A new type of mutation causes a splicing defect in ATM

Pagani, Franco; Buratti, Emanuele; Stuani, Cristiana; Bendix, Regina; Dörk, Thilo; Baralle, Francisco E.

doi:10.1038/ng858

Cited by 204 publications

(207 citation statements)

References 24 publications

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“…Genomic efforts provide larger sets of markers, most of them single-nucleotide polymorphisms (SNPs). Besides, different results in human and other species show that not only nonsynonymous SNPs (giving an amino-acid change) in coding region can be etiological [Di Paola et al, 2002;Pagani et al, 2002], which impacts the number of markers to consider when planing a candidate gene study. The challenge is now to find strategies to optimally use this information in order to detect the role of a candidate gene.…”

Section: Introductionmentioning

confidence: 99%

Improved use of SNP information to detect the role of genes

Jannot

Essioux

Reese

et al. 2003

Genetic Epidemiology

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A topical question in genetic association studies is the optimal use of the information provided by genotyped singlenucleotide polymorphisms (SNPs) in order to detect the role of a candidate gene in a multifactorial disease. We propose a strategy called ''combination test'' that tests the association between a quantitative trait and all possible phased combinations of various numbers of SNPs. We compare this strategy to two alternative strategies: the association test that considers each SNP separately, and a multilocus genotype-based test that considers the phased combination of all SNPs together. To compare these three tests, a quantitative trait was simulated under different models of correspondence between phenotype and genotype, including the extreme case when two SNPs interact with no marginal effects of each SNP. The genotypes were taken from a sample of 290 independent individuals genotyped for three genes with various number of SNPs (from 5-8 SNPs). The results show that the ''combination test'' is the only one able to detect the association when the two SNPs involved in disease susceptibility interact with no marginal effects. Interestingly, even in the case of a single etiological SNP, the ''combination test'' performed well. We apply the three tests to Genetic Analysis Workshop 12 (Almasy et al. [2001] Genet. Edpidemiol. 21:332-338) simulated data, and show that although there was no interactions between the etiological SNPs, the ''combination test'' was preferable to the two other compared methods to detect the role of the candidate gene.

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Section: Introductionmentioning

confidence: 99%

Improved use of SNP information to detect the role of genes

Jannot

Essioux

Reese

et al. 2003

Genetic Epidemiology

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“…The frequency of pseudoexon mutations may be underestimated because it is difficult to identify by direct DNA sequencing of exons and their flanking sequences of a gene. The mutations that cause pseudoexons can be located at intron-pseudoexon boundaries, within pseudoexon sequences that create a new cis element for RNA splicing, or in the pseudoexons through the deletion of intron-splicing processing element (Pagani et al 2002). We analyzed the pseudoexon mutation and wild-type FBN1 sequences using an ESE finder (http://rulai.cshl.edu/tools/ESE/) to investigate the potential mechanism of generating pseudoexon by the IVS63?373 alteration.…”

Section: Discussionmentioning

confidence: 99%

An FBN1 pseudoexon mutation in a patient with Marfan syndrome: confirmation of cryptic mutations leading to disease

Guo¹,

Gupta²,

Tran-Fadulu³

et al. 2008

J Hum Genet

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Marfan syndrome (MFS) results from heterozygous mutations in FBN1. However, genetic analyses of deoxyribonucleic acid (DNA) from approximately 10-30% of MFS patients who meet diagnostic criteria do not reveal an identifiable FBN1 mutation. In a patient who met the diagnostic criteria for MFS, bidirectional DNA sequencing of exons and intron-exon boundaries of FBN1 failed to reveal a mutation. Assessment of the FBN1 message in dermal fibroblasts from the patient revealed insertion of a pseudoexon between exons 63 and 64. Sequencing of intron 63 identified a point mutation, IVS63?373, located near the middle of intron 63 of FBN1 that created a donor splice site in intron 63, leading to inclusion of a 93-bp fragment of intronic sequence in the FBN1 message. Identification of a novel pseudoexon mutation in FBN1, in association with a clinical diagnosis of MFS, confirms that cryptic mutations that are missed by the current DNAbased diagnostic methods have a causative role.

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“…In addition, an intracryptic exon deletion has been shown to cause erroneous splicing (Pagani et al 2002;Eng et al 2004). These observations suggest that cryptic exons are targets for human genetic diseases.…”

Section: Discussionmentioning

confidence: 99%

A novel cryptic exon identified in the 3′ region of intron 2 of the human dystrophin gene

et al. 2005

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The dystrophin gene, which is mutated in Duchenne muscular dystrophy (DMD), is the largest known human gene and is characterized by the huge size of its introns. Intron 2, the second largest intron, is 170-kb long and has been shown to include a 140-bp cryptic exon (exon 2a) in its 5¢ region. The rest of this intron has no known function. In this study, we find that another cryptic exon, located in the 3¢ region of intron 2, is activated in a promoter-or tissue-specific manner. An unknown 98-bp insertion precisely between exons 2 and 3 was identified in one of the dystrophin mRNAs from lymphocytes of a DMD patient with a duplication of exon 2. This 98-bp sequence, located in the 3¢ region of intron 2, was found to possess a branch point, acceptor and donor splice-site consensus sequences, and an exonic splicing enhancer sequence, and thus is a novel exon, which we named ''exon 2b.'' In lymphocytes, exon 2b incorporation was detected in the muscle-specific, promoter-driven transcript. Five of 20 normal human tissue mRNAs, including cardiac and skeletal muscle mRNAs, were confirmed to contain a fragment extending from exon 1 to exon 2b by reverse transcription PCR amplification, indicating that exon 2b is activated in a tissue-specific manner. This provides a clue to a novel cause of dystrophinopathy.

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A new type of mutation causes a splicing defect in ATM

Cited by 204 publications

References 24 publications

Improved use of SNP information to detect the role of genes

Improved use of SNP information to detect the role of genes

An FBN1 pseudoexon mutation in a patient with Marfan syndrome: confirmation of cryptic mutations leading to disease

A novel cryptic exon identified in the 3′ region of intron 2 of the human dystrophin gene

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