Table of Contents
1
UI - 11829138
AU - Sato T; Seyama K; Fujii H; Maruyama H; Setoguchi Y; Iwakami S; Fukuchi
TI -
Y; Hino O
Mutation analysis of the TSC1 and 7TC2 genes in Japanese patients with
pulmonary lymphangioleiomyomatosis.
SO - J Hum Genet 2002;47(1):20-8
AD - Department of Respiratory Medicine Juntendo University, School of
Medicine, Tokyo, Japan.
Pulmonary lymphangioleiomyomatosis (LAM) is a destructive lung disease
characterized by a diffuse hamartomatous proliferation of smooth muscle
cells (LAM cells) in the lungs. Pulmonary LAM can occur as an isolated
form (sporadic LAM) or in association with tuberous sclerosis complex
(TSC) (TSC-LAM), a genetic disorder with autosomal dominant inheritance
with various expressivity resulting from mutations of either the TSC1 or
TSC2 gene. We examined mutations of both TSC genes in 6 Japanese
patients with TSC-LAM and 22 patients with sporadic LAM and identified
six unique and novel mutations. TSC2 germline mutations were detected in
2 (33.3%) of 6 patients with TSC-LAM and TSC1 germline mutation in 1
(4.5%) of 22 sporadic LAM patients. In accordance with the
tumor-suppressor model, loss of heterozygosity (LOH) was detected in LAM
cells from 3 of 4 patients with TSC-LAM and from 4 of 8 patients with
sporadic LAM. Furthermore, an identical LOH or two identical somatic
mutations were demonstrated in LAM cells microdissected from several
tissues, suggesting LAM cells can spread from one lesion to another. Our
results from Japanese patients with LAM confirmed the current concept of
pathogenesis of LAM: TSC-LAM has a germline mutation but sporadic LAM
does not; sporadic LAM is a TSC2 disease with two somatic mutations; and
a variety of TSC mutations causes LAM. However, our study indicates that
a fraction of sporadic LAM can be a TSC1 disease; therefore, both TSC
genes should be examined, even for patients with sporadic LAM.
2
UI - 11836366
AU - Dauwerse JG; Bouman K; van Essen AJ; van Der Hout AH; Kolsters G;
TI -
Breuning MH; Peters DJ
Acrofacial dysostosis in a patient with the TSC2-PKD1 contiguous gene
syndrome.
SO - J Med Genet 2002 Feb;39(2):136-41
3
UI - 11853018
AU - Miloloza A; Kubista M; Rosner M; Hengstschlager M
TI -
Evidence for separable functions of tuberous sclerosis gene products in
mammalian cell cycle regulation.
SO - J Neuropathol Exp Neurol 2002 Feb;61(2):154-63
AD - Department of Obstetrics and Gynecology, University of Vienna, Prenatal
Diagnosis and Therapy, Wahringer Gurtel, Austria.
Tuberous sclerosis is an autosomal dominant disease affecting
approximately 1 in 6,000 individuals. It is caused by mutations in
either TSC1 on chromosome 9q34, which encodes hamartin, or TSC2 on
chromosome 16p13.3, which encodes tuberin. The growths, named
hamartomas, characteristically occur in different organs of patients and
are speculated to result from defects in proliferation control. The
observation that hamartin and tuberin can interact in vivo suggests that
they might function in the same complex. Here we show that hamartin can
affect proliferation control independent of the presence of functional
tuberin and that binding to hamartin is not essential for tuberin to
affect proliferation. Ectopic expression of hamartin negatively
regulates proliferation to a similar extent in tuberin-positive and
tuberin-negative cells; this is accompanied by binding to tuberin and
upregulation of endogenous p27 in tuberin-positive cells and is without
effects on p27 expression in the latter. Our data show for the first
time that TSC proteins possess separable functions. We further
demonstrate that hamartin can deregulate proliferation control by
different mechanisms depending on the presence of tuberin. Besides an
overlap in many features of patients with TSC1 and TSC2 mutations, data
has accumulated that provides evidence for specific clinical
differences. This study provides new insights into the cellular roles of
TSC proteins and initiates a discussion of whether separable functions
of these proteins might be associated with the clinical differences of
TSC1- and TSC2-associated disease.
