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PubMed1999

Neurofibromatosis type 1 peripheral nerve tumors: aberrant activation of the Ras pathway.

BACKGROUND: Neurofibromatosis Type 1 (NF1) is an autosomal dominant transmitted cancer predisposing syndrome, with peripheral nerve tumors being a prominent feature. The NF1 gene encodes a large cytoplasmic protein called neurofibromin, which is a major negative regulator of Ras, a key protein in a major signal transduction pathway. It is hypothesized, based on data from neurogenic sarcoma cell lines, that loss of neurofibromin leads to increased levels of activated Ras-GTP, and subsequent uncontrolled mitogenic signals to the nucleus. However, it is not known whether aberrant activity of the Ras pathway is also a prevalent molecular pathogenetic mechanism in actual peripheral nerve tumors. METHODS: To investigate whether aberrant Ras activity was present, and varied with increased tumorigenic potential in peripheral nerve tumors, we have recently developed and published an enzymatic luciferase-based assay that allows measurement of Ras activity in tissues for the first time. RESULTS AND CONCLUSIONS: Neurofibromin, the gene product of the NF1 gene, was not expressed in the NF1 tumors. Levels of activated Ras-GTP in NF1 neurogenic sarcomas and NF1 plexiform neurofibromas were approximately 15 and 5 times higher, respectively, compared with non-NF1 schwannomas, supporting the hypothesis that aberrant activity of this key signaling pathway is important in the pathogenesis of these tumors. In this article we review this data, the molecular genetics of NF1, and the current knowledge of the role of neurofibromin in cellular control. Our understanding of the molecular pathogenic mechanisms of NF1 tumors should be transferable to sporadic peripheral nerve tumors, and allow development of biological therapies directed against relevant targets such as Ras.

Chromosomes, Human, Pair 17↗
PubMed2000

Neurofibromatosis 2 phenotypes and germ-line NF2 mutations determined by an RNA mismatch method and loss of heterozygosity analysis in NF2 schwannomas.

We used a novel RNase cleavage assay (NIRCA) to screen for neurofibromatosis 2 (NF2) mutations in NF2 schwannomas. Mutations were found in tumors in 16 of 20 patients. Eleven patients (55%) had loss of heterozygosity or loss of one allele, indicating that the mutation was a germ-line mutation. The phenotypes of these patients were consistent with previous NF2 genotype-phenotype correlation studies: patients with nonsense mutations had severe phenotypes, whereas those with splice-site or missense mutations had milder and variable phenotypes. These results confirm the utility of NIRCA as a rapid and convenient method for screening for germ-line NF2 mutations.

Adolescent↗
PubMed1996

Neurofibromatosis type 2: a new mechanism of tumor suppression.

Neurofibromatosis type 2 (NF2) is an autosomal dominant disease which predisposes primarily to CNS tumors such as schwannomas (vestibular and spinal), meningiomas, ependymomas and juvenile posterior lenticular opacities. Allelic losses on chromosome 22q first suggested the existence of a tumor suppressor on this autosome in accordance with Knudson's 'two hit' model. The gene was identified by positional cloning and found to encode a novel protein schwannomin (also known as merlin), with high sequence similarity to the band 4.1 family of proteins. This similarity suggested a new mechanism of tumor suppression since it was the first time a structural protein had been associated with a human tumor. Mutation analysis confirmed that inactivation of the NF2 gene occurred in NF2 tumors and a majority of sporadic schwannomas and meningiomas. Expression and functional studies have provided additional information on the possible involvement of this novel tumor suppressor in cell differentiation, embryogenesis and growth suppression.

Genes, Neurofibromatosis 2↗
PubMed1996

Neurofibromatosis and associated tumour suppressor genes.

Neurofibromatosis 1 and 2 (NF1 and NF2) are autosomal dominantly inherited disorders with close to 100% penetrance. NF1 is one of the most frequent human genetic diseases with an incidence of 1:3000. The incidence of NF2 is about 10 fold lower. NF1 is caused by mutations which inactivate the NF1 gene on chromosome 17q, while the NF2 gene is on chromsome 22. Both genes are tumour suppressor genes. The product of the NF1 gene, called neurofibromin, is a large protein of 2818 amino acids. The protein acts as a negative regulator in the ras signal transduction pathway and may also act downstream of ras. In the cell types that are affected in NF1 patients, the absence of neurofibromin leads to increased proliferation resulting in benign, and in some cases malignant tumours. The product of the NF2 gene is a protein of 595 amino acids. The protein displays in its N-terminal half considerable homology with proteins that are involved in contacts between the cytoskeleton and the cell membrane, and a similar function has been proposed for the NF2 protein. How the absence of the NF2 protein may lead to the development of Schwannomas and meningiomas, which are the major manifestations of NF2 in patients, is not clear at present.

