A novel cryptic exon in intron 3 of the dystrophin gene was incorporated into dystrophin mRNA with a single nucleotide deletion in exon 5

Suminaga, Ryo; Takeshima, Yasuhiro; Adachi, Kayo; Yagi, Minoru; Nakamura, Hajime; Matsuo, Masafumi

doi:10.1007/s100380200023

Cited by 14 publications

(8 citation statements)

References 26 publications

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“…In the junction between exon 20 and 21, 20 bp of the 3¢ end of exon 20 are deleted (upper panel). The normal junction between exons 18 and 19 is shown (lower panel) the genomic sequence was completely normal, however, the activation of exon 18a was attributed to a remote effect induced by a nucleotide change at some distant location (Suminaga et al 2002). When the protein-coding ability of exon 18a was examined by analyzing the translational reading frame of the resulting dystrophin mRNA, a premature stop codon was identified in the 26th codon of exon 18a.…”

Section: Resultsmentioning

confidence: 99%

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Identification of seven novel cryptic exons embedded in the dystrophin gene and characterization of 14 cryptic dystrophin exons

et al. 2007

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The dystrophin gene, which is mutated in Duchenne and Becker muscular dystrophy, is characterized by its extremely large introns. Seven cryptic exons from the intronic sequences of the dystrophin gene have been shown to be inserted into the processed mRNA. In this study, we have cloned seven novel cryptic exons embedded in dystrophin introns that were amplified from dystrophin mRNA isolated from lymphocytes. All of these sequences, which ranged in size from 27 to 151 bp, were found to be cryptic exons because they were completely homologous to intronic sequences (introns 1, 18, 29, 63, 67, and 77), and possessed consensus sequences for branch points, splice acceptor sites, and splice donor sites. Compared with the 77 authentic dystrophin exons, the 14 cryptic exons were characterized by (1) lower Shapiro's splicing probability scores for the splice donor and acceptor sites; (2) smaller and larger densities of splicing enhancer and silencer motifs, respectively; (3) a longer distance between the putative branch site and the splice acceptor site; and (4) with one exception, the introduction of premature stop codons into their respective transcripts. These characteristics indicated that the cryptic exons were weaker than the authentic exons. Our results suggested that a mutation deep within an intron that changed these parameters could cause dystrophinopathy. The cryptic exons identified provide areas that should be examined for the detection of mutations in the dystrophin gene, and they may help us to understand the roles of large dystrophin introns.

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Section: Resultsmentioning

confidence: 99%

“…Subsequently, six additional cryptic exons (exons 2a, 2b, 2c-1, 2c-s, 3a-l, and 3a-s) were disclosed in introns in the 5¢ region of the dystrophin gene ( Fig. 1a) (Dwi Pramono et al 2000;Suminaga et al 2002;Tran et al 2005;Ishibashi et al 2006). Because all of these exons encode a stop codon, their protein-coding abilities were not clear.…”

Section: Introductionmentioning

confidence: 99%

Identification of seven novel cryptic exons embedded in the dystrophin gene and characterization of 14 cryptic dystrophin exons

et al. 2007

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“…By comparison, the mouse genome contains up to three-thousand active L1 elements. L1 retrotransposition accounts for several genetic disorders in humans, including cases of hemophilia A, Duchene muscular dystrophy, type-2 retinitis pigmentosa, ␤-thalassaemia, and chronic granulomatous disease (12)(13)(14)(15)(16). Active human L1 retrotransposons have been cloned, and a tissue culture-based assay has been developed to compare their retrotransposition ability (11,17,18).…”

Section: Human Apobec3gmentioning

confidence: 99%

The Innate Antiretroviral Factor APOBEC3G Does Not Affect Human LINE-1 Retrotransposition in a Cell Culture Assay

