Analysis of theNF1 gene by temperature gradient gel electrophoresis reveals a high incidence of mutations in exon 4b

Toliat, Mohammed R.; Erdogan, Fikret; Gewies, Andreas; Fahsold, Raimund; Buske, Annegret; Tinschert, Sigrid; Nürnberg, Peter

doi:10.1002/(sici)1522-2683(20000201)21:3<541::aid-elps541>3.0.co;2-l

Cited by 30 publications

(16 citation statements)

References 24 publications

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“…Twenty-two of these changes were novel. The recurrent mutations identified were 495delTGTT in exon 4b (three patients) and 2339C→A in exon 15 (three patients); both alterations have been previously reported Toliat et al 1999;Fahsold et al 2000). Of the 11 missense mutations identified, two were located in the GAP-related domain (GRD, exons 21-27a).…”

Section: Dhplc Analysis Of Known Nf1 Gene Lesionssupporting

confidence: 75%

Evaluation of denaturing high performance liquid chromatography (DHPLC) for the mutational analysis of the neurofibromatosis type 1 ( NF1 ) gene

2001

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The identification of mutations in the NF1 gene causing type 1 neurofibromatosis (NF1) has presented a considerable challenge because of the large size of the gene, the lack of significant mutational clustering, the diversity of the underlying pathological lesions and the presence of NF1 pseudogenes. Denaturing high performance liquid chromatography (DHPLC), a high throughput, non-hazardous and largely automated heteroduplex-based technique, is in many ways ideally suited to mutation detection in this condition. DHPLC was therefore optimised for the rapid screening of the 60 exons and splice junctions of the NF1 gene in patients with NF1. The sensitivity of DHPLC was evaluated in a retrospective study of a cohort of 111 unrelated NF1 patients with known germline mutations; 97% of mutations were detected. In a subsequent prospective analysis of 50 unrelated NF1 patients, germline mutations were identified in 34 individuals (68%), 22 of these alterations being novel. This represents the highest rate of mutation detection so far reported for the NF1 gene with a single screening technique and genomic DNA as a target.

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Section: Dhplc Analysis Of Known Nf1 Gene Lesionssupporting

confidence: 75%

Evaluation of denaturing high performance liquid chromatography (DHPLC) for the mutational analysis of the neurofibromatosis type 1 ( NF1 ) gene

2001

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“…The most frequently deleted NF1 region was defined by intron 1 and exon 5 markers. This region includes exon 4b, which has been considered to be one of the NF1 mutational "hot spots" in NF1 patients (Toliat et al, 2000). In one case, a unique loss of the region flanked by intron 27 and intron 38 markers was identified.…”

Section: Nf2 and Nf1 Status In Conventional Schwannomasmentioning

confidence: 59%

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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“…13 OTX2 and NF1 were screened by direct sequencing. 11,14 Sequences were bidirectional and generated from duplicate PCRs. Mutation numbering is in accordance with The Human PAX6 Allelic Variant Database reference sequence (http:// pax6.hgu.mrc.ac.uk/) (PAX6), GenBank AY796305 (NF1) and GenBank NM_172337 (OTX2).…”

Section: Molecular Analysismentioning

confidence: 99%

Inherited PAX6, NF1 and OTX2 mutations in a child with microphthalmia and aniridia

et al. 2007

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A girl with aniridia, microphthalmia, microcephaly and café au lait macules was found to have mutations in PAX6, NF1 and OTX2. A novel PAX6 missense mutation (p.R38W) was inherited from her mother whose iris phenotype had not been evident because of ocular neurofibromatosis. Analysis of the NF1 gene in the proband, prompted by the mother's diagnosis and the presence of café au lait spots, revealed a nonsense mutation (p.R192X). Subsequently an OTX2 nonsense mutation (p.Y179X) was identified and shown to be inherited from her father who was initially diagnosed with Leber's congenital amaurosis. Since individual mutations in PAX6, OTX2 or NF1 can cause a variety of severe developmental defects, the proband's phenotype is surprisingly mild. This case shows that patients with complex phenotypes should not be eliminated from subsequent mutation analysis after one or even two mutations are found.

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Analysis of theNF1 gene by temperature gradient gel electrophoresis reveals a high incidence of mutations in exon 4b

Cited by 30 publications

References 24 publications

Evaluation of denaturing high performance liquid chromatography (DHPLC) for the mutational analysis of the neurofibromatosis type 1 ( NF1 ) gene

Evaluation of denaturing high performance liquid chromatography (DHPLC) for the mutational analysis of the neurofibromatosis type 1 ( NF1 ) gene

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

Inherited PAX6, NF1 and OTX2 mutations in a child with microphthalmia and aniridia

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