Characterization of breakpoint sequences of five rearrangements inL1CAM andABCD1 (ALD) genes

Kutsche, Kerstin; Ressler, Bernadette; Katzera, Heide-Gertrude; Orth, Ulrike; Gillessen‐Kaesbach, Gabriele; Morlot, Susanne; Schwinger, E.; Gal, Andreas

doi:10.1002/humu.10072

Cited by 38 publications

(35 citation statements)

References 29 publications

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“…Based on these results, we propose a comprehensive modeling of the mechanisms involved. Xq28 locus is considered a region at high risk of genomic instability, with micro-rearrangements (deletion or duplication) described, for example, in adrenoleukodystrophy, 15 X-linked mental retardation syndrome (MECP2), 16 and HA. 1,2 Indeed, the F8 gene intron 22 contains a 9.5-kb region known as copy int22h-1, which is outside the gene and situated B0.5 and 0.6 Mb more telomerically to the two other highly homologous copies, namely int22h-2 and int22h-3.…”

Section: Discussionmentioning

confidence: 99%

Intron 22 homologous regions are implicated in exons 1–22 duplications of the F8 gene

et al. 2013

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The intron 22 inversion found in up to 50% of severe hemophilia A patients results from a recombination between three intron 22 homologous copies (int22h). This study evaluated the implication of these copies in the formation of extended duplications comprising exons 1-22 of the factor 8 (F8) gene and their association with hemophilia and mental retardation. Two hemophilic patients with moderate and severe phenotypes and a third nonhemophilic patient with developmental delay were studied. All exhibited a duplication of F8 gene exons 1-22 identified by multiplex ligation-dependent probe amplification along with abnormal patterns on Southern blotting and unexpected long-range PCR amplification. Breakpoint analysis using array comparative genomic hybridization was performed to delimit the extent of these rearrangements. These duplications were bounded on one side by the F8 intragenic int22h-1 repeat and on the other side by extragenic int22h-2 or int22h-3 copies. However, the simultaneous identification of a second duplication containing F8 gene exons 2-14 for the moderate patient and the classical intron 22 inversion for the severe patient are considered in this study as the genetic causal defects of hemophilia. This study shows that the well-known int22h copies are involved in extended duplications comprising F8 gene exons 1-22. These specific duplications are probably not responsible for hemophilia and intellectual disability, but should be carefully considered in genetic counseling, while continuing to investigate the causal mutation of hemophilia.

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Section: Discussionmentioning

confidence: 99%

Intron 22 homologous regions are implicated in exons 1–22 duplications of the F8 gene

et al. 2013

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“…Microrearrangements that lead to disease are reported as the result of NAHR or NHEJ in adrenoleukodystrophy (OMIM 300100) (Kutsche et al 2002), X-linked hydrocephalus (OMIM 307000) (Kutsche et al 2002), red-green color-blindness (OMIM 303800) (Deeb and Kohl 2003), Emery-Dreifuss Muscular Dystrophy (OMIM 310300) (Small and Warren 1998), incontinentia pigmenti (OMIM 308300) (Aradhya et al 2002), and hemophilia A (OMIM 306700) (Bagnall et al 2005). The presence of multiple LCRs (LC1640 to LC1650) in this interval could render this region prone to these subtle rearrangements.…”

Section: Overall Genomic Instability At Xq28mentioning

confidence: 99%

Nonrecurrent MECP2 duplications mediated by genomic architecture-driven DNA breaks and break-induced replication repair

Bauters¹,

Esch²,

Friez³

et al. 2008

Genome Res.

122

124

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Recurrent submicroscopic genomic copy number changes are the result of nonallelic homologous recombination (NAHR). Nonrecurrent aberrations, however, can result from different nonexclusive recombination-repair mechanisms. We previously described small microduplications at Xq28 containing MECP2 in four male patients with a severe neurological phenotype. Here, we report on the fine-mapping and breakpoint analysis of 16 unique microduplications. The size of the overlapping copy number changes varies between 0.3 and 2.3 Mb, and FISH analysis on three patients demonstrated a tandem orientation. Although eight of the 32 breakpoint regions coincide with low-copy repeats, none of the duplications are the result of NAHR. Bioinformatics analysis of the breakpoint regions demonstrated a 2.5-fold higher frequency of Alu interspersed repeats as compared with control regions, as well as a very high GC content (53%). Unexpectedly, we obtained the junction in only one patient by long-range PCR, which revealed nonhomologous end joining as the mechanism. Breakpoint analysis in two other patients by inverse PCR and subsequent array comparative genomic hybridization analysis demonstrated the presence of a second duplicated region more telomeric at Xq28, of which one copy was inserted in between the duplicated MECP2 regions. These data suggest a two-step mechanism in which part of Xq28 is first inserted near the MECP2 locus, followed by breakage-induced replication with strand invasion of the normal sister chromatid. Our results indicate that the mechanism by which copy number changes occur in regions with a complex genomic architecture can yield complex rearrangements.