Animals↗
PubMed1997

Neurofibromatosis type 1 and type 2: review of the central nervous system and related structures.

Although computed tomography (CT) provides a major imaging advance over conventional radiography and tomography in examining the whole body, the development of magnetic resonance (MR) imaging has proven to be an even greater breakthrough in diagnostic medical imaging. The anatomic detail demonstrated in a MR image is a representation of at least three physical properties of static-tissue: proton density, and T1 and T2 relaxation times. Intrinsic differences in proton density and, in particular, in proton relaxation times of tissues allow excellent image contrast between various normal structures and high sensitivity in detecting pathological states. This article discusses imaging features of neurofibromatosis, with particular emphasis on the potential of MR imaging.

Adolescent↗
PubMed1996

Neurofibromatosis 2: loss of merlin's protective spell.

Schwannomas and meningiomas occur as multiple tumors in sufferers of neurofibromatosis 2 (NF2) and as solitary tumors in the general population due to the inactivation of a gene at chromosome 22q12. In 1993, a location cloning approach revealed this tumor suppressor, dubbed merlin, as a novel member of a family of proteins that link elements of the cytoskeleton and the cell membrane. Subsequent investigations have confirmed merlin's role in tumor formation, but have yet to reveal its mechanism of action.

Animals↗
PubMed2003

Mouse models of neurofibromatosis type I: bridging the GAP.

Neurofibromatosis type I (NF1) is an autosomal dominant disorder caused by mutations in the NF1 gene, leading to a variety of abnormalities in cell growth and differentiation, and to learning disabilities. The protein encoded by NF1, neurofibromin, has several biochemical functions and is expressed in a variety of different cell populations. Hence, determination of the molecular and cellular mechanisms that underlie the different NF1 symptoms is difficult. However, studies using mouse models of NF1 are beginning to unravel the mechanisms that underlie the various symptoms associated with the disease. This knowledge will aid the development of treatments for the different pathological processes associated with NF1.

Animals↗
PubMed2005

Sensitive detection of deletions of one or more exons in the neurofibromatosis type 2 (NF2) gene by multiplexed gene dosage polymerase chain reaction.

Mutation detection in the neurofibromatosis type 2 (NF2) gene is challenging because when combining mutation detection methods such as single-strand conformational polymorphism and heteroduplex analysis, denaturing gradient gel electrophoresis, and direct sequencing of aberrant polymerase chain reaction (PCR) fragments only 30 to 60% of the constitutional mutations are detected. Because large deletions and complete chromosome rearrangements are also described methods such as microarray-comparative genomic hybridization and fluorescence in situ hybridization are also used. The one type of mutation often missed corresponds to deletions encompassing one or few exons. To detect this type we have developed a swift and reliable method. We perform a gene dosage analysis with two fluorescent multiplex PCR assays that amplify 15 of the 17 NF2 exons. The labeled PCR products are quantified and gene dose is calculated with respect to controls. We tested the reliability of this method with DNA from eight NF2 patients with known heterozygous NF2 deletions, eight controls and four unknown NF2 patients. In all of the patients with known heterozygous deletions we found in several exons a reduction of gene dosage to 50 to 69%. In one NF2 patient with previously unknown mutation and a severe phenotype we found the gene dosage of two exons reduced by 50% indicating a deletion of these two exons on one allele. This finding was validated by reverse transcriptase-PCR on fibroblast and schwannoma cell cultures of this patient and cDNA sequencing. Our gene dosage assay will detect deletions of one or more exons as well as gross deletions of the whole coding region of the gene. It can complement the existing screening methods because it is faster and easier.

DNA Mutational Analysis↗
PubMed1998

Neurofibromatosis type 1: piecing the puzzle together.

Neurofibromatosis type 1 (NF1) was first described in 1882 and is characterized by a diverse spectrum of clinical manifestations, including neurofibromas, café au lait spots, and Lisch nodules. NF1 is also noted for the higher risk of associated malignancies, making it the most common tumour-predisposing disease in humans. Transmitted in an autosomal dominant manner, the NF1 gene was cloned in 1990, and belongs to the family of tumour suppressor genes. Since then, there has been an explosion in our understanding of how the gene product, neurofibromin, functions in normal cellular physiology, and how its loss in NF1 relates to the wide spectrum of clinical findings, including NF1-associated tumours. Neurofibromin is a major negative regulator of a key signal transduction pathway in cells, the Ras pathway, which transmits mitogenic signals to the nucleus. Loss of neurofibromin leads to increased levels of activated Ras (bound to GTP), and thus increased downstream mitogenic signaling. Our understanding of neurofibromin's role within cells has allowed for the development of pharmacological therapies which target the specific molecular abnormalities in NF1 tumours. These include the farnesyl transferase inhibitors, which inhibit the post-translational modification of Ras, and other agents which modulate Ras-mediated signaling pathways.

