National Cancer Institute®
Last Modified: November 21, 2001
UI - 99364949
AU - Ebert C; von Haken M; Meyer-Puttlitz B; Wiestler OD; Reifenberger G;
TI - Pietsch T; von Deimling A Molecular genetic analysis of ependymal tumors. NF2 mutations and chromosome 22q loss occur preferentially in intramedullary spinal ependymomas.
SO - Am J Pathol 1999 Aug;155(2):627-32
AD - Department of Neuropathology, University of Bonn Medical Center, Bonn Charite, Humboldt University, Berlin, Germany.
Ependymal tumors are heterogeneous with regard to morphology, localization, age at first clinical manifestation, and prognosis. Several molecular alterations have been reported in these tumors, including allelic losses on chromosomes 10, 17, and 22 and mutations in the NF2 gene. However, in contrast to astrocytic gliomas, no consistent molecular alterations have been associated with distinct types of ependymal tumors. To evaluate whether morphological subsets of ependymomas are characterized by specific genetic lesions, we analyzed a series of 62 ependymal tumors, including myxopapillary ependymomas, subependymomas, ependymomas, and anaplastic ependymomas, for allelic losses on chromosome arms 10q and 22q and mutations in the PTEN and NF2 genes. Allelic losses on 10q and 22q were detected in 5 of 56 and 12 of 54 tumors, respectively. Six ependymomas carried somatic NF2 mutations, whereas no mutations were detected in the PTEN gene. All six of the NF2 mutations occurred in ependymomas of WHO grade II and were exclusively observed in tumors with a spinal localization (P = 0.0063). These findings suggest that a considerable fraction of spinal ependymomas are associated with molecular events involving chromosome 22 and that mutations in the NF2 gene may be of primary importance for their genesis. Furthermore, our data suggest that the more favorable clinical course of spinal ependymomas may relate to a distinct pattern of genetic alterations different from that of intracerebral ependymomas.
UI - 21287652
AU - Uhlmann EJ; Gutmann DH
TI - Tumor suppressor gene regulation of cell growth: recent insights into neurofibromatosis 1 and 2 gene function.
SO - Cell Biochem Biophys 2001;34(1):61-78
AD - Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
The development of cancer involves a myriad of genetic changes that impact on multiple processes important for the orderly regulation of cell growth and differentiation. Genes whose protein products are disrupted during neoplastic transformation are termed "tumor suppressor genes" (TSGs). Many of these TSGs are associated with familial cancer predisposition syndromes, in which affected individuals have an increased risk of certain malignancies. Studies on the mechanism of action for known TSGs have revealed three intracellular loci of critical importance: environmental sensing and signal initiation, signal propagation and transduction, and cell cycle control. The neurofibromatosis 1 and neurofibromatosis 2 genes are discussed as illustrative examples of tumor suppressors that function at the levels of signal transduction and environmental sensing, respectively.
UI - 21417763
AU - Yager J; Richards S; Hekmat-Scafe DS; Hurd DD; Sundaresan V; Caprette
TI - DR; Saxton WM; Carlson JR; Stern M Control of Drosophila perineurial glial growth by interacting neurotransmitter-mediated signaling pathways.
SO - Proc Natl Acad Sci U S A 2001 Aug 28;98(18):10445-50
AD - Department of Biochemistry and Cell Biology, MS-140, Rice University, Houston, TX 77005, USA.
Drosophila peripheral nerves, similar structurally to the peripheral nerves of mammals, comprise a layer of axons and inner glia, surrounded by an outer perineurial glial layer. Although it is well established that intercellular communication occurs among cells within peripheral nerves, the signaling pathways used and the effects of this signaling on nerve structure and function remain incompletely understood. Here we demonstrate with genetic methods that the Drosophila peripheral nerve is a favorable system for the study of intercellular signaling. We show that growth of the perineurial glia is controlled by interactions among five genes: ine, which encodes a putative neurotransmitter transporter; eag, which encodes a potassium channel; push, which encodes a large, Zn(2+)-finger-containing protein; amn, which encodes a putative neuropeptide related to the pituitary adenylate cyclase activator peptide; and NF1, the Drosophila ortholog of the human gene responsible for type 1 neurofibromatosis. In other Drosophila systems, push and NF1 are required for signaling pathways mediated by Amn or the pituitary adenylate cyclase activator peptide. Our results support a model in which the Amn neuropeptide, acting through Push and NF1, inhibits perineurial glial growth, whereas the substrate neurotransmitter of Ine promotes perineurial glial growth. Defective intercellular signaling within peripheral nerves might underlie the formation of neurofibromas, the hallmark of neurofibromatosis.
