Nearby Stop Codons in Exons of the Neurofibromatosis Type 1 Gene Are Disparate Splice Effectors

Hoffmeyer, Sven; Nürnberg, Peter; Ritter, Heide; Fahsold, Raimund; Leistner, Werner; Kaufmann, Dieter; Krone, W.

doi:10.1086/301715

Cited by 50 publications

(64 citation statements)

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“…It appears that an alternative mechanism may alter the interaction between an exonic splice enhancer and mRNA splicing factors of the CALD1 via a signaling pathway modifying the splicing apparatus. 2,47,48 The regulation of the transcriptional activation of CALD1 splicing variants could have far-reaching epigenetic effects on the development of molecular targeted anti-angiogenic therapies.…”

Section: Discussionmentioning

confidence: 99%

Differential Expression of Splicing Variants of the Human Caldesmon Gene (CALD1) in Glioma Neovascularization versus Normal Brain Microvasculature

Zheng

Sieuwerts

Luider

et al. 2004

The American Journal of Pathology

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Caldesmon is a cytoskeleton-associated protein whichhas not yet been related to neoplastic angiogenesis. In this study we investigated the expression of the caldesmon gene (CALD1) splicing variants and the protein expression level in glioma microvessels versus normal brain microvasculature. To exclude sources of splice variant expression from non-vascular components all possible cellular components present in control and glioma samples were prescreened by laser-capture microdissection followed by RT-PCR before the cohort study. We discovered differential expression of the splicing variants of CALD1 in the tumor microvessels in contrast to normal brain microvasculature. Missplicing of exons 1, 1 ؉ 4, and 1 ؉ 4 of the gene is exclusively found in glioma microvessels. To exclude the possibility that this missplicing results from splice-site mutations, Genome-wide analyses have revealed that 40 to 60% of human genes undergo alternative splicing. 1 Alternative splicing, therefore, seems to contribute considerably to enable the highly complex and diverse functions encoded by the human genome. Alternative splicing permits vertebrate pre-mRNA to be processed into multiple mRNAs differing in their precise combination of exon sequences, resulting in the encoding of different protein isoforms. 2 Multiple modes of alternative splicing exist, such as alternative 5Ј or 3Јsplice-site usage, differential inclusion or skipping of particular exons, mutually exclusion of exons, and more. 3 Importantly, alternative splicing is often tightly regulated in a cell type-or developmental stage-specific mode. 3 The essential nature of this process is underscored by the fact that misregulation (missplicing events) is often related to human disease. 4 -6

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Section: Discussionmentioning

confidence: 99%

Differential Expression of Splicing Variants of the Human Caldesmon Gene (CALD1) in Glioma Neovascularization versus Normal Brain Microvasculature

Zheng

Sieuwerts

Luider

et al. 2004

The American Journal of Pathology

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“…Among the mutations characterized, three were located in exon 7. One of the three stop mutations has previously been described (Hoffmeyer et al, 1998) and shown to be associated with exon skipping. The remaining two mutations in exon 7 were novel.…”

Section: Introductionmentioning

confidence: 99%

“…The protein truncation test (PTT) provides the advantage over other methods to screen the entire coding region of the NF1 gene for nonsense or frameshift mutations which represent about 80% of the characterised mutations in the NF1 gene so far (Shen et al, 1996). This technique also allows the detection of aberrantly spliced transcripts (Heim et al, 1995;Messiaen et al, 1997;Hoffmeyer et al, 1998;Park and Pivnick, 1998). Usually, aberrant transcripts are indicative for mutations in splice or branching sites of exons.…”

Section: Introductionmentioning

confidence: 99%

“…Usually, aberrant transcripts are indicative for mutations in splice or branching sites of exons. Recently, another mechanism, referred to as exon skipping, which associates premature termination codons (PTC) in DNA with mRNA that lacks the exon containing the PTC, has been shown to cause skipping of exons 37 and 7 of the NF1 gene ( Messiaen et al, 1997;Hoffmeyer et al, 1998). Different explanations how PTCs induce exon skipping have been described (for review see Maquat, 1995;Valentine, 1998).…”

Section: Introductionmentioning

confidence: 99%

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Three different premature stop codons lead to skipping of exon 7 in neurofibromatosis type I patients

et al. 2000

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Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder affecting one in 3,500 individuals. The mutation rate in the NF1 gene is one of the highest known for human genes. Compared to other methods, the protein truncation test (PTT) provides improved efficiency in detecting NF1 mutations which are dispersed throughout the gene which spans 350 kilobases of genomic DNA. We have applied the PTT and subsequent sequence analysis of cloned cDNA to identify mutations in NF1 patients. We report here the identification of two novel (W336X and Q315X), and one recurrent (R304X) mutation located in exon 7 and show that all three premature termination codons lead to skipping of exon 7 in a proportion of the transcripts derived from the mutated allele. Possible mutation-induced alterations of the RNA secondary structure and their impact on skipping of exon 7 of the NF1 gene are explored and discussed.

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“…exon or multiexon deletions/duplications) (Wimmer et al, 2006), and the remaining patients present intragenic minor lesions including single nucleotide changes and small deletions and insertions. Although the existence of several recurrent NF1 mutations has been reported (Hoffmeyer et al, 1998;Ars et al, 2000Ars et al, , 2003Fahsold et al, 2000;Messiaen et al, 2000), each one accounts for only a small proportion of patients, which suggests that complete analysis of the entire coding region should be a mandatory procedure in any screening strategy. Exhaustive double DNA/RNA studies in early 2000 revealed that a significant proportion of mutations affected the correct splicing of the gene, even in cases where canonical splicing sequences were not affected (Ars et al, 2000(Ars et al, , 2003Fahsold et al, 2000;Messiaen, et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Nature and mRNA effect of 282 differentNF1point mutations: focus on splicing alterations

et al. 2008

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Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder caused by mutations in the NF1 gene. In this paper we report our experience using the cDNA-SSCP/HD analysis as a mutational screening approach and the double characterization of all mutations at the DNA and RNA levels. Two hundred and eighty-two different mutations (in 374 independent patients) were identified, 140 of which were novel in our population. Most of these mutations are unique and distributed along the gene. However, we also detected 37 recurrent mutations. Our approach is limited with respect to the detection of single base substitutions, but it is highly effective in the detection of frameshift mutations and mutations that affect the correct splicing. Due to this bias we focus here in the characterization of these two types of mutations. Forty-seven percent of mutations found were frameshift mutations, with small deletions being 2.3 times more common than small insertions. At the mRNA level, 44% of mutations affected the correct splicing, 80% of them located in the consensus sequences, with the donor site being much more frequently involved. The remaining 20% consisted of mutations located in deep intronic sites and mutations located in the coding region. In general the latter group produces different types of mutated transcripts with specific proportions for each mutation. The double characterization of mutations at the DNA and RNA levels enables to detect a broader spectrum of mutations than any single level approach, and provides a greater understanding of their molecular pathogenesis.

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Nearby Stop Codons in Exons of the Neurofibromatosis Type 1 Gene Are Disparate Splice Effectors

Cited by 50 publications

References 46 publications

Differential Expression of Splicing Variants of the Human Caldesmon Gene (CALD1) in Glioma Neovascularization versus Normal Brain Microvasculature

Differential Expression of Splicing Variants of the Human Caldesmon Gene (CALD1) in Glioma Neovascularization versus Normal Brain Microvasculature

Three different premature stop codons lead to skipping of exon 7 in neurofibromatosis type I patients

Nature and mRNA effect of 282 differentNF1point mutations: focus on splicing alterations

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