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.

TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling

https://www.cell.com/molecular-cell/pdf/S1097-2765(02)00568-3.pdf

Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway.

From the Department of Neurology (P.B.C.) and the Division of Medical Genetics (K.L.N.), University of Pennsylvania Medical Center; and the Department of Medical Oncology, Fox Chase Cancer Center (E.P.H.) — both in Philadelphia. Address reprint requests to Dr. Crino at the Department of Neurology, 3 West Gates Bldg., 3400 Spruce St., University of Pennsylvania Medical Center, Philadelphia, PA 19104, or at peter.crino@ uphs.upenn.edu.

The tuberous sclerosis complex.

https://www.pedneur.com/article/S0887-8994%2813%2900490-6/pdf

Tuberous Sclerosis Complex Diagnostic Criteria Update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference

Tuberous sclerosis (TSC) is a relatively common hamartoma syndrome caused by mutations in either of two genes, TSC1 and TSC2. Here we report comprehensive mutation analysis in 224 index patients with TSC and correlate mutation findings with clinical features. Denaturing high-performance liquid chromatography, long-range polymerase chain reaction (PCR), and quantitative PCR were used for mutation detection. Mutations were identified in 186 (83%) of 224 of cases, comprising 138 small TSC2 mutations, 20 large TSC2 mutations, and 28 small TSC1 mutations. A standardized clinical assessment instrument covering 16 TSC manifestations was used. Sporadic patients with TSC1 mutations had, on average, milder disease in comparison with patients with TSC2 mutations, despite being of similar age. They had a lower frequency of seizures and moderate-to-severe mental retardation, fewer subependymal nodules and cortical tubers, less-severe kidney involvement, no retinal hamartomas, and less-severe facial angiofibroma. Patients in whom no mutation was found also had disease that was milder, on average, than that in patients with TSC2 mutations and was somewhat distinct from patients with TSC1 mutations. Although there was overlap in the spectrum of many clinical features of patients with TSC1 versus TSC2 mutations, some features (grade 2–4 kidney cysts or angiomyolipomas, forehead plaques, retinal hamartomas, and liver angiomyolipomas) were very rare or not seen at all in TSC1 patients. Thus both germline and somatic mutations appear to be less common in TSC1 than in TSC2. The reduced severity of disease in patients without defined mutations suggests that many of these patients are mosaic for a TSC2 mutation and/or have TSC because of mutations in an as-yet-unidentified locus with a relatively mild clinical phenotype.

Mutational Analysis in a Cohort of 224 Tuberous Sclerosis Patients Indicates Increased Severity of TSC2, Compared with TSC1, Disease in Multiple Organs

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-γ (IFN-γ) 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-γ. A χ2 analysis was used to examine the association between IFN-γ 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 χ2 analysis and TDT suggested an association between IFN-γ 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-γ allele 2 was 56%; in the group with KAML absent, the frequency of IFN-γ allele 2 was significantly higher, at 78% (P=.02, by χ2 analysis). The family-based TDT analysis gave similar results, with a TDT statistic (TDT χ2=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.

Association between a High-Expressing Interferon-γ Allele and a Lower Frequency of Kidney Angiomyolipomas in TSC2 Patients

Editor—Tuberous sclerosis complex (TSC) is an autosomal dominant familial tumour syndrome (OMIM 19110 and 191092,http://www.ncbi.nlm.nih.gov/omim/). It is characterised by the development of benign tumours (hamartomas), most frequently in the brain, skin, and kidneys. It is highly penetrant although with variable expression. In the majority of cases, there is significant neurological morbidity as seizures and mental retardation are common. Two causative genes for TSC have been identified, TSC1 and TSC2 .1 2 Reports on mutation analysis in TSC show over 300 unique mutations with a varied spectrum. In cases where a mutation can be identified, approximately 80% have a TSC2 mutation and 20% have a TSC1 mutation. All reported TSC1 mutations are small point mutations causing nonsense changes or splice site changes, or small insertions/deletions causing frameshift mutations. In TSC2 , the majority (approximately 85%) are small mutations (point mutations causing splice, nonsense, or missense changes, or small insertion/deletions). The remaining 15% of reported TSC2 mutations are large deletions (ranging in size from 1 kb to 1 Mb). Other large rearrangements (inversions, insertions, translocations) have also been reported, but these account for <1% of reported TSC2 mutations (http://zk.bwh.harvard.edu/ts).1-12 

Because TSC is often a devastating disorder with a high frequency of sporadic cases, there is significant demand for genetic testing. Much progress has been made in detecting small mutations in TSC1 and TSC2 using a variety of techniques, such as heteroduplex (HD) analysis, single stranded conformation analysis (SSCP), protein truncation test (PTT), denaturing gradient gel electrophoresis (DGGE), and most recently denaturing high performance liquid chromatography (DHPLC).3 5 6 8-11 13 14 Although it is important for improving the overall mutation detection rate in TSC patients, there has been less effort to develop new techniques for identifying large deletions in TSC2, which make up a small …

https://jmg.bmj.com/content/jmedgenet/37/11/877.full.pdf

Andres Nieto

Papers

Mutational Analysis in a Cohort of 224 Tuberous Sclerosis Patients Indicates Increased Severity of TSC2, Compared with TSC1, Disease in Multiple Organs

Association between a High-Expressing Interferon-γ Allele and a Lower Frequency of Kidney Angiomyolipomas in TSC2 Patients

Characterisation of six large deletions in TSC2 identified using long range PCR suggests diverse mechanisms including Alu mediated recombination