UI - 21451213
AU - Williams JA; Su HS; Bernards A; Field J; Sehgal A
TI - A circadian output in Drosophila mediated by neurofibromatosis-1 and Ras/MAPK.
SO - Science 2001 Sep 21;293(5538):2251-6
AD - Howard Hughes Medical Institute, Center for Sleep and Respiratory Neurobiology, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Output from the circadian clock controls rhythmic behavior through poorly understood mechanisms. In Drosophila, null mutations of the neurofibromatosis-1 (Nf1) gene produce abnormalities of circadian rhythms in locomotor activity. Mutant flies show normal oscillations of the clock genes period (per) and timeless (tim) and of their corresponding proteins, but altered oscillations and levels of a clock-controlled reporter. Mitogen-activated protein kinase (MAPK) activity is increased in Nf1 mutants, and the circadian phenotype is rescued by loss-of-function mutations in the Ras/MAPK pathway. Thus, Nf1 signals through Ras/MAPK in Drosophila. Immunohistochemical staining revealed a circadian oscillation of phospho-MAPK in the vicinity of nerve terminals containing pigment-dispersing factor (PDF), a secreted output from clock cells, suggesting a coupling of PDF to Ras/MAPK signaling.
UI - 20558893
AU - Evans DG; Sainio M; Baser ME
TI - Neurofibromatosis type 2.
SO - J Med Genet 2000 Dec;37(12):897-904
AD - Department of Medical Genetics, St Mary's Hospital, Hathersage Road, Manchester M13 0JH, UK. email@example.com
Neurofibromatosis type 2 is an often devastating autosomal dominant disorder which, until relatively recently, was confused with its more common namesake neurofibromatosis type 1. Subjects who inherit a mutated allele of the NF2 gene inevitably develop schwannomas, affecting particularly the superior vestibular branch of the 8th cranial nerve, usually bilaterally. Meningiomas and other benign central nervous system tumours such as ependymomas are other common features. Much of the morbidity from these tumours results from their treatment. It is now possible to identify the NF2 mutation in most families, although about 20% of apparently sporadic cases are actually mosaic for their mutation. As a classical tumour suppressor, inactivation of the NF2 gene product, merlin/schwannomin, leads to the development of both NF2 associated and sporadic tumours. Merlin/schwannomin associates with proteins at the cell cytoskeleton near the plasma membrane and it inhibits cell proliferation, adhesion, and migration.
UI - 21425285
AU - Koul RL; Chacko A; Leven HO
TI - Dandy-Walker syndrome in association with neurofibromatosis in monozygotic twins.
SO - Saudi Med J 2000 Apr;21(4):390-2
AD - Department of Pediatric Neurology, Sultan Qaboos University Hospital, PO Box 38, Al-Khoud 123, Sultanate of Oman.
Dandy-Walker syndrome in monozygotic twins is reported. The twins reported, presented with delayed development, big head and dysmorphic features. In addition, there were significant cafe-au-lait spots on the trunk and other minor features consistent with the diagnosis of neurofibromatosis. To the best of our knowledge, Dandy-Walker syndrome in combination with neurofibromatosis in monozygotic twins has not been previously reported.
UI - 21385471
AU - Lakkis MM; Tennekoon GI
TI - Neurofibromatosis type 1: II. Answers from animal models.
SO - J Neurosci Res 2001 Aug 1;65(3):191-4
AD - Department of Neurology, Children's Hospital of Philadelphia, 3400 Civic Center Boulevard, Philadelphia, PA 19104-4399, USA. firstname.lastname@example.org
UI - 21424526
AU - Blaydes SM; Kogan SC; Truong BT; Gilbert DJ; Jenkins NA; Copeland NG;
TI - Largaespada DA; Brannan CI Retroviral integration at the Epi1 locus cooperates with Nf1 gene loss in the progression to acute myeloid leukemia.
SO - J Virol 2001 Oct;75(19):9427-34
AD - Department of Molecular Genetics and Microbiology, Center for Mammalian Genetics, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
Juvenile myelomonocytic leukemia (JMML) is a disease that occurs in young children and is associated with a high mortality rate. In most patients, JMML has a progressive course leading to death by virtue of infection, bleeding, or progression to acute myeloid leukemia (AML). As it is known that children with neurofibromatosis type 1 syndrome have a markedly increased risk of developing JMML, we have previously developed a mouse model of JMML through reconstitution of lethally irradiated mice with hematopoietic stem cells homozygous for a loss-of-function mutation in the Nf1 gene (D. L. Largaespada, C. I. Brannan, N. A. Jenkins, and N. G. Copeland, Nat. Genet. 12:137-143, 1996). In the course of these experiments, we found that all these genetically identical reconstituted mice developed a JMML-like disorder, but only a subset went on to develop more acute disease. This result strongly suggests that additional genetic lesions are responsible for disease progression to AML. Here, we describe the production of a unique tumor panel, created using the BXH-2 genetic background, for identification of these additional genetic lesions. Using this tumor panel, we have identified a locus, Epi1, which maps 30 to 40 kb downstream of the Myb gene and appears to be the most common site of somatic viral integration in BXH-2 mice. Our findings suggest that proviral integrations at Epi1 cooperate with loss of Nf1 to cause AML.