Genes, Neurofibromatosis 1↗
PubMed1998

Genetic variation in the 3' untranslated region of the neurofibromatosis 1 gene: application to unequal allelic expression.

Neurofibromatosis type 1 (NF1) is a common genetic disorder caused by inactivation of neurofibromin, a protein capable of modulating signal transduction by activating Ras-GTPase activity. We have used cDNA cloning and Northern blot analysis to confirm the NF1 gene produces alternatively polyadenylated mRNAs with 3' untranslated regions (3' UTR) that show striking evolutionary conservation. Scanning of the 3'UTRs for genetic variation revealed three common sequence polymorphisms (> 30% heterozygosity), one less informative polymorphism (approximately 5% heterozygosity) and one rare variant (1/144 chromosomes). These differences were used to examine relative levels of expression of normal and mutant NF1 alleles in lymphoblast cell lines and in one case, autopsy tissue, from patients with NF1. Unequal allelic expression (up to 4-fold) was observed in a subset of both sporadic and familial NF1 cases. Where linkage phase could be determined, the allele segregating with the disorder displayed a relative reduction in expression. However, the magnitude of this effect was variable suggesting the operation of additional, non-genetic factors in determining the degree of relative expression of the mutant allele.

3' Untranslated Regions↗
PubMed2000

Molecular analysis of the 5'-flanking region of the neurofibromatosis type 1 (NF1) gene: identification of five sequence variants.

Dideoxy fingerprinting was used to analyse the 5' flanking region of the neurofibromin (NF1) gene in a panel of 380 neurofibromatosis type 1 (NF1) patients. Five polymorphisms/rare variants were identified at positions -412, - 402, + 16, + 25 and + 132, but control data indicated that these were unlikely to be of pathological significance. Promoter mutations in the NF1 gene are not, therefore, a common cause of NF1. This notwithstanding, a reporter gene assay was performed to determine if these variants could affect the expression of the NF1 gene, and all three changes in the 5'-untranslated region (UTR) (+ 16, + 25, + 132) were found to be associated with a 60-70% increase in reporter gene expression.

DNA Fingerprinting↗
PubMed1991

A de novo Alu insertion results in neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder with a high mutation rate and variable expression, characterized by neurofibromas, café-au-lait spots, Lisch nodules of the iris, and less frequent features including bone deformities and learning disabilities. The recently cloned NF1 gene encodes a transcript of 13 kilobases from a ubiquitously expressed locus on chromosome 17. Most NF1 patients are expected to have unique mutations, but only a few have so far been characterized, restricting genetic and functional information and the design of DNA diagnostics. We report an unusual NF1 mutation, that of a de novo Alu repetitive element insertion into an intron, which results in deletion of the downstream exon during splicing and consequently shifts the reading frame. This previously undescribed mechanism of mutation indicates that Alu retrotransposition is an ongoing process in the human germ line.

Adult↗
PubMed1993

Somatic deletion of the neurofibromatosis type 1 gene in a neurofibrosarcoma supports a tumour suppressor gene hypothesis.

Individuals with neurofibromatosis type 1 (NF1) have an increased risk of developing benign and malignant tumours. The NF1 gene is thought to be a tumour suppressor gene, yet no direct proof at the molecular level exists to support this hypothesis. Here we describe a neurofibrosarcoma from a patient with NF1 with loss of heterozygosity for all chromosome 17 polymorphisms tested. On the remaining chromosome 17 homologue, a 200 kilobase (kb) tumour specific deletion of NF1 was demonstrated. This is the first example of a homozygous inactivation of NF1 at the molecular level in a malignant tumour from an NF1 patient and the results strongly support the tumour suppressor gene hypothesis for this disease.

Adult↗
PubMed1995

Benign neurofibromas in type 1 neurofibromatosis (NF1) show somatic deletions of the NF1 gene.

Neurofibromatosis type 1 (NF1) is one of the most common human autosomal dominant diseases. NF1 is characterized by café-au-lait spots (CLS), axillary freckles and Lisch nodules of the iris. Another hallmark of NF1 is the development of neurofibromas, benign tumours that arise from peripheral nerve sheaths. NF1 patients also have an increased incidence of certain malignant tumours. Malignancies in NF1 are believed to follow the 'two-hit' hypothesis, in which one allele is constitutionally inactivated while the other allele is subsequently inactivated ('second hit') at the somatic level. This hypothesis has not, however, been fully tested in the aetiology of benign neurofibromas. This is a crucial issue since it addresses not only the basic mechanism behind the genesis of neurofibromas, but may also indicate a mechanism common to many or all NF1 features. Using both NF1 intragenic polymorphisms as well as markers from flanking and more distal regions of chromosome 17, we have investigated loss of heterozygosity (LOH) in 22 neurofibromas from five unrelated NF1 patients. Eight of these tumours revealed somatic deletions involving NF1, indicating that inactivation of NF1 is associated with at least some neurofibromas.