4
UI - 11603814
AU - Przkora R; Meyer-Puttlitz B; Schmitt O; Berthold F; Nothen M; Krauss J;
TI -
Tonn JC; von Deimling A; Wiestler OD; Pietsch T
Analysis of the TSC2 gene in human medulloblastoma.
SO - Acta Neuropathol (Berl) 2001 Oct;102(4):380-4
AD - Department of Neuropathology, University of Bonn Medical Center,
Germany.
Medulloblastoma (MB) represents the most frequent malignant brain tumor
of childhood. Recent studies have shown that deregulation of
developmental control genes may play an important role in its
pathogenesis. Tuberous sclerosis is associated with hamartomas and
cortical tubers, consisting of both glial and neuronal cellular
components. MBs can also show markers of these lineages, raising the
question of the potential involvement of TSC genes in these malignant
tumors. Here we investigated tuberous sclerosis 2 (TSC2), one of the two
genes responsible for tuberous sclerosis, in sporadic MBs. We analyzed
MBs for allelic losses at the TSC2 locus and for the frequency of a
polymorphism first described in gangliogliomas. Sixty-eight MBs were
examined for this polymorphism located in intron 4, 3 base pairs 5' to
the first coding nucleotide of exon 5. The distribution of the alleles
was significantly different in MBs as compared to 208 control samples,
(P=0.0017, Chi-square test). In MBs the frequency of the rare allele
(A2) was 0.184 (18.4%), whereas in the control group it occurred in a
frequency of 8.7%. Microsatellite analysis of the TSC2 region in 50
tumors did not identify allelic losses. TSC2 mRNA transcript was
detectable via reverse transcription-PCR in all tumors as well as in
normal cerebellum. Northern blot analysis of an MB cell line homozygous
for the rare allele of the polymorphism and two other cell lines
homozygous for the frequent allele revealed normal splicing patterns and
normal expression levels of the TSC2 transcript. These findings may
indicate that the presence of the rare TSC2 allele is associated with a
predisposition for the development of MBs.
5
UI - 11686512
AU - Hengstschlager M
TI -
Tuberous sclerosis complex genes: from flies to human genetics.
SO - Arch Dermatol Res 2001 Aug;293(8):383-6
AD - Obstetrics and Gynecology, University of Vienna, Prenatal Diagnosis and
Therapy, Wahringer Gurtel, Austria.
markus.hengstschlaeger@akh-wien.ac.at
6
UI - 11688396
AU - Roccatello D; Obert R; Sena GM; Longa L; Rossi D; Grosso E; Cavallo R;
TI -
Sena LM; Giachino O; Migone N
Treatment of the pulmonary involvement in the patient with tuberous
sclerosis complex.
SO - Contrib Nephrol 2001;(136):292-8
AD - Centro Multidisciplinare di Immunopatologia e Documentazione su Malattie
Rare (CMID), Presidi Ospedalieri ASL4, sede Osp. Luigi Einaudi, Torino,
Italia. cmid@iol.it
7
UI - 11847020
AU - Blanchard JM
TI -
[Molecular mechanisms of oncogenic transformation: what's new?]
SO - Bull Cancer 2002 Jan;89(1):9-16
AD - Institut de genetique moleculaire, CNRS, UMR5535, IFR24, 1919, route de
Mende, 34293 Montpellier Cedex 5.
During the past two years, new molecular targets have been discovered
which link cell cycle, cell proliferation and cellular growth. It has
become more and more evident that whereas gain-of-function mutations in
specific genes can lead to cancer, genomic instability plays also an
important role in tumour progression. With examples taken from the
recent literature, we describe in this short review crucial findings on
the molecular mechanisms controlling cell cycle and proliferation. We
illustrate how specific combinations of proto-oncogenes alterations can
result in tissue-specific tumours. Finally, impairment of the
interactions of a cancer cell with its surrounding neighbours is also
shown to participate in the progression toward aggressive phenotypes.
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