National Cancer Institute®
Last Modified: September 1, 2002
UI - 9054942
AU - Silva AJ; Frankland PW; Marowitz Z; Friedman E; Laszlo GS; Cioffi D;
TI - Jacks T; Bourtchuladze R; Lazlo G A mouse model for the learning and memory deficits associated with neurofibromatosis type I.
SO - Nat Genet 1997 Mar;15(3):281-4
AD - Cold Spring Harbor Laboratory, New York 11724, USA. Silva@cshl.org
Neurofibromatosis type I (NF1) is one of the most commonly inherited neurological disorders in humans, affecting approximately one in 4,000 individuals. NF1 results in a complex cluster of developmental and tumour syndromes that include benign neurofibromas, hyperpigmentation of melanocytes and hamartomas of the iris. Some NF1 patients may also show neurologic lesions, such as optic pathway gliomas, dural ectasia and aqueduct stenosis. Importantly, learning disabilities occur in 30% to 45% of patients with NF1, even in the absence of any apparent neural pathology. The learning disabilities may include a depression in mean IQ scores, visuoperceptual problems and impairments in spatial cognitive abilities. Spatial learning has been assessed with a variety of cognitive tasks and the most consistent spatial learning deficits have been observed with the Judgement of Line Orientation test. It is important to note that some of these deficits could be secondary to developmental abnormalities and other neurological problems, such as poor motor coordination and attentional deficits. Previous studies have suggested a role for neurofibromin in brain function. First, the expression of the Nf1 gene is largely restricted to neuronal tissues in the adult. Second, this GTPase activating protein may act as a negative regulator of neurotrophin-mediated signalling. Third, immunohistochemical studies suggest that activation of astrocytes may be common in the brain of NF1 patients. Here, we show that the Nf1+/- mutation also affects learning and memory in mice. As in humans, the learning and memory deficits of the Nf1+/- mice are restricted to specific types of learning, they are not fully penetrant, they can be compensated for with extended training, and they do not involve deficits in simple associative learning.
UI - 12154062
AU - Li H; Velasco-Miguel S; Vass WC; Parada LF; DeClue JE
TI - Epidermal growth factor receptor signaling pathways are associated with tumorigenesis in the Nf1:p53 mouse tumor model.
SO - Cancer Res 2002 Aug 1;62(15):4507-13
AD - Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
The human disease neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene, and is characterized by the formation of benign and malignant tumors of the peripheral nervous system. We have shown previously that aberrant expression of the epidermal growth factor receptor (EGFR) is a common feature of human NF1-related tumor development in humans and in NF1 animal models. One recent approach taken to investigate the changes associated with NF1 tumor formation is the development of the Nf1:p53 mouse tumor model. Here, we examined a series of tumor cell lines derived from Nf1:p53 mice for their expression of EGFR family members. Immunoblotting analyses revealed that 23 of the 24 cell lines examined express the EGFR, and 24 of 24 express the related tyrosine kinase erbB2, whereas erbB3 was detected in only 6 of 24. All of the cell lines expressing EGFR responded to epidermal growth factor (EGF) by activation of the downstream signaling pathways, mitogen-activated protein (MAP)/extracellular signal-regulated kinase kinase/MAP kinase, and phosphatidylinositol 3'-kinase (PI3k)/AKT. Growth of the cell lines was greatly stimulated by EGF in vitro and could be blocked by an antagonist of the EGFR. In addition, inhibition of the PI3k pathway potently inhibited the EGF-dependent growth of these cell lines, whereas inhibition of the MAP/extracellular signal-regulated kinase kinase/MAP kinase pathway had more limited effects. We conclude that EGFR expression is a common feature of the Nf1:p53 tumor cell lines and that inhibition of this molecule or its downstream target PI3k, may be useful in the treatment of NF1-related malignancies.
UI - 12237234
AU - Koga T; Iwasaki H; Ishiguro M; Matsuzaki A; Kikuchi M
TI - Losses in chromosomes 17, 19, and 22q in neurofibromatosis type 1 and sporadic neurofibromas: a comparative genomic hybridization analysis.
SO - Cancer Genet Cytogenet 2002 Jul 15;136(2):113-20
AD - Department of Pathology, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
Neurofibromatosis type 1 (von Recklinghausen's NF1) is an autosomal dominant disease associated with an increased risk of benign and malignant neoplasia including malignant peripheral nerve sheath tumors (MPNSTs). In this study, we employed comparative genomic hybridization (CGH) to determine changes in the relative chromosome copy number in 24 patients with neurofibromas, including 12 NF1-associated and 12 sporadic cases. Differences in the frequency and distribution of chromosomal imbalances were observed in both NF1-asociated and sporadic neurofibromas. Chromosomal imbalances were more common in NF1-associated tumors than in sporadic neurofibromas. In both groups, the number of losses was higher than the number of gains, suggesting a predominant role of tumor suppressor gene in tumorigenesis. A number of new chromosomal imbalances were noted including chromosomes 17, 19, and chromosome arm 22q, which may be related to oncogenes or tumor suppressor genes in neurofibromas. In NF1-associated neurofibromas, the most frequent losses were found in chromosome 17 (the minimal common regions were 17p11.2-->p13 in nine cases and 17q24-->q25 in six cases) and 19p (19p13.2 in nine cases). In addition, both NF1-associated and sporadic neurofibromas often exhibited losses at chromosome arms 19q and 22q (in NF1 tumors, the minimal common regions were 19q13.2-->qter in seven cases).
