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PubMed2005

Biallelic somatic inactivation of the NF1 gene through chromosomal translocations in a sporadic neurofibroma.

Neurofibroma is a benign tumor originating from Schwann cells in peripheral nerve sheaths and may occur as a sporadic tumor or as part of the dominantly inherited tumor syndrome NF1. NF1 is caused by constitutional mutations in the NF1 gene, located in chromosome band 17q11. Whereas the involvement of the NF1 gene in neurofibroma development in NF1 patients has been fairly well characterized, the significance of inactivation of this gene in sporadic neurofibromas remains less well investigated. Inactivation of both copies of NF1 has been described in a few neurofibromas from NF1 patients, and LOH at the same locus has been reported in additional cases. In the present study, we report the cytogenetic and molecular cytogenetic findings in a sporadic neurofibroma that at G-banding analysis showed a translocation between one chromosome 2 and the long arms of both copies of chromosome 17. FISH analysis using a set of 3 BAC clones covering the entire coding region of NF1 revealed the complete loss of one allele and the deletion of the 5' portion of the second allele as a result of 2 translocation events. To the best of our knowledge, this represents the first demonstration of a somatic biallelic inactivation of the NF1 gene in neurofibroma, providing further evidence for the importance of NF1 inactivation also in sporadic neurofibromas.

Adult↗
PubMed2005

Tumorigenic properties of neurofibromin-deficient Schwann cells in culture and as syngrafts in Nf1 knockout mice.

Neurofibromatosis type 1 (NF1) is one of the most common dominantly inherited genetic diseases associated with the nervous system. Functional loss of the NF1 tumor suppressor is frequently associated with the generation of benign neurofibromas that can progress to malignancy. Recent evidence in genetic mouse models indicates that the development of neurofibromas requires a loss of Nf1 in the cells destined to become neoplastic as well as heterozygosity in nonneoplastic cells. We tested this hypothesis in a newly developed syngraft mouse model in which Nf1-/- Schwann cells isolated from knockout embryos were grafted into the sciatic nerves of Nf1+/- mice, corresponding to the genetic background of NF1 patients. Furthermore, we also characterized in vitro growth of these cells. We found that embryonic mouse Nf1-/- Schwann cells exhibit increased proliferation and less growth factor-dependence in vitro compared with heterozygous and wild-type counterparts. Moreover, Nf1-/- Schwann cells showed tumorigenic growth when implanted into nerve of adult Nf1 heterozygous mice. These findings support the conclusion that loss of Nf1 in embryonic mouse Schwann cells is sufficient for tumor development in the heterozygous environment of adult mouse nerve. In addition, this syngraft model provides a practical means for the controlled induction of neurofibromas, greatly facilitating localized application of therapeutic agents and gene delivery.

Animals↗
PubMed2006

Novel NF1 gene mutation in a Japanese patient with neurofibromatosis type 1 and a gastrointestinal stromal tumor.

Many mutations of the NF1 gene have been reported in patients with neurofibromatosis type 1 (NF1); however, there have been no documented NF1 gene mutations in Japanese NF1 patients. In the present study, we used the polymerase chain reaction (PCR) and DNA sequencing analysis to characterize the NF1 gene in a 53-year-old Japanese patient with NF1 who suffered from neurofibroma, pheochromocytoma, and gastrointestinal stromal tumor (GIST). Direct sequence analyses revealed a single base substitution in the splicing donor site of intron 6 (IVS6 888+1, G --> A) in one NF1 allele, resulting in an altered splice site (ss) in the mutated allele. Splicing at the cryptic 5' ss in the mutated allele generated mRNA with an insertion of 60 nucleotides. In addition, we screened for mutations in exons 9, 11, 13, and 17 of the c-kit gene in GIST and the succinate dehydrogenase subunit D (SDHD) gene in the pheochromocytoma, but we did not detect any somatic mutations. We report here the first case of an NF1 patient with four neoplasms: neurofibroma, pheochromocytoma, astrocytoma and GIST. Our results suggest that the molecular pathogenesis of GISTs in NF1 patients is different from that in non-NF1 patients.

Female↗
PubMed2006

Two neurofibromatosis type 1 cases associated with rhabdomyosarcoma of bladder, one with a large deletion in the NF1 gene.

