Table of Contents
1
UI - 11803526
AU - Bellivier F; Laplanche JL; Fournier G; Wolkenstein P
TI -
Serotonin transporter gene polymorphism and psychiatric disorders in NF1
patients.
SO - Am J Med Genet 2001 Dec 8;105(8):758-60
AD - Service de Psychiatrie Adulte, Hopital Henri Mondor et Albert Chenevier,
Assistance Publique-Hopitaux de Paris, Creteil, France.
bellivier@im3.inserm.fr
Neurofibromatosis type 1 (NF1) is an autosomal-dominant genetic disease
characterized by a broad clinical expression. Comorbid affective
disorders, anxiety disorders, and suicide are frequently observed during
NF1. The promoter marker (5-HTTLPR) of the serotonin transporter gene
(5-HTT) has been shown to be associated with major affective disorders,
anxiety-related trait, and more recently with suicidal behavior. This
gene is adjacent to the NF1 gene, raising the question of the
implication of the 5-HTT gene in the psychiatric comorbidity during NF1.
Eighty-eight patients with NF1 and 184 screened controls were typed for
the 5-HTTLPR. No deviation from the Hardy-Weinberg equilibrium in
patients was observed. In addition, allele and genotype frequencies were
similar in the two groups. Our data do not support the implication of
the 5-HTT gene in the psychiatric comorbidities of NF1. Copyright 2001
Wiley-Liss, Inc.
2
UI - 11836375
AU - Barbi G; Rossier E; Vossbeck S; Hummler H; Lang D; Flock F; Terinde R;
TI -
Wirth J; Vogel W; Kehrer-Sawatzki H
Constitutional de novo interstitial deletion of 8 Mb on chromosome
22q12.1-12.3 encompassing the neurofibromatosis type 2 (NF2) locus in a
dysmorphic girl with severe malformations.
SO - J Med Genet 2002 Feb;39(2):E6
AD - Abteilung Humangenetik, Universitatsklinikum Ulm, D-89073 Ulm, Germany.
3
UI - 11748857
AU - Fang LJ; Vidaud D; Vidaud M; Thirion JP
TI -
Identification and characterization of four novel large deletions in the
human neurofibromatosis type 1 (NF1) gene.
SO - Hum Mutat 2001 Dec;18(6):549-50
AD - Departement de Microbiologie et d'Infectiologie, Faculte de Medecine,
Universite de Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada.
We studied 20 unrelated NF1 patients by Southern blots with seven cDNA
probes and loss of heterozygosity (LOH) analysis with four intragenic
microsatellites (IVS26-2.3, IVS27AC28.4, IVS27AC33.1, and IVS38GT53.0).
Four novel large deletions (178, 184, 236, and 237) have been identified
and characterized. The breakpoint of deletion 178 was located in between
exons 23-2 and 27b and the sequences downstream of the breakpoint were
deleted. For deletion 184, the breakpoint was in between exons 27b and
29, and the region upstream of the breakpoint was deleted. With deletion
236, the breakpoint was in between exons 14 and 18 and the region
downstream of the breakpoint was deleted. The breakpoint of deletion 237
was in between exons 38 and 45 and the sequences upstream of the
breakpoint were deleted. These deletions were distributed randomly
across the NF1 gene and no deletion hot spot was found. Our study
suggests that the combination of analyses of loss of heterozygosity,
southern blotting and southern blot densitometry can be used as a
powerful method to detect large deletions, especially when family record
is not available or the patient is a sporadic case. Copyright 2001
Wiley-Liss, Inc.
4
UI - 11838793
AU - Baser ME; Makariou EV; Parry DM
TI -
Predictors of vestibular schwannoma growth in patients with
neurofibromatosis Type 2.
