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 TSC2 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 - 11827743
AU - Andres C
TI -
Molecular genetics and animal models in autistic disorder.
SO - Brain Res Bull 2002 Jan 1;57(1):109-19
AD - INSERM U316, Tours Cedex, France. andres@med.univ-tours.fr
Autistic disorder is a behavioural syndrome beginning before the age of
3 years and lasting over the whole lifetime. It is characterised by
impaired communication, impaired social interactions, and repetitive
interests and behaviour. The prevalence is about 7/10,000 taking a
restrictive definition and more than 1/500 with a broader definition,
including all the pervasive developmental disorders. The importance of
genetic factors has been highlighted by epidemiological studies showing
that autistic disorder is one of the most genetic neuropsychiatric
diseases. The relative risk of first relatives is about 100-fold higher
than the risk in the normal population and the concordance in
monozygotic twin is about 60%. Different strategies have been applied on
the track of susceptibility genes. The systematic search of linked loci
led to contradictory results, in part due to the heterogeneity of the
clinical definitions, to the differences in the DNA markers, and to the
different methods of analysis used. An oversimplification of the
inferred model is probably also cause of our disappointment. More work
is necessary to give a clearer picture. One region emerges more
frequently: the long arm of chromosome 7. Several candidate genes have
been studied and some gave indications of association: the Reelin gene
and the Wnt2 gene. Cytogenetical abnormalities are frequent at 15q11-13,
the region of the Angelman and Prader-Willi syndrome. Imprinting plays
an important role in this region, no candidate gene has been identified
in autism. Biochemical abnormalities have been found in the serotonin
system. Association and linkage studies gave no consistent results with
some serotonin receptors and in the transporter, although it seems
interesting to go further in the biochemical characterisation of the
serotonin transporter activity, particularly in platelets, easily
accessible. Two monogenic diseases have been associated with autistic
disorder: tuberous sclerosis and fragile X. A better knowledge of the
pathophysiology of these disorders can help to understand autism.
Different other candidate genes have been tested, positive results await
replications in other samples. Animal models have been developed,
generally by knocking out the different candidate genes. Behaviour
studies have mainly focused on anxiety and learning paradigms. Another
group of models results from surgical or toxic lesions of candidate
regions in the brain, in general during development. The tools to
analyse these animals are not yet standardised, and an important effort
needs to be undertaken.
3
UI - 11893726
AU - Albelda SM
TI -
Pulmonary genetics, genomics, and gene therapy: conference summary.
SO - Chest 2002 Mar;121(3 Suppl):105S-110S
AD - Pulmonary, Allergy, and Critical Care Division, University of
Pennsylvania Medical Center, Philadelphia, PA 19104, USA.
Albelda@mail.med.upenn.edu
4
UI - 11893686
AU - Pacheco-Rodriguez G; Kristof AS; Stevens LA; Zhang Y; Crooks D; Moss J
TI -
Giles F. Filley Lecture. Genetics and gene expression in
lymphangioleiomyomatosis.
SO - Chest 2002 Mar;121(3 Suppl):56S-60S
AD - Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood
Institute, National Institutes of Health, Bethesda, MD 20892-1590, USA.
Lymphangioleiomyomatosis (LAM) is a disease of unknown etiology that is
characterized by the proliferation of abnormal smooth muscle cells (LAM
cells) in the lung, which leads to cystic parenchymal destruction and
progressive respiratory failure. Recent evidence suggests that the
proliferative and invasive nature of LAM cells may be due, in part, to
somatic mutations in the TSC2 gene, which has been implicated in the
pathogenesis of tuberous sclerosis complex. Here, we describe the
clinical and molecular characteristics of LAM, as well as the efforts
now under way to understand the genetic and biochemical factors that
lead to progressive pulmonary destruction and, ultimately, to lung
transplantation or death.
5
UI - 11893688
AU - McCormack F; Brody A; Meyer C; Leonard J; Chuck G; Dabora S; Sethuraman
TI -
G; Colby TV; Kwiatkowski DJ; Franz DN
Pulmonary cysts consistent with lymphangioleiomyomatosis are common in
women with tuberous sclerosis: genetic and radiographic analysis.
SO - Chest 2002 Mar;121(3 Suppl):61S
AD - Department of Pediatrics, Division of Pulmonary and Critical Care
Medicine, University of Cincinnati, Cincinnati, OH 45267-0564, USA.
frank.mccormack@uc.edu
6
UI - 11288117
AU - Benit P; Bonnefont JP; Kara Mostefa A; Francannet C; Munnich A; Ray PF
TI -
Denaturing high-performance liquid chromatography (DHPLC)-based prenatal
diagnosis for tuberous sclerosis.
SO - Prenat Diagn 2001 Apr;21(4):279-83
AD - Unite de genetique and U-393, Hopital Necker Enfants Malades, 149 rue de
Sevres, 75743 Paris Cedex 15, France.