UI - 12077526
AU - Schultz ES; Kaufmann D; Tinschert S; Schell H; von den Driesch P;
TI - Schuler G Segmental neurofibromatosis.
SO - Dermatology 2002;204(4):296-7
AD - Department of Dermatology, University of Erlangen-Nuremberg, Germany. firstname.lastname@example.org
Segmental neurofibromatosis is characterised by a limited, segmental distribution of cutaneous neurofibromatosis type 1 (NF1) lesions. It has been suggested that segmental NF results from a postzygotic NF1 gene mutation, and, recently, this hypothesis has been proven in a patient with regionally distributed cafe-au-lait (CAL) spots and freckles by demonstrating an NF1 microdeletion restricted to fibroblasts cultured from CAL spots. We describe here a patient with segmental NF in which we could not demonstrate any NF1 gene mutation in fibroblasts cultured from neurofibromas by use of the protein truncation test, enzymatic mutation detection and fluorescence in situ hybridisation. These data are in line with the concept that NF1 mutations in Schwann cells, but not in fibroblasts, correlate with neurofibroma formation. Copyright 2002 S. Karger AG, Basel
UI - 12124168
AU - McLaughlin ME; Jacks T
TI - Thinking beyond the tumor cell: Nf1 haploinsufficiency in the tumor environment.
SO - Cancer Cell 2002 Jun;1(5):408-10
AD - Howard Hughes Medical Institute, Department of Biology and Center for Cancer Research, Massachusetts Institute of Technology, Cambridge 02139, USA.
Deletion of both copies of the Nf1 gene in Schwann cells combined with Nf1 heterozygosity in the tumor environment promotes neurofibroma formation in mice.
UI - 12118253
AU - Fernandez-Valle C; Tang Y; Ricard J; Rodenas-Ruano A; Taylor A; Hackler
TI - E; Biggerstaff J; Iacovelli J Paxillin binds schwannomin and regulates its density-dependent localization and effect on cell morphology.
SO - Nat Genet 2002 Aug;31(4):354-62
AD - Department of Molecular Biology and Microbiology, University of Central Florida, Orlando, Florida 32826, USA. email@example.com
Neurofibromatosis type 2 is an autosomal dominant disorder characterized by tumors, predominantly schwannomas, in the nervous system. It is caused by mutations in the gene NF2, encoding the growth regulator schwannomin (also known as merlin). Mutations occur throughout the 17-exon gene, with most resulting in protein truncation and undetectable amounts of schwannomin protein. Pathogenic mutations that result in production of defective schwannomin include in-frame deletions of exon 2 and three independent missense mutations within this same exon. Mice with conditional deletion of exon 2 in Schwann cells develop schwannomas, which confirms the crucial nature of exon 2 for growth control. Here we report that the molecular adaptor paxillin binds directly to schwannomin at residues 50-70, which are encoded by exon 2. This interaction mediates the membrane localization of schwannomin to the plasma membrane, where it associates with beta 1 integrin and erbB2. It defines a pathogenic mechanism for the development of NF2 in humans with mutations in exon 2 of NF2.
UI - 12217765
AU - Ceccaroni M; Genuardi M; Legge F; Lucci-Cordisco E; Carrara S; D'Amico
TI - F; Greggi S; Scambia G BRCA1-related malignancies in a family presenting with von Recklinghausen's disease.
SO - Gynecol Oncol 2002 Sep;86(3):375-8
AD - Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Largo E. Gemelli 8, 00168 Rome, Italy.
BACKGROUND: The association between neurofibromatosis and gynecologic malignancies is rarely reported in the literature. Both BRCA1 and NF1 genes are located on the long arm of chromosome 17. CASE: We have observed a pedigree showing several individuals affected by both type 1 neurofibromatosis (NF1) and breast or coelomatic cancers. The number of individuals affected, their degree of relationship, and the early age at onset were suggestive of an hereditary breast/ovarian cancer syndrome. Linkage analysis was performed in order to establish whether markers in the chromosome 17 region containing the BRCA1 and NF1 loci were shared by affected individuals. Screening for BRCA1 mutations was performed by PTT and SSCP. Analysis of chromosome 17 DNA markers in the five family members tested show that three individuals affected by both NF1 and carcinomas share a common haplotype including the NF1 and BRCA1 loci on chromosome 17. Mutation analysis showed the presence of a nonsense mutation within BRCA1 exon 12 in two individuals, mother and daughter, affected by breast and peritoneal cancer, respectively, as well as in the son, who had rectal cancer at the early age of 27 years. All three subjects also had NF1. CONCLUSION: The concurrence of NF1 and hereditary breast/ovarian cancer in this family is likely due to the presence of two linked mutations at the NF1 and BRCA1 loci.
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