UI - 21450508
AU - Zuccoli G; Ferrozzi F; Tognini G; Troiso A
TI - Enlarging tongue masses in neurofibromatosis type 1: MR findings of two cases.
SO - Clin Imaging 2001 Jul-Aug;25(4):268-71
AD - Radiology Department, Arcispedale Santa Maria Nuova, Viale Risorgimento 80, 42100, Reggio Emilia, Italy. email@example.com
Plexiform neurofibromas usually occur in the neck, pelvis, and extremities. Jaws and oral cavity plexiform neurofibromas have also been described. Magnetic resonance (MR) patterns for neurofibromas are typical. They include low-to-intermediate signal intensity on T1-weighted images, enhancement of the solid component of the tumor after contrast medium administration, heterogeneity on T2-weighted images, and in some cases, multiple target signs due to a collagen central area. We report MR findings of two neurofibromatosis type 1 (NF1) patients with enlarging tongue plexiform neurofibromas.
UI - 21318335
AU - Garavelli L; Donadio A; Sigorini M; Grassi L; Banchini G
TI - [Genetics of type 1 neurofibromatosis]
SO - Acta Biomed Ateneo Parmense 2000;71(3-4):89-95
AD - Ambulatorio di Genetica Clinica, Unita Operativa di Pediatria, Dipartimento Materno-Infantile Arcispedale S. Maria Nuova, Reggio Emilia.
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterised by cafe au lait spots, multiple neurofibromas and Lisch nodules of the iris, with marked variability of expression. The NF1 gene is located at 17q11.2, spans 350 kb genomic DNA and comprises 60 exons encoding a 11-13 kb transcript (Viskochil et al.). Four alternatively spliced NF1 transcripts have been identified and they show differential expression in various tissues. NF1 gene is a member of the tumor suppressor gene family. The protein encoded by NF1, neurofibromin, has a domain homologous to the GTPase activating protein (GAP) family, and downregulates ras activity. Neurofibromin is involved in the control of cellular growth and differentiation and germline mutation analysis has shown that around 82% of all the fully characterised NF1 specific mutations so far predict severe truncation of neurofibromin. The current demand for molecular diagnosis of NF1 is low. Many couples would probably request a prenatal diagnosis if it could predict disease severity. Molecular prediction of disease severity and prognosis may either be very complicated or even impossible. Presymptomatic DNA diagnosis is probably not going to be in huge demand because the clinical diagnosis of NF1 is usually straightforward, even in early childhood. Further knowledge of the gene function may also lead to the development of new therapy for the disease.
UI - 21413906
AU - Jannatipour M; Dion P; Khan S; Jindal H; Fan X; Laganiere J; Chishti AH;
TI - Rouleau GA Schwannomin isoform-1 interacts with syntenin via PDZ domains.
SO - J Biol Chem 2001 Aug 31;276(35):33093-100
AD - Center for Research in Neuroscience, McGill University and the Montreal General Hospital, 1650 Cedar Avenue, Montreal, Quebec, Canada.
The neurofibromatosis type 2 gene (NF2) is involved in the pathogenesis of benign tumors of the human nervous system. The NF2 protein, called schwannomin or merlin, is inactivated in virtually all schwannomas and meningiomas. The molecular mechanisms by which schwannomin functions as a tumor suppressor is unknown but believed to involve plasma membrane-cytoskeletal interactions. Two major alternatively spliced isoforms of schwannomin differing in their C termini have been reported. Using the yeast two-hybrid system, we have identified syntenin as a binding partner for schwannomin isoform-1 (sch-1). Syntenin is an adapter protein that couples transmembrane proteoglycans to cytoskeletal components and is involved in intracellular vesicle transport. The C terminus 25 amino acids of sch-1 and the two PDZ domains of syntenin mediate their binding, and mutations introduced within the VAFFEEL region of sch-1 defined a sequence crucial for syntenin recognition. We have showed that the two proteins interacted in vitro and in vivo and localized underneath the plasma membrane. Fibroblast cells expressing heterologous antisense syntenin display alterations in the subcellular distribution of sch-1. Together, these results provide the first functional clue to the existence of schwannomin isoforms and could unravel novel pathways for the transport and subcellular localization of schwannomin in vivo.