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“…Although this scenario remains formally possible, genomic rearrangements can accompany L1, Alu, and simple poly(A) insertions in vivo (9,20,28,37,41,42,60,67,70,75). Thus, it is unlikely that these arrangements are peculiar to HeLa cells.…”

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confidence: 99%

Multiple Fates of L1 Retrotransposition Intermediates in Cultured Human Cells

Gilbert

Lutz

Morrish

et al. 2005

Molecular and Cellular Biology

260

375

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LINE-1 (L1) retrotransposons comprise ϳ17% of human DNA, yet little is known about L1 integration. Here, we characterized 100 retrotransposition events in HeLa cells and show that distinct DNA repair pathways can resolve L1 cDNA retrotransposition intermediates. L1 cDNA resolution can lead to various forms of genetic instability including the generation of chimeric L1s, intrachromosomal deletions, intrachromosomal duplications, and intra-L1 rearrangements as well as a possible interchromosomal translocation. The L1 retrotransposition machinery also can mobilize U6 snRNA to new genomic locations, increasing the repertoire of noncoding RNAs that are mobilized by L1s. Finally, we have determined that the L1 reverse transcriptase can faithfully replicate its own transcript and has a base misincorporation error rate of ϳ1/7,000 bases. These data indicate that L1 retrotransposition in transformed human cells can lead to a variety of genomic rearrangements and suggest that host processes act to restrict L1 integration in cultured human cells. Indeed, the initial steps in L1 retrotransposition may define a host/parasite battleground that serves to limit the number of active L1s in the genome.Long interspersed element 1 (LINE-1 or L1) is an abundant retrotransposon that comprises ϳ17% of human DNA (43, 69). Most L1s are retrotransposition defective because they are 5Ј truncated, contain internal rearrangements, or harbor mutations within their open reading frames (25, 43). However, the average human genome is estimated to contain ϳ80 to 100 retrotransposition-competent L1s (RC-L1s), and approximately 10% of these elements are classified as highly active or "hot" (6, 63).Human RC-L1s are ϳ6.0 kb and contain a 5Ј untranslated region (UTR), two nonoverlapping open reading frames (ORF1 and ORF2), and a 3Ј UTR that ends in a poly(A) tail (Fig. 1A) (13,53,66). ORF1 encodes a 40-kDa nucleic acid binding protein (30,31,33), whereas ORF2 has the potential to encode a 150-kDa protein with demonstrated endonuclease (L1 EN) and reverse transcriptase (L1 RT) activities (15,19,22,51). ORF2p also contains a cysteine-rich domain (CX 3 CX 7 HX 4 C) of unknown function (17, 54). Both proteins are required for retrotransposition in cis (54), which most probably occurs by a mechanism termed "target site primed reverse transcription" (TPRT) (19,47,54,72). However, how L1 integration is completed remains a mystery.We recently developed a plasmid-based rescue system that allows the recovery of L1 insertions in cultured human HeLa cells with minimal influence from selective pressures that occur during genome evolution. We found that L1 retrotransposition is associated with various forms of genetic instability and that the nascent L1 cDNA can undergo recombination with endogenous L1 elements, resulting in the formation of chimeric L1s. Consistent findings by Symer et al., using a colon cell line (HCT116) with an essentially normal karyotype, have led to the hypothesis that L1 retrotransposition can lead to various types of genomic instability (2...

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Characterization of breakpoint sequences of five rearrangements inL1CAM andABCD1 (ALD) genes

Cited by 38 publications

References 29 publications

Intron 22 homologous regions are implicated in exons 1–22 duplications of the F8 gene

Intron 22 homologous regions are implicated in exons 1–22 duplications of the F8 gene

Nonrecurrent MECP2 duplications mediated by genomic architecture-driven DNA breaks and break-induced replication repair

Multiple Fates of L1 Retrotransposition Intermediates in Cultured Human Cells

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