Neurofibromatosis type 1 (NF1) is the most common neurogenetic disorder, affecting approximately 1 in 3,500 individuals worldwide. Mutations of the NF1 tumor suppressor gene predispose individuals to a variety of benign and malignant tumors. Rhabdomyosarcoma (RMS) is an uncommon malignant soft tissue sarcoma and is also a rare tumor type in NF1 patients. We report two cases of NF1 with RMS. The first is that of an infant with overlapping phenotypic features of NF1 and Noonan syndrome (NS) who presented with RMS of the bladder. The second infant likewise exhibited NF1 features and was also associated with bladder RMS. DNA samples were extracted from peripheral blood and tumor tissue samples. We performed loss of heterozygosity (LOH) analysis of the NF1 gene by using seven intragenic markers (IVS27AAAT2.1, IVS27EVI-20, IVS27AC24.8, IVS27AC28.4, M98509, IVS27AC33.1, IVS38TG53.0) and one extragenic polymorphic marker (3'NF1). A large deletion was detected in the NF1 gene in the NF1-Noonan syndrome (NF-NS) case associated with RMS.

Gene Deletion↗
PubMed2005

Stimulus-evoked release of neuropeptides is enhanced in sensory neurons from mice with a heterozygous mutation of the Nf1 gene.

Neurofibromatosis type I is a common autosomal dominant disease characterized by formation of multiple benign and malignant tumors. People with this disorder also experience chronic pain, which can be disabling. Neurofibrinomin, the protein product of the NF1 gene (neurofibromin gene (human)), is a guanosine triphosphate activating protein for p21(ras). Loss of NF1 results in an increase in activity of the p21(ras) transduction cascade. Because of the growing evidence suggesting involvement of downstream components of the p21(ras) transduction cascade in the sensitization of nociceptive sensory neurons, we examined the stimulus-evoked release of the neuropeptides, substance P and calcitonin gene-related peptide, from primary sensory neurons of mice with a mutation of the Nf1 gene (neurofibromin gene (mouse)) (Nf1+/-). Measuring immunoreactive substance P and immunoreactive calcitonin gene-related peptide by radioimmunoassay, we demonstrated that capsaicin-stimulated release of neuropeptides is three to five-fold higher in spinal cord slices from Nf1+/- mice than from wildtype mouse tissue. In addition, the potassium and capsaicin-stimulated release of immunoreactive calcitonin gene-related peptide from cultures of sensory neurons isolated from Nf1+/- mice was more than double that from cultures of wildtype neurons. Treatment of wildtype sensory neurons with nerve growth factor for 5-7 days mimicked the enhanced stimulus-evoked release observed from the Nf1+/- neurons. When nerve growth factor was removed 48 h before conducting release experiments, nerve growth factor-induced augmentation of immunoreactive calcitonin gene-related peptide release from Nf1+/- neurons was more pronounced than in Nf1+/- sensory neurons that were treated with nerve growth factor continuously for 5-7 days. Thus, sensory neurons from mice with a heterozygous mutation of the Nf1 gene that is analogous to the human disease neurofibromatosis type I, exhibit increased sensitivity to chemical stimulation. This augmented responsiveness may explain the abnormal pain sensations experienced by people with neurofibromatosis type I and suggests an important role for guanosine triphosphate activating proteins, in the regulation of nociceptive sensory neuron sensitization.

Afferent Pathways↗
PubMed1999

Urinary bladder transitional cell carcinogenesis is associated with down-regulation of NF1 tumor suppressor gene in vivo and in vitro.

The NF1 gene product (neurofibromin) is known to act as a tumor suppressor protein by inactivating ras. The best documented factors involved in urinary bladder transitional cell carcinoma (TCC) are ras proto-oncogene activation and p53 suppressor gene mutations. This is the first study reporting alterations in NF1 gene expression in TCC. We examined NF1 gene expression in a total of 29 surgical urinary bladder TCC specimens representing grades 1 to 3 and in three cell lines, RT4, 5637, and T24 (representing grades 1 to 3, respectively). Decreased NF1 gene expression was observed in 23 of 29 (83%) TCC specimens as estimated by immunohistochemistry, the decrease being more pronounced in high-grade tumors. NF1 mRNA levels were markedly lower in TCC tissue compared with adjacent non-neoplastic urothelium, as studied by in situ hybridization for grade 3 TCC. Immunohistochemistry and Western blotting demonstrated that TCC cell lines expressed NF1 protein at different levels, expression being almost undetectable in T24 (grade 3) cells. Northern blotting for cell lines demonstrated reduced NF1 mRNA levels in grade 3 TCC cells. Reverse transcription polymerase chain reaction for cell lines and selected grade 2 and grade 3 tissue samples demonstrated NF1 type II mRNA isoform predominance in all samples studied. Our results show that both NF1 mRNA and protein levels are decreased in high-grade TCC, suggesting that alterations of NF1 gene expression may be involved in bladder TCC carcinogenesis.

