Characterisation of two different nonsense mutations, C6792A and C6792G, causing skipping of exon 37 in the NF1 gene

Messiaen, Ludwine; Callens, Tom; Paepe, Anne De; Craen, Margarita; Mortier, Geert

doi:10.1007/s004390050590

Cited by 49 publications

(48 citation statements)

References 32 publications

(44 reference 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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“…Recent identification of the mutational hot spot in exon 37 strongly supports the hypothesis that specific sequences, which may encode functional domain, are in this region. Therefore, its mutational inactivation may play an important role in tumorigenesis (Boddrich et al, 1997;Messiaen et al, 1997;Robinson et al, 1995;Upadhyaya et al, 1996).…”

Section: Nf2 and Nf1 Status In Conventional Schwannomasmentioning

confidence: 99%

Evaluation of NF2 and NF1 Tumor Suppressor Genes in Distinctive Gastrointestinal Nerve Sheath Tumors Traditionally Diagnosed as Benign Schwannomas: A Study of 20 Cases

Lasota

Wasąg

Dansonka-Mieszkowska

et al. 2003

Laboratory Investigation

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SUMMARY:A significant percentage of conventional schwannomas, whether sporadic or associated with neurofibromatosis 2 (NF2), show loss of heterozygosity (LOH) at NF2 and/or NF2 inactivating mutations. Similarly, a significant percentage of neurofibromas show LOH at NF1 and/or NF1 inactivating mutations. There are no molecular genetic data on gastrointestinal (GI) nerve sheath tumors traditionally diagnosed as benign schwannomas, rare neoplasms possibly derived from the schwannian elements dispersed between the smooth muscle fibers. In this study, we analyzed 1 esophageal, 16 gastric, 1 small intestinal, and 2 colonic tumors of such type. Histologically, all were spindle cell neoplasms positive for S-100 protein, vimentin, and glial fibrillary acidic protein, and negative for smooth muscle markers, KIT, CD34, neurofilament proteins, and HMB45. Focal or extensive lymphoid cuffs, often containing germinal centers, were present in most cases. None of the patients had NF2 or NF1. Chromosomes 22 and 17, particularly NF2 and NF1 loci, were analyzed for LOH in all GI tumors and for comparative purposes in 10 conventional schwannomas. LOH on 22q was seen in 40% of conventional schwannomas but in only 5% (1 of 20) of GI schwannomas. PCR amplification followed by direct sequencing of PCR products failed to identify mutations in NF2 coding sequences (exons 1-15) in 13 cases, including a case with LOH on 22q. Losses on 17q involving NF1 were seen in both GI and conventional schwannomas in 50% and 33% of analyzed tumors, respectively. LOH at NF1 might be one of the genetic features seen in peripheral nerve sheath tumors from different locations and should be interpreted with caution. However, lack of NF2 alterations strongly supports the hypothesis that GI schwannomas represent a morphologically and genetically distinct group of peripheral nerve sheath tumors that are different from conventional schwannomas. (Lab Invest 2003, 83:1361-1371. Distinctive benign nerve sheath tumors traditionally diagnosed as schwannomas have been documented in the gastrointestinal (GI) tract. Their most common location is the stomach, followed by the colon and the rectum. Occasionally, similar tumors have been reported in the small intestine and esophagus. GI schwannomas are cellular spindle cell tumors with a microtrabecular pattern and lack of nuclear palisading. Peripheral lymphoid foci, sometimes with germinal center formation, are a common histologic feature. The tumor cells are positive for S-100 protein and glial fibrillary acidic protein (GFAP) and negative for desmin and ␣-smooth muscle actin (SMA), unlike true leiomyomas, and negative for KIT (CD117) and CD34, unlike GI stromal tumors. All tumors with such phenotypic features reported thus far have followed a benign clinical course (Daimaru et al, 1988;Hirose et al, 1997;Miettinen et al, 2001;Prévot et al, 1999;Sarlomo-Rikala and Miettinen, 1995;Sasatomi et al, 2000;Skopelitou et al, 1998;Tomozawa et al, 1998;Yagihashi et al, 1997).Neurofibromatosis 2 (NF2) is an autosomal dominant diso...

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“…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%

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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Characterisation of two different nonsense mutations, C6792A and C6792G, causing skipping of exon 37 in the NF1 gene

Cited by 49 publications

References 32 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

Evaluation of NF2 and NF1 Tumor Suppressor Genes in Distinctive Gastrointestinal Nerve Sheath Tumors Traditionally Diagnosed as Benign Schwannomas: A Study of 20 Cases

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

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