Sequences of junction fragments in the deletion-prone region of the dystrophin gene

Love, Donald R.; England, Sarah B.; Speer, Astrid; Marsden, Rosalind F.; Bloomfield, J.; Roche, A.; Cross, Gareth; Mountford, Roger; Smith, Terry J.; Davies, Kay E.

doi:10.1016/0888-7543(91)90484-v

Cited by 48 publications

(39 citation statements)

References 33 publications

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Section: Discussionsupporting

confidence: 78%

“…One of the breakpoints was located in LINE-1 repetitive elements in all patients, but the other ends were not associated with any particular repetitive elements. These observations in the patients with del45-55 are consistent with those in the cases with other types of deletion in DMD, [12][13][14][17][18][19] again supporting that homologous recombination is not the major cause of deletions in DMD.Human gene deletions are induced by several mechanisms, the relative importance of which is probably governed by local and secondary DNA structures. 20 Krawczak and Cooper 20 have pointed out that human sequences involved in deletion events often contain a short deletion consensus sequence, TG(A/G)(A/G)(G/T)(A/C), and are often associated with palindromic sequences.…”

supporting

confidence: 77%

“…To our knowledge, only two breakpoints have been precisely described in intron 44, 12 which is the major deletion-prone region in DMD. 1,6,7,13 On the other hand, an analysis of breakpoints in intron 55 has never been reported.…”

Section: Introductionmentioning

confidence: 99%

“…The breakpoints in intron 44 in these patients gathered in the 3¢-half of that intron (Figure 1; S2, Electric Supplementary material), as pointed out earlier. 6,12,13 Further the breakpoints in intron 55 showed a relative clustering within a region of approximately 10 kb (Figure 1; S2, Electric Supplementary material). None of the breakpoints appeared to have a close association with MAR sites.…”

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confidence: 99%

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Characterization of deletion breakpoints in patients with dystrophinopathy carrying a deletion of exons 45–55 of the Duchenne muscular dystrophy (DMD) gene

et al. 2009

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Deletion of exons 45-55 (del45-55) in the Duchenne muscular dystrophy gene (DMD) has gained particular interest in the field of molecular therapy, because it causes a milder phenotype than DMD, and therefore, may represent a good candidate for the goal of a multiple exon-skipping strategy. We have precisely characterized deletion breakpoints in three patients with del45-55 in DMD. Two of them were young adult males of the X-linked dilated cardiomyopathy phenotype, and the third patient revealed the mild Becker muscular dystrophy phenotype of late onset. The deletion breakpoints differed among patients. The deletion started at nt 226 604, 231 518, 117 284 in intron 44, and ended at nt 64 994, 59 314, 71 806 in intron 55, respectively. Deletion junctions showed no significant homology between the sequences adjacent to the distal and proximal end joints in these patients. Deletion breakpoints were not primarily associated with any particular sequence element, or with a matrix attachment region. However, there were several palindromic sequences and short tandem repeats at or near the breakpoints. These sequences, with a marked propensity to form secondary DNA structure intermediates, may predispose local DNA to breakage and intragenic recombination in these patients. Keywords: breakpoint; deletion; Duchenne muscular dystrophy (DMD); dystrophin; genomic sequence; X-linked dilated cardiomyopathy (XLDCM) INTRODUCTIONThe Duchenne muscular dystrophy gene (DMD) is the largest one so far identified, spanning more than 2.5 Mb and occupying roughly 0.1% of the human genome. 1 Mutations in DMD cause a devastating muscular dystrophy named Duchenne/Becker muscular dystrophy (DMD/BMD). The cardio-specific phenotype of dystrophinopathy is also known as X-linked dilated cardiomyopathy (XLDCM). 1 Intragenic deletions and duplications together account for over two-thirds of the mutations found in DMD/BMD patients. [2][3][4][5][6][7] Despite heterogeneity in both deletion size and location, two deletion 'hotspots' have been identified in DMD: a minor 'hotspot' including exons 2-19, and the major one involving exons 40-50 or 45-55. 2,4,5,7 Among deletions of variable sizes and locations found in DMD/ BMD patients, deletion of exons 45-55 (del45-55) in DMD has gained particular attention because an artificial dystrophin with del45-55 created by a multiple exon-skipping strategy could transform the DMD phenotype into the asymptomatic or milder BMD phenotype. 8 We reported three patients with del45-55 who presented with the phenotypes far from DMD. 9 Two of them were young adult males of the XLDCM phenotype. 9,10 The third patient revealed the mild BMD phenotype of late onset. 9,11 Our patients support the hypothesis that del45-55 could be a good candidate for the goal of a multiple exonskipping strategy for DMD.To elucidate the molecular basis of del45-55 in more detail, we have characterized the breakpoints of del45-55 in DMD in these three patients. To our knowledge, only two breakpoints have been precisely described in intron 44,...

