National Cancer Institute®
Last Modified: October 1, 2002
UI - 12111193
AU - Langkau N; Martin N; Brandt R; Zugge K; Quast S; Wiegele G; Jauch A;
TI - Rehm M; Kuhl A; Mack-Vetter M; Zimmerhackl LB; Janssen B TSC1 and TSC2 mutations in tuberous sclerosis, the associated phenotypes and a model to explain observed TSC1/ TSC2 frequency ratios.
SO - Eur J Pediatr 2002 Jul;161(7):393-402
AD - Institute of Human Genetics, University of Heidelberg, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.
Tuberous sclerosis (TSC) is a multisystem disease with manifestations in the central nervous system, skin, kidneys, heart, and other visceral organs. The development of TSC is associated with alterations within a gene on chromosome 9q34 ( TSC1) and a gene on chromosome 16p13 ( TSC2). Most de-novo patients show a mutation in TSC2, whereas only 50% of all familial cases can be related to TSC2 mutations. In the present study, 68 unrelated patients with confirmed clinical manifestations of TSC were tested for mutations in the TSC1 and TSC2 genes. In total, we studied 59 sporadic cases and 9 familial cases, including one large family with TSC2 linkage. Two pathogenic mutations were found in TSC1. The TSC2 gene analysis revealed 29 mutations, including 3 large deletions and 26 small mutations, 15 of them truncating. CONCLUSION: the TSC1-TSC2 mutation ratio in our group of patients differs significantly from the 1:1 ratio previously predicted on the basis of linkage studies. There is an obvious paradox between the observed frequency of TSC1 mutations in familial cases and sporadic cases. An interestingly mild phenotype, observed in one of our TSC1 mutation carriers, led to the elaboration of a model that provides a plausible explanation for this paradox. We propose the presence of a very mildly affected patient group with TSC1-related disease who are not regularly detected by clinical diagnosis.
UI - 12172553
AU - Inoki K; Li Y; Zhu T; Wu J; Guan KL
TI - TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling.
SO - Nat Cell Biol 2002 Sep;4(9):648-57
AD - Department of Biological Chemistry, University of Michigan Medical School, 1301 Catherine Road, Ann Arbor, MI 48109, USA. email@example.com
Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by the formation of hamartomas in a wide range of human tissues. Mutation in either the TSC1 or TSC2 tumour suppressor gene is responsible for both the familial and sporadic forms of this disease. TSC1 and TSC2 proteins form a physical and functional complex in vivo. Here, we show that TSC1-TSC2 inhibits the p70 ribosomal protein S6 kinase 1 (an activator of translation) and activates the eukaryotic initiation factor 4E binding protein 1 (4E-BP1, an inhibitor of translational initiation). These functions of TSC1-TSC2 are mediated by inhibition of the mammalian target of rapamycin (mTOR). Furthermore, TSC2 is directly phosphorylated by Akt, which is involved in stimulating cell growth and is activated by growth stimulating signals, such as insulin. TSC2 is inactivated by Akt-dependent phosphorylation, which destabilizes TSC2 and disrupts its interaction with TSC1. Our data indicate a molecular mechanism for TSC2 in insulin signalling, tumour suppressor functions and in the inhibition of cell growth.
UI - 8944308
AU - Kerfoot C; Wienecke R; Menchine M; Emelin J; Maize JC Jr; Welsh CT;
TI - Norman MG; DeClue JE; Vinters HV Localization of tuberous sclerosis 2 mRNA and its protein product tuberin in normal human brain and in cerebral lesions of patients with tuberous sclerosis.