Turelli

Vianin

Trono

2004

Journal of Biological Chemistry

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APOBEC3G (apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G) is an innate intracellular antiretroviral factor that can inhibit viral retroelements such as retroviruses and hepadnaviruses. However, it is unknown whether it can act on non-viral substrates. Retrotransposons are transposable elements that cumulatively account for about one third of the human genome. They are commonly classified in long terminal repeat (LTR) retrotransposons, which are strongly homologous to retroviruses, and non-LTR retrotransposons also known as L1 elements or LINE-1 (long interspersed nucleotide element-1) elements. Most of the L1 elements are defective and only a small number are very active in vivo, but they are responsible for nearby all of the retrotransposition in the human population. The cloning of active human L1 elements has allowed the development of tissue culture-based assays for measuring their retrotransposition potential. We used such an assay to demonstrate that APOBEC3G, which impairs the replication of exogenous retroelements, does not affect the replication of endogenous L1 retrotransposons. Human APOBEC3G1 (apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G), also known as CEM15, is a cytidine deaminase that can block the replication of a wide array of retroelements (1-3). Packaged in retroviral particles, APOBEC3G (APO3G) associates with the reverse transcription complex where it deaminates cytosine residues to uracil in the growing minus-strand viral DNA. These dU-rich transcripts are either degraded or yield G-to-A hypermutated hence largely non-functional proviruses (1, 2, 4). APOBEC3G is countered by the Vif (virion infectivity factor) protein of lentiviruses, which associates with the cellular enzyme to prevent its virion incorporation and trigger its proteasomal degradation (1, 2, 5-8). In the absence of Vif, the innate antiviral protein can inhibit human and simian immunodeficiency viruses (HIV and SIV, respectively), equine infectious anemia virus, and the gammaretrovirus murine leukemia virus (MLV). In addition, APOBEC3G can block the replication of hepatitis B virus, a hepadnavirus whose life cycle also includes reverse transcription (3). In this case, however, one observes an inhibition of viral pregenomic RNA packaging, and thus of viral DNA synthesis, rather than the lethal editing of viral reverse transcripts.Retrotransposons are commonly classified as long terminal repeat (LTR) and non-LTR retrotransposons (9). The Ty1/3 elements and copia elements are LTR retrotransposons of yeast and Drosophila melanogaster, respectively, and actively participate in the genome remodeling of these organisms. In higher species, LTR retrotransposons, also known as endogenous retroviruses, are most commonly defective and usually cannot spread from cell to cell. Evidence exists for ongoing LTR retrotransposition in the mouse, but no active LTR retrotransposon has so far been isolated in humans, even though human endogenous retroviruses (HERVs) make up roughly 7% of the genome. Yet t...

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“…The presence of dispersed repeated DNA sequences is a genetic liability because interrepeat recombination can cause deletions, duplications, inversions or translocations, depending on the configuration and orientation of the repeat units. In humans, recombination between repeats is at the origin of disease-causing deletions, such as ␣-thalassemias, Duchenne muscular dystrophy, and familial hypercholesterolemia (4)(5)(6)(7).…”

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confidence: 99%

The frequency and structure of recombinant products is determined by the cellular level of MutL

Elez

Radman

Matić

2007

Proc. Natl. Acad. Sci. U.S.A.

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The presence of repeated DNA sequences is a genomic liability, because interrepeat recombination can result in chromosomal rearrangements. The mismatch repair system prevents recombination between nonidentical repeats, but the mechanism of antirecombination has not been established. Although the MutS protein binds to base pair mismatches in heteroduplex DNA, the role of the MutL protein in preventing recombination is unknown. In a screen designed to identify new cellular functions that suppress deletion formation involving nonidentical DNA repeats, we isolated a mutL mutant having a separation-of-function phenotype. The mutant showed an increased frequency of deletions but not of mutations. The split phenotype is due to a decreased MutL level, indicating that recombination, but not replication editing, is highly sensitive to MutL level. By altering the MutL level, we found that the frequency of deletion-generating recombination is inversely related to the amount of cellular MutL. DNA sequence analysis of the recombined repeats shows that the tolerance of base pair mismatches in heteroduplex DNA is also inversely correlated with MutL level. Unlike recombination, correction of misincorporation errors by mismatch repair is insensitive to fluctuations in MutL level. Overproduction of MutS does not affect either of these phenotypes, suggesting that, unlike MutL, MutS is not limiting for mismatch repair activities. These results indicate that MutL (i) determines effective DNA homology in recombination processes and (ii) fine tunes the process of deletion formation involving repeated, diverged DNA sequences.deletions ͉ DNA repeats ͉ mismatch repair ͉ recombination ͉ replication P rokaryotic genomes are riddled with DNA sequence repeats, which are found in intergenic regions, genes, and transposable elements (1). Repeats are even more abundant in eukaryotic genomes (2), and at least 34% of the human genome consists of such sequences (3). The presence of dispersed repeated DNA sequences is a genetic liability because interrepeat recombination can cause deletions, duplications, inversions or translocations, depending on the configuration and orientation of the repeat units. In humans, recombination between repeats is at the origin of disease-causing deletions, such as ␣-thalassemias, Duchenne muscular dystrophy, and familial hypercholesterolemia (4-7).Recombination between repeats is constantly initiated by DNA damage and/or DNA replication blockage that results from exogenous and endogenous genomic insults. Therefore, natural selection for genome stability has resulted in the emergence of mechanisms that prevent interrepeat recombination. Newly arising repeats are identical at the DNA sequence level, but established repeats have usually diverged (8). The degree and distribution of sequence divergence are structural parameters that influence recombination between repeats because they affect the activity of recombination enzymes and determine whether the antirecombinogenic activity of mismatch repair (MMR) proteins is trig...

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A novel cryptic exon in intron 3 of the dystrophin gene was incorporated into dystrophin mRNA with a single nucleotide deletion in exon 5

Cited by 14 publications

References 26 publications

Identification of seven novel cryptic exons embedded in the dystrophin gene and characterization of 14 cryptic dystrophin exons

Identification of seven novel cryptic exons embedded in the dystrophin gene and characterization of 14 cryptic dystrophin exons

The Innate Antiretroviral Factor APOBEC3G Does Not Affect Human LINE-1 Retrotransposition in a Cell Culture Assay

The frequency and structure of recombinant products is determined by the cellular level of MutL

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