UI - 21456738
AU - de Goede-Bolder A; Cnossen MH; Dooijes D; van den Ouweland AM;
TI - Niermeijer MF [From gene to disease; neurofibromatosis type 1]
SO - Ned Tijdschr Geneeskd 2001 Sep 8;145(36):1736-8
AD - Erasmus Medisch Centrum-Sophia Kinderziekenhuis, Postbus 2060, 3000 CB Rotterdam. firstname.lastname@example.org
Neurofibromatosis type 1 (NF1) is an autosomal dominant disease characterised by cafe-au-lait spots, freckling in the axillary or inguinal region, dermal and plexiform neurofibromas and Lisch nodules. Complications are severe in one third of patients, and the clinical variability is pronounced, even within families. The NF1 gene has been localised to chromosome 17q11.2 and encodes the protein neurofibromin. The gene is proposed to be a tumour suppressor gene. Inactivation of neurofibromin leads to a disruption in cell growth regulation. Mutation analysis is possible but laborious, and therefore NF1 is generally a clinical diagnosis based on diagnostic criteria.
UI - 21393562
AU - Wei F; Cheng S; Badie N; Elder F; Scott C Jr; Nicholson L; Ross JL; Zinn
TI - AR A man who inherited his SRY gene and Leri-Weill dyschondrosteosis from his mother and neurofibromatosis type 1 from his father.
SO - Am J Med Genet 2001 Sep 1;102(4):353-8
AD - McDermott Center for Human Growth and Development, UT Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, TX 75390-8591, USA.
We report on a man with neurofibromatosis type 1 (NF1) and Leri-Weill dyschondrosteosis (LWD). His father had NF1. His mother had LWD plus additional findings of Turner syndrome (TS): high arched palate, bicuspid aortic valve, aortic stenosis, and premature ovarian failure. The proband's karyotype was 46,X,dic(X;Y)(p22.3;p11.32). Despite having almost the same genetic constitution as 47,XXY Klinefelter syndrome, he was normally virilized, although slight elevation of serum gonadotropins indicated gonadal dysfunction. His mother's karyotype was mosaic 45,X[17 cells]/46,X,dic(X;Y)(p22.3;p11.32)[3 cells].ish dic(X;Y)(DXZ1 +,DYZ1 + ). The dic(X;Y) chromosome was also positive for Y markers PABY, SRY, and DYZ5, but negative for SHOX. The dic(X;Y) chromosome was also positive for X markers DXZ1 and a sequence < 300 kb from PABX, suggesting that the deletion encompassed only pseudoautosomal sequences. Replication studies indicated that the normal X and the dic(X;Y) were randomly inactivated in the proband's lymphocytes. LWD in the proband and his mother was explained by SHOX haploinsufficiency. The mother's female phenotype was most likely due to 45,X mosaicism. This family segregating Mendelian and chromosomal disorders illustrates extreme sex chromosome variation compatible with normal male and female sexual differentiation. The case also highlights the importance of karyotyping for differentiating LWD and TS, especially in patients with findings such as premature ovarian failure or aortic abnormalities not associated with isolated SHOX haploinsufficiency. Copyright 2001 Wiley-Liss, Inc.
UI - 21426413
AU - Neill GW; Crompton MR
TI - Binding of the merlin-I product of the neurofibromatosis type 2 tumour suppressor gene to a novel site in beta-fodrin is regulated by association between merlin domains.
SO - Biochem J 2001 Sep 15;358(Pt 3):727-35
AD - Centre for Cutaneous Research, St Bartholomew's and the Royal London, Queen Mary and Westfield College, 2 Newark Street, London E1 2AT, UK.
The mechanism underlying the tumour-suppressor activity of the neurofibromatosis type 2 (NF2) gene product, merlin, is largely undefined but there is evidence that the biological function of the protein might be mediated partly through interactions with the cytoskeleton. Merlin is expressed predominantly as two isoforms that differ at their C-termini owing to alternative splicing of exon 16. By expressing merlin isoform I as bait in a yeast two-hybrid screen, we isolated a clone encoding a region of the cytoskeletal protein beta-fodrin. Confirmation of the merlin-fodrin interaction was provided by using the mammalian two-hybrid system and binding assays in vitro. In addition, these assays and co-immunoprecipitation from mammalian cells revealed that the binding site for fodrin is located in the C-terminal half of merlin at a site that is masked in the native protein. Co-expression of the N-terminus of merlin decreased the interaction of its C-terminus with fodrin, implicating homophilic interactions of merlin isoform I in masking the fodrin-binding site. The effect of three disease-associated mutations on the merlin-fodrin interaction and merlin dimerization was also investigated. The mutation L535P, but not L360P or K413E, significantly decreased the merlin-fodrin interaction but not dimerization, indicating that the tumour suppressor ability of merlin might reside partly in its ability to interact with the cytoskeleton via fodrin.
