516–523 & 2011 The Japan Society of Human Genetics All rights reserved 1434-5161/11 $32.00 www.nature.com/jhg ORIGINAL ARTICLE LCR-initiated rearrangements at the IDS locus, completed with Alu-mediated recombination or non-homologous end joining Junko Oshima1,4, Jennifer A Lee1, Amy M Breman1, Priscilla H Fernandes1, Dusica Babovic-Vuksanovic2, Patricia A Ward1, Lynne A Wolfe3,5, Christine M Eng1 and Daniela del Gaudio1,6 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. Journal of Human Genetics (2011) 56, 516–523; doi:10.1038/jhg.2011.51; published online 19 May 2011 Keywords: array CGH; chromosomal rearrangements; clinical molecular genetics; Hunter syndrome; lysosomal storage diseases; mucopolysaccharidoses; X-linked diseases INTRODUCTION chromosome Xq28.2.2 Its 1650-bp open reading frame encodes the Mucopolysaccharidosis type II (MPS II; Hunter syndrome; OMIM # 550 amino-acid lysosomal enzyme iduronate-2-sulfatase.3 A1.4-kb 309900) is a rare X-linked recessive lysosomal storage disorder. It is alternative transcript that lacks exons 8 and 9 but contains an caused by deficiency of the enzyme iduronate-2-sulfatase (IDS; EC alternative terminal exon 7 has been reported, although the signifi- 3.1.6.13), one of the enzymes in the pathway of heparan sulfate cance of this alternative form is not well known.4 At 20 kb telomeric to and dermatan sulfate degradation. The clinical severity of MPS II the IDS locus, there is a predicted locus, LOC727913 (RefSeq occurs along a spectrum with the severe form being characterized by XM_001126136), that is highly homologous to part of exon 2, intron progressive cognitive decline, developmental regression and involve- 2 and exon 3 of the IDS gene (Figure 1c).5–7 The IDSP1 locus, which ment of multiple organ systems occurring during the first few years is the only pseudogene of IDS in the human genome, is located of life. Progressive respiratory and cardiac failure may lead to death in B25 kb telomeric to IDS and spans 1.6 kb in an inverse orientation. the first or second decade. In patients with the attenuated form, IDSP1 is highly homologous to a 1.6-kb region within IDS intron 7 the central nervous system is not (or is minimally) compromised, (Figure 1c).8,9 although skeletal deformities and other organ involvement can To date, more than 350 IDS disease-causing mutations have been be present to the same degree as in the severe form. Cardiac or described (Human Genome Mutation Database),10 with the majority respiratory failure may lead to death during the third to fourth represented by missense, nonsense, splicing and small deletion muta- decades of life. Treatment for MPS II is currently focused on tions. Genomic rearrangements account for B20% of IDS cases.10 enzyme replacement therapy and on the management of the clinical There have been a number of previous reports documenting various symptoms.1 rearrangements involving IDS and IDSP1.8,9 Among them is a MPS II is caused by mutations in the IDS gene (RefSeq common inversion involving low-copy repeats (LCRs) in IDS intron NM_000202.4), which consists of nine exons and spans B24 kb on 7andIDSP1 that has been observed in multiple independent 1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; 2Department of Medical Genetics, Mayo Clinic, Rochester, MN, USA and 3Department of Genetics, Yale University School of Medicine, New Haven, CT, USA 4Present address: Department of Pathology, University of Washington, Seattle, WA, USA. 5Present address: National Human Genome Research Institute, Bethesda, MD, USA. 6Present address: Department of Human Genetics, University of Chicago, IL, USA. Correspondence: Dr D del Gaudio, Department of Human Genetics, University of Chicago, 5841 S. Maryland Avenue, Room L155, MC 0077, Chicago, IL 60637, USA. E-mail: [email protected] Received 13 January 2011; revised 11 February 2011; accepted 16 March 2011; published online 19 May 2011 IDS genomic rearrangement JOshimaet al 517 Figure 1 RT-PCR analysis for case 1. (a) Ethidium bromide staining of the RT-PCR products spanning IDS exons 6 through 9 (left), nested PCR reaction spanning exons 7 through 9 (middle) and the repeated nested PCR reaction (right). M: 100 bp marker, P: patient, C: control. B: water blank. (b) Nucleotide sequences and the alignments of the junction of the IDS exons and cryptic inserts from RT-PCR products showed in a.The5¢ (left) and 3¢ (right) junctions of the longer insert are shown. Nucleotide positions follow the numbering in RefSeq NC_000023.9. (c) Diagram of the region surrounding the IDS locus. Loci in this chromosome