In vitro splicing analysis showed that availability of a cryptic splice site is not a determinant for alternative splicing patterns caused by +1G-&gt;A mutations in introns of the dystrophin gene

Habara, Yasuaki; Takeshima, Yasuhiro; Awano, Hiroyuki; Okizuka, Yo; Zhang, Zhujun; Saiki, Kayoko; Yagi, Minoru; Matsuo, Masafumi

doi:10.1136/jmg.2008.061259

Cited by 35 publications

(22 citation statements)

References 34 publications

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“…Confirming a previous work [56], our data indicate that the availability of cryptic splice site does not determine the main splicing pathway, since numerous potential sites are found in most analyzed exons according to HSF and MaxEnt predictions. Habara et al proposed that in +1G>A mutations a strong exon recognition, resulting from the combination of a high 3′ ss score and a long exon length, is necessary for cryptic site activation [56]. Our data indicate that the splicing pathway in 5′ ss mutations is determined by the interplay between the relative strength of 3′ ss and the density of ESE elements (Figure 3).…”

Section: Discussionsupporting

confidence: 85%

“…The abundance of cryptic splice sites has been suggested as a main factor determining whether a mutation induces exon-skipping or cryptic splice site activation [55]. Confirming a previous work [56], our data indicate that the availability of cryptic splice site does not determine the main splicing pathway, since numerous potential sites are found in most analyzed exons according to HSF and MaxEnt predictions. Habara et al proposed that in +1G>A mutations a strong exon recognition, resulting from the combination of a high 3′ ss score and a long exon length, is necessary for cryptic site activation [56].…”

Section: Discussionsupporting

confidence: 81%

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Interplay between DMD Point Mutations and Splicing Signals in Dystrophinopathy Phenotypes

et al. 2013

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DMD nonsense and frameshift mutations lead to severe Duchenne muscular dystrophy while in-frame mutations lead to milder Becker muscular dystrophy. Exceptions are found in 10% of cases and the production of alternatively spliced transcripts is considered a key modifier of disease severity. Several exonic mutations have been shown to induce exon-skipping, while splice site mutations result in exon-skipping or activation of cryptic splice sites. However, factors determining the splicing pathway are still unclear. Point mutations provide valuable information regarding the regulation of pre-mRNA splicing and elements defining exon identity in the DMD gene. Here we provide a comprehensive analysis of 98 point mutations related to clinical phenotype and their effect on muscle mRNA and dystrophin expression. Aberrant splicing was found in 27 mutations due to alteration of splice sites or splicing regulatory elements. Bioinformatics analysis was performed to test the ability of the available algorithms to predict consequences on mRNA and to investigate the major factors that determine the splicing pathway in mutations affecting splicing signals. Our findings suggest that the splicing pathway is highly dependent on the interplay between splice site strength and density of regulatory elements.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionsupporting

confidence: 81%

Interplay between DMD Point Mutations and Splicing Signals in Dystrophinopathy Phenotypes

et al. 2013

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“…The splicing pathway affected by these mutations differed from mutation to mutation. 33 Exon skipping was occurring in 12 cases. Cryptic splice site activation occurred in 12 cases, and in 3 cases both exon skipping and cryptic splice site activation occurred.…”

Section: Splice Site Mutationsmentioning

confidence: 99%

Mutation spectrum of the dystrophin gene in 442 Duchenne/Becker muscular dystrophy cases from one Japanese referral center

et al. 2010

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Recent developments in molecular therapies for Duchenne muscular dystrophy (DMD) demand accurate genetic diagnosis, because therapies are mutation specific. The KUCG (Kobe University Clinical Genetics) database for DMD and Becker muscular dystrophy is a hospital-based database comprising 442 cases. Using a combination of complementary DNA (cDNA) and chromosome analysis in addition to conventional genomic DNA-based method, mutation detection was successfully accomplished in all cases, and the largest mutation database of Japanese dystrophinopathy was established. Among 442 cases, deletions and duplications encompassing one or more exons were identified in 270 (61%) and 38 (9%) cases, respectively. Nucleotide changes leading to nonsense mutations or disrupting a splice site were identified in 69 (16%) or 24 (5%) cases, respectively. Small deletion/insertion mutations were identified in 34 (8%) cases. Remarkably, two retrotransposon insertion events were also identified. Dystrophin cDNA analysis successfully revealed novel transcripts with a pseudoexon created by a single-nucleotide change deep within an intron in four cases. X-chromosome abnormalities were identified in two cases. The reading frame rule was upheld for 93% of deletion and 66% of duplication mutation cases. For the application of molecular therapies, induction of exon skipping was deemed the first priority for dystrophinopathy treatment. At one Japanese referral center, the hospital-based mutation database of the dystrophin gene was for the first time established with the highest levels of quality and patient's number.

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“…The splicing effect caused by theses mutations includes exon skipping and activation of a cryptic splice site [Hertel, 2008;Anna et al, 2018]. The definite splicing effects may relate to the strength of canonical and cryptic splice sites, exon and intron length, the order of intron removal, the abundance of exonic splice enhancers and silencers, or a RNA secondary structure [Takahara et al, 2002;Tazon-Vega et al, 2007;Habara et al, 2009;Anna et al, 2018]. In our study, the results of the minigene assay showed that both c.2917+1G>A and c.2917+1G>C mutations had 3 functional consequences: 2 of them caused the skipping of 1 or 2 exons, and the third transcript activated a donor cryptic splice site located at position c.2820-2821.…”

Section: Discussionmentioning

confidence: 99%

Comparative Functional Analysis in vitro of 2 <b><i>COL4A5</i></b> Splicing Mutations at the Same Site in 2 Unrelated Alport Syndrome Chinese Families

Lv¹,

Wu²,

Zhang³

et al. 2020

Cytogenet Genome Res

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Alport syndrome (AS) is a common hereditary nephropathy, characterized by hematuria, progressive renal failure, erratically associated with sensorineural hearing loss and ocular defects [Kashtan, 1998; Pirson, 1999]. AS is caused by mutations in COL4A3, COL4A4, COL4A5 genes, encoding the α3, α4, α5 chains of type IV collagen, respectively, which is a major constituent of the basement membrane in the kidney, eye, and ear [Kashtan 1999; Hertz et al., 2015; Liu et al., 2017]. X-linked Alport syndrome (XLAS), caused by mutations in the COL4A5 gene, is the most common AS and accounts for 85% [Feingold et al., 1985; Savige et al., 2013]. The genotype-phenotype correlation in XLAS is relatively well established, and splice site mutations tend to cause a moderate severe phenotype [Bekheirnia et al., 2010; Gross et al., 2012]. More than 1,168 mutations in the COL4A5 gene have hitherto been identified among which splicing mutations account for about 13-20% [Hertz et al., 2015]. However, functional analyses of most splicing mutations in AS patients have not been performed. Furthermore, comparative transcript analyses of different nucleotide substitutions at the same position have not been reported.

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In vitro splicing analysis showed that availability of a cryptic splice site is not a determinant for alternative splicing patterns caused by +1G->A mutations in introns of the dystrophin gene

Cited by 35 publications

References 34 publications

Interplay between DMD Point Mutations and Splicing Signals in Dystrophinopathy Phenotypes

Interplay between DMD Point Mutations and Splicing Signals in Dystrophinopathy Phenotypes

Mutation spectrum of the dystrophin gene in 442 Duchenne/Becker muscular dystrophy cases from one Japanese referral center

Comparative Functional Analysis in vitro of 2 <b><i>COL4A5</i></b> Splicing Mutations at the Same Site in 2 Unrelated Alport Syndrome Chinese Families

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