UI - 21473117
AU - Perry A; Giannini C; Raghavan R; Scheithauer BW; Banerjee R; Margraf L;
TI - Bowers DC; Lytle RA; Newsham IF; Gutmann DH Aggressive phenotypic and genotypic features in pediatric and NF2-associated meningiomas: a clinicopathologic study of 53 cases.
SO - J Neuropathol Exp Neurol 2001 Oct;60(10):994-1003
AD - Divisions of Neuropathology, Washington University School of Medicine, St. Louis, Missouri 63110-1093, USA.
Pediatric and NF2-associated meningiomas are uncommon and poorly characterized in comparison to sporadic adult cases. In order to elucidate their molecular features, we analyzed MIB-1, progesterone receptor (PR), NF2, merlin, DAL-1, DAL-1 protein, and chromosomal arms 1p and 14q in 53 meningiomas from 40 pediatric/NF2 patients using immunohistochemistry and dual-color fluorescence in situ hybridization (FISH). Fourteen pediatric (42%) patients, including 5 previously undiagnosed patients, had NF2. The remaining 19 (58%) did not qualify. All 7 of the adult patients had NF2. Meningioma grading revealed 21 benign (40%), 26 atypical (49%), and 6 anaplastic (11%) examples. Other aggressive findings included high mitotic index (32%), high MIB-1 LI (37%), aggressive variant histology (e.g. papillary, clear cell) (25%), brain invasion (17%), recurrence (39%), and patient death (17%). FISH analysis demonstrated deletions of NF2 in 82%, DAL-1 in 82%, 1p in 60%, and 14q in 66%. NF2-associated meningiomas did not differ from sporadic pediatric tumors except for a higher frequency of merlin loss in the former (p = 0.020) and a higher frequency of brain invasion in the latter (p = 0.007). Thus, although pediatric and NF2-associated meningiomas share the common molecular alterations of their adult, sporadic counterparts, a higher fraction are genotypically and phenotypically aggressive. Given the high frequency of undiagnosed NF2 in the pediatric cases, a careful search for other features of this disease is warranted in any child presenting with a meningioma.
UI - 93257179
AU - Bower C; Parker R; Lockley J; Hee G; Fernandez G; Hockey A
TI - Attitudes towards molecular genetic testing for neurofibromatosis type 1 in Western Australia.
SO - J Paediatr Child Health 1993 Apr;29(2):158
UI - 21523846
AU - Joachim T; Ram Z; Rappaport ZH; Simon M; Schramm J; Wiestler OD; von
TI - Deimling A Comparative analysis of the NF2, TP53, PTEN, KRAS, NRAS and HRAS genes in sporadic and radiation-induced human meningiomas.
SO - Int J Cancer 2001 Oct 15;94(2):218-21
AD - Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
Irradiation to the head is associated with a significantly increased incidence of meningiomas. Radiation-induced meningiomas morphologically resemble their sporadically arising counterparts; however, they frequently exhibit a more malignant phenotype. Several genes have been shown to carry mutations in meningiomas, with the NF2 gene being most frequently affected. To examine whether the NF2 gene also plays a role in the development of radiation-induced meningiomas, we compiled a series of meningiomas from 25 patients with a history of previous cranial radiation. This series was compared with 21 atypical WHO grade II meningiomas and 15 anaplastic WHO grade III meningiomas, all from patients without a history of prior irradiation. NF2 mutations occurred significantly more often in sporadic atypical and anaplastic than in radiation-induced meningiomas (p < 0.02). In addition, all meningiomas were examined for mutations in the PTEN, TP53, HRAS, KRAS and NRAS genes. Two mutations in the TP53 gene in a sporadic and a radiation-induced tumor were detected. PTEN mutations were observed in 1 anaplastic and 1 radiation-induced meningioma. No structural alterations were seen in the RAS genes. Our data suggest that, while there is a certain overlap in the mutational spectrum, NF2 mutations may not play such a prominent role in the pathogenesis of radiation-induced compared to sporadic meningiomas. Copyright 2001 Wiley-Liss, Inc.
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