Xq (ChXq) region are shown; centromere, cen; telomere, tel. The relevant repeat and repetitive sequences are shown: LCR, low-copy repeat; L1-Alu-L1, a combination of LINE and Alu repeats: L1MD2-AluSg-L1MD2 (left) and L1MB3-AluSc-L1MB3 (right). (d) Diagram of the six cryptic exons inserted between IDS exons 7 and 9. Genomic coordinates of the exons and the locations of the loci annotated in the Entrez Gene Database are shown. pedigrees.11 Also reported are large deletions of the IDS locus ranging In this report we present two novel rearrangements involving the from single or multiple exon deletions to deletions of the entire gene, IDS gene and its pseudogene, IDSP1, in two unrelated patients with with or without the involvement of neighboring genes. Complex MPS II. One consists of a deletion including IDS exon 8 and an rearrangements reported previously include recombination between inverted duplication of an B49-kb region distal to IDS that is inserted the IDS gene and the IDSP1 pseudogene,8,9 a deletion with an inverted into the deleted region. The other consists of an B36-kb deletion duplication,12 and an Alu-mediated deletion with an insertion.13 encompassing IDS exons 1 through 7 and an B8-kb deletion, In particular, two highly homologous regions within IDS and IDSP1 interrupted by an inverted 2-kb region, and a point mutation that appear to facilitate intrachromosomal recombination events leading to destroys the usual translation termination signal. In silico analysis of complex rearrangements.5,8,14 These two regions span B1.6 kb and the breakpoints, aimed at identifying consensus sequences of motifs are designated as LCRs (UCSC Genome Browser, Human March 2006 involved in complex rearrangements, suggests that the close proximity Assembly (hg18); http://genome.ucsc.edu/). LCRs are thought to of the two LCRs, combined with the nearby Alu and other repetitive mediate non-allelic homologous recombination (NAHR) events sequences, confers significant instability to this region, potentially resulting in recurrent rearrangements of a various number of contributing to these novel genomic rearrangements. loci.15,16 Non-homologous end joining (NHEJ) is another well- known rearrangement repair mechanism that is thought to be MATERIALS AND METHODS facilitated by the presence of repetitive DNA sequences, such as Alu Patient samples or LINE repeats, although the precise causal mechanisms remain Peripheral blood samples from the patients and one mother were submitted for elusive.15–17 IDS clinical testing to the DNA Diagnostic Laboratory at Baylor College of Journal of Human Genetics IDS genomic rearrangement J Oshima et al 518 Medicine. The families subsequently gave their consent for further analysis a GeneChip Scanner 3000 7G (Affymetrix) and results were analyzed using of the pertinent genomic region on a research basis. This study was approved Genotyping Console version 2.1 software (Affymetrix). by the Baylor College of Medicine Institutional Review Board. Determination of rearrangement breakpoints Mutation analysis The rearrangement breakpoints were ascertained by PCR primer walking using Genomic DNA was isolated from blood leukocytes on the AutoPure LS FastTaq (Applied Biosystems) and the Expand Long Template PCR System robotic workstation (Gentra Systems, Minneapolis, MN, USA) using a Pure- (Roche Diagnostics, Indianapolis, IN, USA). PCR primers were designed based gene DNA isolation kit (Gentra Systems). Total RNA was isolated from whole on the GenBank reference sequence NC_000023.9, and are listed in Table 1. blood using Trizol LS (Invitrogen, Carlsbad, CA, USA) as previously PCR products were sequenced as described above. All chromosome positions described.18 PCR primers were designed for amplification of all coding exons were determined using the Human March 2006 Assembly (hg18). and flanking intronic sequences of IDS (RefSeq NM_000202.2) and are available upon request. PCR products were sequenced using the Big Dye terminator version 3.1 chemistry on an ABI 3730 XL Genetic Analyzer (Applied RESULTS Biosystems, Foster City, CA, USA). Clinical presentations of MPS II patients The patient (case 1) is a 3-year-old European Caucasian male with clinical features consistent with a diagnosis of MPS II. He was born Reverse transcriptase (RT)-PCR analysis after a normal term pregnancy by Cesarean section to a 25-year-old Three hundred nanograms of total RNA were reverse-transcribed in a 20 ml reaction volume with Superscript III Reverse Transcriptase (Invitrogen) mother.
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