SO - Brain Pathol 1996 Oct;6(4):367-75
AD - Department of Pathology and Laboratory Medicine (Neuropathology), UCLA Medical Center 90095, USA. firstname.lastname@example.org
Tuberous sclerosis (TSC), an autosomal dominant disorder, is characterized by malformations, hamartomas and tumors in various organs including the brain. TSC is genetically linked to two loci: TSC1 on chromosome 9q34 and TSC2 on 16p13.3. TSC2 has been cloned, sequenced and encodes a protein (tuberin) which functions as a tumor suppressor. We have analyzed the distribution of TSC2 mRNA and tuberin in the brains of TSC patients and non-affected individuals using both autopsy and biopsy material. High levels of transcript and protein expression were observed in choroid plexus epithelium, ependymal cells, most brainstem and spinal cord motor neurons, Purkinje cells and the external granule cell layer of the cerebellum in both TSC and control cases. Individual balloon cells from TSC patients showed very faint expression while other glia showed no expression of either transcript or tuberin. Neocortical and hippocampal neurons expressed high levels of TSC2 transcript, but only modest levels of tuberin. The internal granule cell layer of the cerebellum expressed abundant transcript but low levels of tuberin. These observations suggest either that tuberin expression is controlled at the level of both transcription and translation or the antibody and in-situ hybridization recognize different splice variants of the TSC2 gene. In TSC patients, dysmorphic cytomegalic neurons expressed high levels of tuberin and transcript, particularly when in an 'ectopic' location. Individual cells within subependymal giant cell astrocytomas (SEGAs) and hamartomas from TSC patients expressed moderate to high levels of TSC2 transcript and tuberin. While the TSC2 transcript is widely expressed primarily within neurons, tuberin is demonstrable primarily within dysplastic/cytomegalic cells of the cortex and subependymal hamartomas/SEGAs. CNS expression of tuberin is unique in that primarily non-dividing cells express it in this location, whereas extra-CNS expression of tuberin is mainly found in actively proliferating cell types such as epithelium.
UI - 12111364
AU - Rickert CH; Paulus W
TI - No chromosomal imbalances detected by comparative genomic hybridisation in subependymal giant cell astrocytomas.
SO - Acta Neuropathol (Berl) 2002 Aug;104(2):206-8
AD - Institute of Neuropathology, University Hospital Munster, Domagkstr. 19, 48149 Munster, Germany. email@example.com
Eight subependymal giant cell astrocytomas (SEGA) were studied by comparative genomic hybridisation. These consisted of six primary SEGA and two recurrences gained from six paediatric patients suffering from tuberous sclerosis complex (TSC). No DNA copy number changes were found in any of the tumours. Our data show that chromosomal imbalances are absent or very rare events in primary and recurrent SEGA and that no aberrations were detected at the sites of the TSC-associated genes, thus indicating that mutational inactivation of one of the TSC genes is not followed by genomic instability.
UI - 12192641
AU - Dabora SL; Roberts P; Nieto A; Perez R; Jozwiak S; Franz D; Bissler J;
TI - Thiele EA; Sims K; Kwiatkowski DJ Association between a high-expressing interferon-gamma allele and a lower frequency of kidney angiomyolipomas in TSC2 patients.
SO - Am J Hum Genet 2002 Oct;71(4):750-8
AD - Division of Hematology, Brigham and Women Hospital, Boston, MA 02115,USA. firstname.lastname@example.org
Tuberous sclerosis complex (TSC) is a familial hamartoma syndrome in which renal involvement is common and, at times, life threatening. We have investigated the potential effect of a non-TSC gene on renal disease in a cohort of 172 TSC patients with TSC2 mutations. Patients were genotyped for an interferon-gamma (IFN-gamma) microsatellite polymorphism, within intron 1, for which one common allele (allele 2, with 12 CA repeats) has been shown to have a higher expression of IFN-gamma. A chi(2) analysis was used to examine the association between IFN-gamma allele 2 and the development of kidney angiomyolipomas (KAMLs) in this TSC2 cohort. Because of the age-dependent development of KAMLs in TSC, we initially focused on the 127 patients who were >5 years old. Additional subgroup analyses were done to investigate the influence of age and gender. The transmission/disequilibrium test (TDT) was also performed in a subset of this cohort (46 probands) for whom parent and/or sibling samples were available for analysis. Both chi(2) analysis and TDT suggested an association between IFN-gamma allele 2 and the absence of KAMLs in patients who have known TSC2 mutations. Among the 127 patients who were >5 years old, KAMLs were present in 95 (75%) and were absent in 32 (25%). In the group with KAML present, the frequency of IFN-gamma allele 2 was 56%; in the group with KAML absent, the frequency of IFN-gamma allele 2 was significantly higher, at 78% (P=.02, by chi(2) analysis). The family-based TDT analysis gave similar results, with a TDT statistic (TDT chi2=5.45) corresponding to a P value of.02. Subgroup analyses show that both age and gender may influence the impact of this association. Although these results should be replicated in other populations with TSC, the present study suggests that modifier genes play a role in the variable expression of TSC and also suggests a potential therapy for KAMLs in patients with TSC.
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