Deletions with inversions: Report of a mutation and review of the literature

Ketterling, Rhett P.; Ricke, Darrell O.; Wurster, Mark; Sommer, Steve S.

doi:10.1002/humu.1380020110

Cited by 19 publications

(6 citation statements)

References 27 publications

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“…So far, the mechanisms associated with the genomic rearrangement of large F9 deletions have not been well described. In the previously reported breakpoint junctions, most of them were associated with insertions, which can be inversions (10,11), orphan sequences (9), inversions with orphan sequences or sense strand insertions (7). However, microhomology was the main feature identified in our studied patients.…”

Section: Discussionmentioning

confidence: 99%

“…factorix.org/), among which 60% were gross deletions encompassing all the exons of the F9 gene. Altogether, the exact junctions of 11 large deletions have been found until now, and the deletion extents of them ranged from 1.1 kb to 26.8 kb (4)(5)(6)(7)(8)(9)(10)(11)(12). The latest one was a 5969 bp deletion including the exon 4 with 13 bp duplication inserted near the 3' breakpoint site identified by the long-chain polymerase chain reaction (LC-PCR) method (4).…”

Section: Introductionmentioning

confidence: 99%

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Characterisation of large F9 deletions in seven unrelated patients with severe haemophilia B

Wu¹,

Lu²,

Ding³

et al. 2014

Thromb Haemost

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Large deletions in the F9 gene are detected in approximately 5% of patients with severe haemophilia B, but only a few deletion breakpoints have been characterised precisely until now. In this study we identified a total of seven large F9 deletions in the index patients and nine female carriers by the AccuCopy technique. We also successfully characterised the exact breakpoints for each large deletion including four deletions encompassing the entire F9 gene by the genome walking method combined with primer walking strategy. The extents of deletion regions ranged from 11.1 to 884 kb. Microhomologies ranged from 2 to 6 bp were identified in the breakpoint junctions of six deletions. The other deletion occurred between two highly homologous sequences of the same long interspersed nuclear element 1 (LINE/L1). Non-homologous end joining (NHEJ) and microhomology-mediated break-induced replication (MMBIR) may be the main causative mechanisms for the six large deletions with microhomologies. Non-allelic homologous recombination (NAHR) may mediate the deletion occurred between the two tandem LINEs in the other large deletion. Repetitive elements and non-B DNA forming motifs identified in the junction regions may contribute to DNA breakage leading to large deletions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characterisation of large F9 deletions in seven unrelated patients with severe haemophilia B

Wu¹,

Lu²,

Ding³

et al. 2014

Thromb Haemost

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“…Recombination events promoted by very small stretches of homology have been described for experimental systems 23 and for mutations leading to human disease. 24,25 The sequence CTGGT occurs once in intron 3 and twice in intron 7. It is likely that the multiple presence of this sequence motif played a role in the stepwise rearrangement of IDS-2 during evolution, as it represents the overlap between the intron 3 and intron 7 homologous regions.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 1998

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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.

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“…In these genes the inserted sequence constitutes an internal portion of the removed sequence, but in inverted orientation. Sommer and Ketterling [1993] originally proposed a ''double-loop'' model for the above two F9 mutations [Solera et al, 1992;Ketterling et al, 1993] and the RB1 mutation [Greger et al, 1990]. During replication, single-stranded DNA is proposed to form a ''double-loop'' structure mediated by FIGURE 3.…”

Section: Inversions That Involve the Partial Reinsertion Of The Removmentioning

confidence: 99%

Intrachromosomal serial replication slippage intransgives rise to diverse genomic rearrangements involving inversions

et al. 2005

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Serial replication slippage in cis (SRScis) provides a plausible explanation for many complex genomic rearrangements that underlie human genetic disease. This concept, taken together with the intra- and intermolecular strand switch models that account for mutations that arise via quasipalindrome correction, suggest that intrachromosomal SRS in trans (SRStrans) mediated by short inverted repeats may also give rise to a diverse series of complex genomic rearrangements. If this were to be so, such rearrangements would invariably generate inversions. To test this idea, we collated all informative mutations involving inversions of >or=5 bp but <1 kb by screening the Human Gene Mutation Database (HGMD; www.hgmd.org) and conducting an extensive literature search. Of the 21 resulting mutations, only two (both of which coincidentally contain untemplated additions) were found to be incompatible with the SRStrans model. Eighteen (one simple inversion, six inversions involving sequence replacement by upstream or downstream sequence, five inversions involving the partial reinsertion of removed sequence, and six inversions that occurred in a more complicated context) of the remaining 19 mutations were found to be consistent with either two steps of intrachromosomal SRStrans or a combination of replication slippage in cis plus intrachromosomal SRStrans. The remaining lesion, a 31-kb segmental duplication associated with a small inversion in the SLC3A1 gene, is explicable in terms of a modified SRS model that integrates the concept of "break-induced replication." This study therefore lends broad support to our postulate that intrachromosomal SRStrans can account for a variety of complex gene rearrangements that involve inversions.

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Deletions with inversions: Report of a mutation and review of the literature

Cited by 19 publications

References 27 publications

Characterisation of large F9 deletions in seven unrelated patients with severe haemophilia B

Characterisation of large F9 deletions in seven unrelated patients with severe haemophilia B

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

Intrachromosomal serial replication slippage intransgives rise to diverse genomic rearrangements involving inversions

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