Blotting, Western↗
PubMed2003

Mlh1 deficiency accelerates myeloid leukemogenesis in neurofibromatosis 1 (Nf1) heterozygous mice.

Defects in DNA mismatch repair (MMR) have been implicated in the genesis of a diverse set of human cancers. Recent studies have suggested that one of the targets of MMR is the neurofibromatosis 1 (NF1) gene. To evaluate the contribution of Mlh1 MMR deficiency to Nf1 tumorigenesis, Mlh1-/-;Nf1+/- mice were generated. All Mlh1-/-;Nf1+/- mice (n=21) were dead by 260 days compared to none of the Nf1+/- mice. In all, 50% of the Mlh1-/-;Nf1+/- mice were dead at 150 days compared to 252 days for Mlh1-/- mice. Nine of the Mlh1-/-;Nf1+/- mice were found to harbor intrathoracic NOS2-immunoreactive myeloid leukemias similar to the hematopoietic malignancies observed in older Nf1+/- mice. As expected, significant microsatellite instability was observed in six of six tumors and neurofibromin expression was lost in all tumors analysed. These results suggest that MMR deficiency can accelerate myeloid leukemogenesis in Nf1+/- mice, presumably by inactivating Nf1 gene expression.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Toward a survey of somatic mutation of the NF1 gene in benign neurofibromas of patients with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1), a common autosomal dominant disorder caused by mutations of the NF1 gene, is characterized by multiple neurofibromas, pigmentation anomalies, and a variety of other possible complications, including an increased risk of malignant neoplasias. Tumorigenesis in NF1 is believed to follow the two-hit hypothesis postulated for tumor-suppressor genes. Loss of heterozygosity (LOH) has been shown to occur in NF1-associated malignancies and in benign neurofibromas, but only few of the latter yielded a positive result. Here we describe a systematic approach of searching for somatic inactivation of the NF1 gene in neurofibromas. In the course of these studies, two new intragenic polymorphisms of the NF1 gene, a tetranucleotide repeat and a 21-bp duplication, could be identified. Three tumor-specific point mutations and two LOH events were detected among seven neurofibromas from four different NF1 patients. Our results suggest that small subtle mutations occur with similar frequency to that of LOH in benign neurofibromas and that somatic inactivation of the NF1 gene is a general event in these tumors. The spectrum of somatic mutations occurring in various tumors from individual NF1 patients may contribute to the understanding of variable expressivity of the NF1 phenotype.

Adult↗
PubMed1997

Confirmation of a double-hit model for the NF1 gene in benign neurofibromas.

Neurofibroma is a benign tumor that arises from small or large nerves. This neoplastic lesion is a common feature of neurofibromatosis type 1 (NF1), one of the most common autosomal dominant disorders. The NF1 gene codes for a protein called "neurofibromin." It possesses a region that shares a high homology with the family of GTPase-activating proteins, which are negative regulators of RAS function and thereby control cell growth and differentiation. The evidence points to the NF1 gene being a tumor-suppressor gene. NF1 patients also have an increased incidence of certain malignant tumors that are believed to follow the "two hit" hypothesis, with one allele constitutionally inactivated and the other somatically mutated. Recently, somatic loss of heterozygosity (LOH) has been described for neurofibromas, and mutations in both copies of the NF1 gene have been reported for a dermal neurofibroma. The aim of our study was the analysis of the NF1 locus in benign neurofibromas in NF1 patients. We performed LOH analysis on 60 neurofibromas belonging to 17 patients, 9 of them with family history of the disease and 8 of them sporadic. We have analyzed five intragenic NF1 markers and six extragenic markers, and we have found LOH in 25% of the neurofibromas (corresponding to 53% of the patients). In addition, we found that in the neurofibromas of patients from familial cases the deletions occurred in the allele that is not transmitted with the disease, indicating that both copies of the NF1 gene were inactivated in these tumors. Therefore, the recent reports mentioned above, together with our findings, strongly support the double inactivation of the NF1 gene in benign neurofibromas.