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Section: Discussionsupporting

confidence: 78%

supporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Characterization of deletion breakpoints in patients with dystrophinopathy carrying a deletion of exons 45–55 of the Duchenne muscular dystrophy (DMD) gene

et al. 2009

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“…In the present paper we report that the dystrophin gene is a target for LI insertion. From (34). (e) Homologous recombination between Alu sequences, the other repetitive sequence ofthe human genome, have been shown to result in the deletion of a receptor gene coding for low density lipoprotein (35).…”

Section: Discussionmentioning

confidence: 99%

Insertion of a 5' truncated L1 element into the 3' end of exon 44 of the dystrophin gene resulted in skipping of the exon during splicing in a case of Duchenne muscular dystrophy.

Narita

Nishio²,

Kitoh³

et al. 1993

J. Clin. Invest.

188

111

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We report here the second evidence of retrotransposition of L1, which was found inserted into the dystrophin gene of a patient, causing Duchenne muscular dystrophy (DMD). When the PCR was used to amplify a region of the dystrophin gene encompassing exon 44 from genomic DNA of two Japanese brothers with DMD, it was found to be -600 bp larger than expected. Both the normal and the abnormally large products were amplified from the DNA of their mother. However, the maternal grandparents did not have the abnormal allele, and the mutation must therefore have occurred in the mother. Analysis of nucleotide sequence of the amplified product from a patient disclosed that the insertion was present zero to two bases upstream from the 3' end of exon 44 and that two to four bases of the exon sequence were deleted from the insertion site. The insertion sequence was found to be composed of 606-608 bp and to be almost identical to the inverse complement of 3' portion of the Li retrotransposon consensus sequence. The dystrophin gene transcript from peripheral lymphocytes of one of the patients was analyzed by using reverse transcription/ semi-nested PCR. The size of the amplified product encompassing exon 42 to 46 was smaller than expected. Sequencing of the amplified product disclosed that the sequence of exon 43 was directly joined to that of exon 45. Exon 44 of the transcript was thus shown to be skipped during splicing. This novel mutation of the dystrophin gene has important implications regarding retrotransposition of an active Ll element and provides a new insight into the origins of mutations in the dystrophin gene. (J.

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

et al. 2002

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Mutations in L1CAM are responsible for X-linked hydrocephalus, whereas those in the ALD gene (ABCD1) cause adrenoleukodystrophy. In both genes, most of the mutations reported so far are short-length mutations and only a few patients with larger rearrangements have been documented. We have characterized three intragenic deletions of the ALD gene at the molecular level and describe here the first two L1CAM rearrangements resulting in deletion of several exons in one case and about 50 kb, including the entire gene, in the second case. At both breakpoints of an ALD deletion, Alu repeats have been found and, additionally, a short Alu region of approximately 130 bp was inserted, suggesting that this rearrangement is the result of a more complex non-allelic homologous recombination event. Only one Alu element was present at the breakpoint of the second ALD rearrangement, including a 26-bp Alu core sequence that was suggested to be a recombinogenic hot spot. These data suggest the involvement of an Alu core sequence-stimulated non-homologous recombination as a possible cause for this rearrangement. Short direct repeats were identified at all putative mispaired sequences in the L1CAM breakpoints and at both breakpoints of the third ALD deletion characterized, suggesting non-homologous (illegitimate) recombination as the molecular mechanism by which these latter deletions occurred. In conclusion, our results indicate that highly repetitive elements as well as short direct repeats are frequently involved in the formation of ALD and L1CAM gene rearrangements.

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Sequences of junction fragments in the deletion-prone region of the dystrophin gene

Cited by 48 publications

References 33 publications

Characterization of deletion breakpoints in patients with dystrophinopathy carrying a deletion of exons 45–55 of the Duchenne muscular dystrophy (DMD) gene

Characterization of deletion breakpoints in patients with dystrophinopathy carrying a deletion of exons 45–55 of the Duchenne muscular dystrophy (DMD) gene

Insertion of a 5' truncated L1 element into the 3' end of exon 44 of the dystrophin gene resulted in skipping of the exon during splicing in a case of Duchenne muscular dystrophy.

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

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