Adult↗
PubMed2005

Neurofibromatosis type 1 - a model for nervous system tumour formation?

Neurofibromatosis type 1 (NF1) is a common genetic condition in which affected individuals develop benign and malignant nervous system tumours. Genetically engineered mouse (GEM) models of these NF1-associated nervous system tumours recapitulate several of the unique clinical aspects of the disease. Moreover, these Nf1 GEM models allow for a direct examination of the earliest stages of tumour evolution, including the contributions that Nf1(+/-) cellular elements and cooperating genetic changes make to facilitate the transition from the pre-neoplastic to the neoplastic state and, in some cases, to promote malignant progression.

Animals↗
PubMed2006

Neurofibromatosis 1.

Neurofibromatosis 1 predisposes affected individuals to the development of benign and malignant tumours that are frequently disfiguring and difficult to manage. However, advances in molecular biology and the development of mouse models have facilitated our understanding of disease pathogenesis. Positron emission tomography has demonstrated that sophisticated imaging techniques have a role in diagnosing complex problems like malignant peripheral nerve sheath tumours, while the prospect of targeted therapies for Nf1 complications is tantalisingly close.

Genes, Neurofibromatosis 1↗
PubMed1998

Impairment of cell adhesion by expression of the mutant neurofibromatosis type 2 (NF2) genes which lack exons in the ERM-homology domain.

Neurofibromatosis 2 (NF2) is an inherited disorder characterized by a predisposition to multiple intracranial tumors. The protein encoded by the NF2 gene has striking similarities to ezrin, radixin and moesin (ERM) proteins which link membrane proteins to the cytoskeleton. Therefore, it can be speculated that the disruption of cytoskeletal organization by alterations in the NF2 gene is involved in the development of tumors. It has been reported that the majority of NF2 mutations were nonsense or frameshift mutations that result in premature termination of translation. To facilitate the detection of these mutations, we performed protein truncation test and found that 11 of 14 NF2 patients had truncational mutations (79%). Seven of the 11 patients (64%) had a splicing abnormality which lead to absence of exons in the ERM homology domain. To examine the biological significance of the exon-missing mutations in the ERM homology domain, we expressed the wild-type (wt-NF2) and the various mutant NF2s (mu-NF2s) in a fibroblast cell line by using both liposome-mediated transfection and nuclear microinjection of the expression plasmids. The wt-NF2 showed intense punctate staining in the perinuclear cytoplasm in addition to overall staining of the submembranous area, whereas the mu-NF2s lacking exons in the ERM homology domain showed granular staining at the perinuclear region without any accumulation at the submembrane region. Microinjection of wt-NF2 cDNA into the nucleus of VA13 cells revealed that wt-NF2 protein induced a progressive elongation of cell processes. Furthermore, cells that expressed mu-NF2 had decreased adhesion, which resulted in detachment from the substratum. These findings suggested that the exon-missing mutations in the ERM-homology domain may affect cell membrane-cytoskeleton signaling and consequently disrupt cell-to-cell or cell-to-matrix interaction.

Adolescent↗
PubMed1999

Haploinsufficiency for the neurofibromatosis 1 (NF1) tumor suppressor results in increased astrocyte proliferation.

Individuals affected with neurofibromatosis 1 (NF1) harbor increased numbers of GFAP-immunoreactive cerebral astrocytes and develop astrocytomas that can lead to blindness and death. Mice heterozygous for a targeted Nf1 mutation (Nf1+/-) were employed as a model for the human disease to evaluate the hypothesis that reduced NF1 protein (neurofibromin) expression may confer a growth advantage for astrocytes, such that inactivation of only one NF1 allele is sufficient for abnormal astrocyte proliferation. Here, we report that Nf17+/- mice have increased numbers of cerebral astrocytes and increased astrocyte proliferation compared to wild-type littermates. Intriguingly, primary Nf1+/- astrocyte cultures failed to demonstrate a cell-autonomous growth advantage unless they were cocultured with C17 neuronal cells. This C17 neuronal cell-induced Nf1+/- increase in proliferation was blocked by MEK inhibition (PD98059), suggesting a p21-ras-dependent effect. Furthermore, mice heterozygous for a targeted mutation in another GAP molecule, p120-GAP, demonstrated no increases in cerebral astrocyte number. These findings suggest that reduced NF1 expression results in a cell context-dependent increase in astrocyte proliferation that may be sufficient for the development of astrocytic growth abnormalities in patients with NF1.

Animals↗