Alleles↗
PubMed1993

Novel alleles, hemizygosity and deletions at an Alu-repeat within the neurofibromatosis type 1 (NF1) gene.

Neurofibromatosis type 1 (NF1) (von Recklinghausen) is a common autosomal dominant disorder, characterised by the presence of peripheral neurofibromas, café-au-lait spots and Lisch nodules of the iris. Due to the high mutation rate at the NF1 locus, most patients are expected to have different mutations, limiting molecular analysis and genetic counseling to the identification of the mutation in each patient or family, or to the use of DNA polymorphisms. We have analysed an Alu-repeat polymorphic sequence (AAAT), located in intron 27 of the NF1 gene, in 70 NF1 and 40 CEPH families and we have detected several genetic and molecular abnormalities. In two families the NF1 individuals were hemizygous at the AAAT-repeat and/or at the CA-repeat of intron 27 of NF1, due to interstitial deletions, which include intron 27 to exon 37 of the NF1 gene. A 71-bp deletion at the Alu sequence was detected in non-NF1 chromosomes of members of three NF1 families. New alleles at the AAAT-repeat were found in one NF1 family and in three CEPH families giving a mutation rate for this AAAT-repeat of 0.36% per allele, which is one of the highest detected for a microsatellite locus.

Alleles↗
PubMed1997

Binding of NF1 to the MMTV promoter in nucleosomes: influence of rotational phasing, translational positioning and histone H1.

To analyse the role of rotational orientation and translational positioning of nucleosomal DNA on transcription factor binding we have generated a series of mutant MMTV promoters containing insertions of various lengths between the hormone-responsive region and the binding site for NF1. These various MMTV promoter fragments were assembled in mononucleosomes and used for structural studies and binding experiments. We show that the insertions change the rotational phase and translational positioning of the NF1 site as predicted if the sequences upstream of the insertion site were the main determinants of nucleosome phasing. In band shift experiments with recombinant NF1 we cannot detect binding of the protein to NF1 sites included within the limits of a nucleosome, independent of their rotational orientation. Moving the NF1 site closer to the nucleosome border also did not permit NF1 binding. This behaviour probably reflects the way NF1 binds DNA, namely it almost completely surrounds the circumference of the double helix establishing a large number of contacts with the bases and the backbone. In contrast to the wild-type and short insertion mutants, NF1 bound readily to nucleosomes containing 30 or 50 bp insertions which placed the NF1 site at the nucleosome edge or within linker DNA. NF1 binding to the linker DNA was unaffected by incorporation of histone H1 into the nucleosome particle. These findings are discussed in relation to chromatin remodelling initiated by steroid hormones during induction of the MMTV promoter.

Animals↗
PubMed2001

Cancer-related gene expression profiles in NF1-associated pilocytic astrocytomas.

BACKGROUND: Individuals affected with neurofibromatosis 1 (NF1) develop juvenile pilocytic astrocytomas (JPA) at an increased frequency, suggesting that the NF1 gene product, neurofibromin, functions as a negative growth regulator for astrocytes. Previously, the authors demonstrated that NF1-associated astrocytomas exhibit deletions and loss of NF1 gene expression on the DNA and protein levels. However, little is known about additional genetic events in clinically and radiographically progressive NF1-associated pilocytic astrocytomas. OBJECTIVE/METHODS: To understand the potential role of cooperating genetic events in the development of these low-grade tumors, the authors used immunohistochemistry and selected confirmatory Western blots to examine nine symptomatic NF1-associated pilocytic astrocytomas for gene products whose expression patterns are altered in fibrillary astrocytomas. RESULTS: The authors demonstrate that p53, p16, retinoblastoma (RB), epidermal growth factor receptor (EGFR), cyclin-dependent kinase 4 (CDK4), platelet-derived growth factor A (PDGF-A) and PDGF receptor alpha (PDGF-Ralpha) protein expression profiles are not altered in NF1-associated pilocytic astrocytomas. Similar to their sporadic counterparts, NF1-associated JPA also strongly expressed PEN5, a marker of post-O2A stage oligodendroglial precursor cells. CONCLUSIONS: These results suggest that NF1-associated pilocytic astrocytomas lack the genetic changes typically associated with the more clinically aggressive fibrillary astrocytomas and lay the foundation for future studies to identify NF1 JPA-specific alterations.