SO - J Neurosurg 2002 Feb;96(2):217-22
AD - Department of Radiology, Georgetown University Medical Center,
Washington, DC, USA. baser@earthlink.net
OBJECT: The results of two longitudinal studies of growth rates of
vestibular schwannomas (VSs) in patients with neurofibromatosis Type 2
(NF2) differ as to whether VS growth rates decrease or increase with
increasing patient age. The authors undertook this study to assess the
relationship between VS growth rates and patient age and type of
constitutional NF2 mutation; they also examined variability in VS growth
rates among multiple patients in families with NF2. METHODS:
Gadolinium-enhanced magnetic resonance images obtained in 18 patients
with inherited NF2 from 11 unrelated families were retrospectively
analyzed. The patients had been observed for a median of 4 years.
Volumes of the VSs were measured using a two-component box model
(intrameatal and extrameatal parts measured separately). Single-strand
conformation polymorphism analysis and Southern blot analysis were used
to identify constitutional NF2 mutations. Growth rates of the VSs were
highly variable, but tended to decrease with increasing patient age both
at onset of signs or symptoms of NF2 (r2 = 0.35, p = 0.026) and at
diagnosis (r2 = 0.33, p = 0.012). The VS growth rates did not vary
significantly with the type of constitutional NF2 mutation or the number
of non-VS cerebral or spinal tumors. The VS growth rates were highly
variable within families and did not correspond to clinical indices of
NF2 disease severity, such as patient age at symptom onset and the
number of non-VS cerebral and spinal tumors. CONCLUSIONS: The growth
rates of VSs in patients with NF2 are highly variable, but tend to
decrease with increasing patient age. Clinical treatment of multiple
patients in families with NF2 cannot be based on the expectations of
similar VS growth rates, even when other clinical aspects of disease
severity are similar.
5
UI - 11838794
AU - Mautner VF; Baser ME; Thakkar SD; Feigen UM; Friedman JM; Kluwe L
TI -
Vestibular schwannoma growth in patients with neurofibromatosis Type 2:
a longitudinal study.
SO - J Neurosurg 2002 Feb;96(2):223-8
AD - Department of Neurology, Klinikum Nord Ochsenzoll, Hamburg, Germany.
OBJECT: The factors that determine the growth rates of vestibular
schwannomas (VSs) in patients with neurofibromatosis Type 2 (NF2) are
unknown. The authors undertook this study to determine if clinical
factors or type of constitutional NF2 mutation were associated with VS
growth rates in cases of NF2. METHODS: The authors reviewed serial
gadolinium-enhanced magnetic resonance (MR) images of the head and full
spine of 37 patients with sporadic NF2 who had been observed over
periods ranging from 0.2 to 8 years (median 3.9 years) at a specialized
referral clinic for NF2. A box model was used to calculate VS volumes so
that tumor growth rates could be estimated. Temperature-gradient gel
electrophoresis was used to screen for constitutional NF2 mutations. The
VS growth rates tended to decrease with increasing patient age at onset
of signs or symptoms (r2 = 0.23, p = 0.003) and at the time the baseline
gadolinium-enhanced MR image was obtained (r2 = 0.38, p < 0.001). The
authors did not find significant associations between VS growth rates
and the number of non-VS cerebral or spinal tumors or different types of
constitutional NF2 mutations. CONCLUSIONS: There is considerable
variability in growth rates of VSs in patients with NF2, but they tend
to be higher in patients who are younger at onset of signs or symptoms.
6
UI - 11826364
AU - Sinkre P; Perry A; Cai D; Raghavan R; Watson M; Wilson K; Barton Rogers
TI -
B
Deletion of the NF2 region in both meningioma and juxtaposed
meningioangiomatosis: case report supporting a neoplastic relationship.
