Table of Contents
1
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.
2
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.
3
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.
4
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.
5
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. gevans@central.cmht.nwest.nhs.uk
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.
6
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.
7
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. mlakkis@curagen.com
8
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.
9
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. rx@netvalley.it
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.
10
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.
11
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.
12
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. degoede@alkg.azr.nl
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.
13
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.
14
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.
15
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.
16
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
17
UI - 97207921
AU - Crisci C
TI -
Tribute--and a clinical lesson in bioethics and quality of life.
SO - J Med Ethics 1997 Feb;23(1):18
AD - Salvatore Maugeri Foundation, Campoli, Italy.
18
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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