Adolescent↗
PubMed1995

Expression of the neurofibromatosis 1 (NF1) isoforms in developing and adult rat tissues.

The neurofibromatosis 1 (NF1) gene encodes a large M(r) approximately 250,000 phosphoprotein, the expression of which in adult tissues is limited to neurons, Schwann cells, oligodendrocytes, adrenal medulla, and leukocytes. The presence of two alternatively spliced exons (23a and 48a) in the NF1 gene allow for the generation of four possible neurofibromin isoforms. Type 1 neurofibromin contains neither 23a or 48a exon sequences, while type 2 neurofibromin contains only the 23a exon insertion. Previous studies have demonstrated that types 1 and 2 neurofibromin might have different functional properties relative to microtubule association and GTPase-activating protein activity towards p21-ras. To determine the normal pattern of expression of these NF1 isoforms, the adult and developmental expression of types 1 and 2 NF1 was examined. Herein, we demonstrate that NF1 mRNA is expressed at varying levels in adult tissues and is developmentally regulated during embryogenesis. Neurons in the central nervous system express predominantly type 1 NF1. Using mouse neocortical cultures enriched for neurons or glial cells, type 1 NF1 predominance was demonstrated in neurons, while type 2 NF1 predominated in glial cells. In contrast to central nervous system neurons, neurons expressing the type 2 NF1 isoform were identified in the developing dorsal root ganglia and spinal cord by in situ hybridization using a type 2-specific oligonucleotide probe. The elucidation of the differential expression pattern of these two NF1 isoforms during development and in adult life provides the foundations for future studies aimed at determining the functions of these neurofibromin isoforms.

Animals↗
PubMed2003

Status of the NF1 tumor suppressor locus in uveal melanoma.

BACKGROUND: A clinical association has been observed between uveal melanoma and neurofibromatosis type 1 (NF1). This study aims to determine whether the NF1 tumor suppressor gene is mutated in uveal melanoma. METHODS: Thirty-eight uveal melanomas, as well as normal uveal melanocytes, were examined for NF1 deletions by dual-color fluorescence in situ hybridization, and for expression of the NF1 protein (neurofibromin) by immunohistochemistry and Western blot analysis. RESULTS: Normal uveal melanocytes strongly express neurofibromin. Eighteen (47%) of uveal melanomas demonstrated weak expression of neurofibromin. One large tumor contained a deletion of the NF1 locus and lacked neurofibromin expression. Two other tumors contained additional copies of the NF1 chromosomal region. CONCLUSION: Mutations of the NF1 gene may occasionally play a role in the pathogenesis of uveal melanoma. Clinical Relevance A search for biallelic NF1 mutations in uveal melanomas from patients with neurofibromatosis will be of interest to determine whether germline NF1 mutations may predispose to uveal melanoma.

Adult↗
PubMed2004

Screening 500 unselected neurofibromatosis 1 patients for deletions of the NF1 gene.

A total of 500 unselected unrelated neurofibromatosis 1 (NF1) patients were screened for deletions of the NF1 gene. After excluding 67 patients with known intragenic NF1 mutations, the remaining 433 were genotyped using six intragenic and one distal microsatellite marker for the NF1 gene. A total of 28 patients were hemi- or homozygous for all seven markers and were thus considered as candidates for NF1 deletion with a calculated probability of 99.99%. Metaphase or interphase cells were available from 23 of these 28 individuals for molecular cytogenetics. Fluorescence in situ hybridization (FISH) confirmed an NF1 deletion in 22 (96%) of the 23 patients. Thus, a constitutional deletion of the NF1 gene is responsible for the disease phenotype in at least 4.4% of the 500 unselected NF1 patients. Genotyping using multiple microsatellite markers may provide a simple, inexpensive, and efficient strategy for screening deletions of the NF1 gene, and can as well be applied for other large genes.