SO - Pediatr Dev Pathol 2001 Nov-Dec;4(6):568-72
AD - Department of Pathology, University of Texas Southwestern Medical
Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
We report a case of juxtaposed atypical meningioma and
meningioangiomatosis (MA) in an 8-year-old boy with no clinical stigmata
or family history of neurofibromatosis. We studied the proliferative
activity and genetic changes in the two lesions in an attempt to define
their biologic and pathogenetic relationships. The MIB-1 index was 11%
in the meningioma and <1% in the MA, indicating increased proliferative
activity in the meningioma. Fluorescence in situ hybridization was done
for two chromosomal regions commonly deleted in meningiomas. There was
loss of the neurofibromatosis 2 locus (22q12) in both the meningioma and
MA. Conversely, the region of 1p32 was not deleted. Our results indicate
that both the meningioma and MA arose from the same clonal process, with
the meningioma probably undergoing additional, but undefined, genetic
alterations that confer upon it a more proliferative potential. This
loss of 22q12 in the MA raises doubt about the presumed hamartomatous
nature of MA.
7
UI - 11857752
AU - Kluwe L; Friedrich RE; Korf B; Fahsold R; Mautner VF
TI -
NF1 mutations in neurofibromatosis 1 patients with plexiform
neurofibromas.
SO - Hum Mutat 2002 Mar;19(3):309
AD - Laboratory for Brain Tumor Biology, Department of Neurosurgery,
University Hospital Hamburg-Eppendorf, Germany. kluwe@uke.uni-hamburg.de
Neurofibromatosis 1 (NF1) is an autosomal dominant disorder caused by
genetic alterations of the NF1 gene on 17q11.2. About 30% of NF1
patients develop plexiform neurofibromas (PNFs), which often cause
severe clinical deficits. To determine whether there is a certain
genotype underlying PNFs or subtypes of PNFs, we screened 42 NF1
patients from 41 families with PNFs for mutations in the NF1 gene. In 33
out of the 41 (80%) unrelated patients NF1 mutations were found, 24 are
novel while the other 9 have been described in previous studies. The 33
mutations included 23 nonsense and frameshift, six splice and four
missense mutations. The tumors in these patients had various sizes and
features/growth characteristics. No correlation was found between the
type or location of the NF1 mutations and size, location or feature of
the PNFs, suggesting that many types of NF1 mutations can lead to
development of PNFs. Copyright 2002 Wiley-Liss, Inc.
8
UI - 11751683
AU - Gutmann DH; Wu YL; Hedrick NM; Zhu Y; Guha A; Parada LF
TI -
Heterozygosity for the neurofibromatosis 1 (NF1) tumor suppressor
results in abnormalities in cell attachment, spreading and motility in
astrocytes.
SO - Hum Mol Genet 2001 Dec 15;10(26):3009-16
AD - Department of Neurology, Washington University School of Medicine, Box
8111, 660 South Euclid Avenue, St Louis, MO 63110, USA.
gutmannd@neuro.wustl.edu
Individuals with the neurofibromatosis 1 (NF1) tumor predisposition
syndrome develop low-grade pilocytic astrocytomas at an increased
frequency. Previously, we demonstrated that astrocytes from mice
heterozygous for a targeted mutation in the Nf1 gene (Nf1+/- astrocytes)
exhibit a cell autonomous growth advantage associated with increased RAS
pathway activation. In this report, we extend our initial
characterization of the effect of reduced Nf1 gene expression on
astrocyte function by demonstrating that Nf1+/- astrocytes exhibit
decreased cell attachment, actin cytoskeletal abnormalities during the
initial phases of cell spreading, and increased cell motility. Whereas
these cytoskeletal abnormalities were also observed in Nf1-/-
astrocytes, astrocytes expressing a constitutively active RAS molecule
showed increased cell motility and abnormal actin cytoskeleton
organization during cell spreading, but exhibited normal cell
attachment. Based on ongoing gene expression profiling experiments on
human astrocytoma tumors, we demonstrate increased expression of two
proteins implicated in cell attachment, spreading and motility (GAP43
and T-cadherin) in Nf1+/- and Nf1-/- astrocytes. These results support
the emerging notion that tumor suppressor gene heterozygosity results in
abnormalities in cell function that may contribute to the pathogenesis
of non-tumor phenotypes in NF1.
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