Tuberous sclerosis (TSC) is a frequent autosomal-dominant condition
(affecting 1 in 6000 individuals) caused by various mutations in either
the hamartin (TSC1) or the tuberin gene (TSC2). This allelic and
non-allelic heterogeneity makes genetic counseling and prenatal
diagnosis difficult, especially as a significant proportion of TSC cases
are due to de novo mutations. For this reason the identification of the
disease causing mutation is mandatory for accurate counseling, yet
current mutation detection methods such as single-strand conformation
polymorphism (SSCP) or denaturing gradient gel electrophoresis (DGGE)
are labor intensive with limited detection efficiency. Denaturing
high-performance liquid chromatography (DHPLC) is a high-throughput,
semi-automated mutation detection system with a reported mutation
detection rate close to 100% for PCR fragments of up to 800 bp. We used
a recently described DHPLC assay allowing the efficient detection of
mutations in TSC1 to analyze the DNA extracted from a chorion villus
sample in order to perform a prenatal diagnosis for TSC. The fetus was
found not to have inherited the deleterious mutation and the DHPLC
diagnosis was confirmed by haplotype analysis. This represents the first
DHPLC-based prenatal diagnosis of a genetic disease. Copyright 2001 John
Wiley & Sons, Ltd.
7
UI - 9309130
AU - Hino O
TI -
[VHL gene and TSC 2 gene]
SO - Gan To Kagaku Ryoho 1997 Sep;24(11):1386-91
AD - Dept. of Experimental Pathology, Cancer Institute.
Hereditary cancer is rare, but it has served as a useful model in the
understanding of carcinogenesis. A number of cancer genes have been
identified by the study of hereditary human cancers and implicated in
sporadic forms of the some tumors. In this article, I reviewed von
Hippel-Lindau disease (VHL) gene and tuberous sclerosis 2 (TSC 2) gene.
8
UI - 10768593
AU - Iliopoulos O; Eng C
TI -
Genetic and clinical aspects of familial renal neoplasms.
SO - Semin Oncol 2000 Apr;27(2):138-49
AD - Department of Adult Oncology, Dana-Farber Cancer Institute and Harvard
Medical School, Boston, MA 02115, USA.
Genetic studies of families at high risk for developing malignant and
benign renal neoplasms led to cloning of genes whose alteration results
in tumor formation. These genes are either tumor suppressors (VHL, TSC)
or oncogenes (MET). Their significance in understanding oncogenesis
extends far beyond the familial syndromes. The identification of these
genes and the elucidation of their biochemical functions are likely to
facilitate (1) our understanding of the full clinical spectrum of the
corresponding diseases, (2) genetic counseling, and (3) rational design
of effective strategies to prevent and/or treat familial and sporadic
forms of these neoplasms.
9
UI - 11758789
AU - Wataya-Kaneda M; Kaneda Y; Hino O; Adachi H; Hirayama Y; Seyama K; Satou
TI -
T; Yoshikawa K
Cells derived from tuberous sclerosis show a prolonged S phase of the
cell cycle and increased apoptosis.
SO - Arch Dermatol Res 2001 Sep;293(9):460-9
AD - Department of Dermatology, Osaka University Graduate School of Medicine,
Suita City, Osaka, Japan. mkaneda@derma.med.osaka-u.ac.jp
Tuberous sclerosis complex (TSC) is a multisystemic disorder
characterized by systemic hamartomas. Although the disease-determining
genes TSC1 and TSC2 have been isolated, the molecular pathogenesis of
the disease is not understood. We examined cell cycle abnormalities in
skin specimens and cultured cells derived from specific lesions of TSC
patients with confirmed TSC1 or TSC2 mutations. None of the specimens
used in this study showed loss of heterozygosity (LOH). We detected more
cells positive for PCNA and fewer cells positive for MPP2 in the
epidermis of TSC patients than in the epidermis of control patients
without TSC. Incorporation of 5-bromo-2-deoxyuridine (BrdU) was similar
in fibroblasts derived from TSC lesions and in normal human fibroblasts.
These results suggest that the cell cycle of TSC cells shows a prolonged
S phase. Flow cytometric analysis confirmed S phase prolongation in TSC
cells. Many apoptotic cells were detected by a nick end labeling assay
in both skin tissue and cultured fibroblasts derived from specific TSC
lesions. Examination of cyclin levels showed increased nuclear cyclin A
and cytoplasmic cyclin B and decreased nuclear cdc2 levels. We conclude
that suppression of either TSC1 or TSC2 may change cyclin levels,
prolong S phase and induce apoptotic cell death.
10
UI - 11770299
AU - Kimmelman A; Liang BC
TI -
Familial neurogenic tumor syndromes.
SO - Hematol Oncol Clin North Am 2001 Dec;15(6):1073-84
AD - Mount Sinai-NYU Medical Center and Health Systems, Derald H. Ruttenberg
Cancer Center, New York, New York, USA.
Cancer caused more than 0.5 million deaths in the United States in 2000.
This estimate includes patients who have a genetic predisposition to
neoplastic disease, including brain neoplasms. Familial tumor syndromes
are important to identify clinically because family members require high
degrees of monitoring and genetic counseling. Study of these individuals
and families has led to the discovery of genes that are an intrinsic
aspect of cell regulation and will continue to be relevant in defining
mechanisms of neoplastic development in brain and other tissues.
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