Female↗
PubMed2004

Novel and recurrent mutations in the NF1 gene in Italian patients with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders in humans, affecting 1 in 3500 individuals. NF1 is a fully penetrant exhibiting a mutation rate some 10-fold higher compared to most other disease genes. As a consequence, a high number of cases (up to 50%) are sporadic. Mutation detection is complex due to the large size of NF1 gene, the presence of pseudogenes and the great variety of lesions. In the present study we attempted to delineate the NF1 mutational spectrum in the Italian population reporting four-year experience with the direct analysis of the whole NF1 coding region in 110 unrelated subjects affected by NF1. For each patient, the whole coding sequence and all splice sites were studied for mutations, either by the protein truncation test (PTT), or, most often, by denaturing high performance liquid chromatography (DHPLC). Mutations were identified in 75 (68%) patients. Twenty-two mutations were found to be novel. The detection rate for the different methods was 7/18 (39%) for PTT, and 68/103 (66%) for DHPLC. The mutations were evenly distributed along the NF1 coding sequence. Thirty-two of the 75 unrelated NF1 patients in which germline mutations were identified (32/75, 43%) harbour 23 different recurrent mutations. Fifteen sequence variants likely to represent non-pathogenic polymorphisms were observed at the NF1 locus. Genotype-phenotype analysis was unable to detect any obvious correlation.

Chromatography, High Pressure Liquid↗
PubMed2006

The heterogeneous nature of germline mutations in NF1 patients with malignant peripheral serve sheath tumours (MPNSTs).

Malignant peripheral nerve sheath tumours (MPNSTs) are a major cause of mortality in patients with neurofibromatosis 1 (NF1). We have analysed lymphocyte DNA samples from 30 NF1 patients with MPNSTs to determine their underlying constitutional NF1 gene mutations. Mutations were detected in 27/30 (90%) of these patients. NF1 mutations identified included nonsense, missense, frameshift, splice site mutation and single or multi-exonic deletions and with no obvious clustering of the mutations across the gene. Fourteen of the mutations represent novel gene changes. There did not appear to be any relationship between the mutation type and the level of clinical severity observed. Of the 20 patients with high grade MPNSTs, seven patients had small (<20 bp) and multi-exonic deletions and three had small insertions (<20 bp). Several studies have suggested that NF1 patients with a constitutional 1.5 Mb deletion of the NF1 gene have an increased risk of developing malignant peripheral nerve sheath tumours (MPNSTs). None of our patients had a 1.5 Mb deletion. Larger prospective studies are needed to ascertain whether there is a different spectrum of NF1 mutations in NF1 patients with high grade compared to low grade MPNSTs and of patients with the 1.5Mb deletion, in order to determine the true frequency of MPNST in this sub-group of NF1 patients.

Adolescent↗
PubMed1995

Analysis of the GAP-related domain of the neurofibromatosis type 1 (NF1) gene in childhood brain tumors.

The neurofibromatosis type-1 (NF1) gene contains a 360-bp region with significant homology to the catalytic domain of mammalian GTPase-activating protein. This particular GAP-related domain of the NF1 gene (NF1-GRD) stimulates ras GTPase and inactivates ras protein p21ras. Therefore, it has been suggested that the NF1 gene represents another tumor-suppressor gene. In the search for molecular markers of possible diagnostic relevance, childhood brain-tumor specimens of different histologic diagnoses were tested for mutations of the so-called FLR-exon within the NF1-GRD. This part of the NF1-GRD has been shown to be most crucial for the GAP-like function. Using a highly sensitive PCR-SSCP technique, we tested 51 tumor specimens were tested, but found no mutations. We conclude that inactivation of this putative tumor-suppressor gene by mutations does not play a significant role in tumorigenesis of childhood brain tumors. Next, we compared the splice variants of the NF1-GRD in 33 brain tumors and 8 extraneural embryonal tumors. Primitive neuroectodermal tumors (PNET) (n = 10) and one intracranial teratoma were the only tumors that predominantly expressed a splice pattern that can be observed in the immature developing brain. In contrast to other embryonal neuronal tumors, this NF1-GRD splicing pattern could not be modified in a newly established medulloblastoma cell line by retinoic acid treatment. Since this particular splice variant suppresses p21ras more effectively than other NF1-GRD transcripts, its predominant expression may interfere with the physiological signal transduction of p21ras during differentiation of neurons. There may be a neurofibromin-induced and p21ras-mediated differentiation pathway of neuronal stem cells that is blocked in PNET. Such an arrest of a p21ras-dependent differentiation pathway may explain the persistence of primitive pluripotent neuronal cells in PNET.

Alternative Splicing↗