Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the widespread development of distinctive tumors termed hamartomas. TSC-determining loci have been mapped to chromosomes 9q34 (TSC1) and 16p13 (TSC2). The TSC1 gene was identified from a 900-kilobase region containing at least 30 genes. The 8.6-kilobase TSC1 transcript is widely expressed and encodes a protein of 130 kilodaltons (hamartin) that has homology to a putative yeast protein of unknown function. Thirty-two distinct mutations were identified in TSC1, 30 of which were truncating, and a single mutation (2105delAAAG) was seen in six apparently unrelated patients. In one of these six, a somatic mutation in the wild-type allele was found in a TSC-associated renal carcinoma, which suggests that hamartin acts as a tumor suppressor.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterised by the development of hamartomas in multiple organs and tissues. TSC is caused by mutations in either the TSC1 or TSC2 gene. We searched for mutations in both genes in a cohort of 490 patients diagnosed with or suspected of having TSC using a combination of denaturing gradient gel electrophoresis, single-strand conformational polymorphism, direct sequencing, fluorescent in situ hybridisation and Southern blotting. We identified pathogenic mutations in 362 patients, a mutation detection rate of 74%. Of these 362 patients, 276 had a definite clinical diagnosis of TSC and in these patients 235 mutations were identified, a mutation detection rate of 85%. The ratio of TSC2:TSC1 mutations was 3.4:1. In our cohort, both TSC1 mutations and mutations in familial TSC2 cases were associated with phenotypes less severe than de novo TSC2 mutations. Interestingly, consistent with other studies, the phenotypes of the patients in which no mutation was identified were, overall, less severe than those of patients with either a known TSC1 or TSC2 mutation.

Tuberous sclerosis (TSC) is an autosomal dominant disorder caused by a mutation in either the TSC1 or TSC2 tumour suppressor gene. The disease is characterized by a broad phenotypic spectrum that can include seizures, mental retardation, renal dysfunction and dermatological abnormalities. TSC2 encodes tuberin, a putative GTPase activating protein for rap1 and rab5. The TSC1 gene was recently identified and codes for hamartin, a novel protein with no significant homology to tuberin or any other known vertebrate protein. Here, we show that hamartin and tuberin associate physically in vivo and that the interaction is mediated by predicted coiled-coil domains. Our data suggest that hamartin and tuberin function in the same complex rather than in separate pathways.

Normal cellular functions of hamartin and tuberin, encoded by the TSC1 and TSC2 tumor suppressor genes, are closely related to their direct interactions. However, the regulation of the hamartin-tuberin complex in the context of the physiologic role as tumor suppressor genes has not been documented. Here we show that insulin or insulin growth factor (IGF) 1 stimulates phosphorylation of tuberin, which is inhibited by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 but not by the mitogen-activated protein kinase inhibitor PD98059. Expression of constitutively active PI3K or active Akt, including Akt1 and Akt2, induces tuberin phosphorylation. We further demonstrate that Akt/PKB associates with hamartin-tuberin complexes, promoting phosphorylation of tuberin and increased degradation of hamartin-tuberin complexes. The ability to form complexes, however, is not blocked. Akt also inhibits tuberin-mediated degradation of p27 kip1 , thereby promoting CDK2 activity and cellular proliferation. Our results indicate that tuberin is a direct physiological substrate of Akt and that phosphorylation of tuberin by PI3K/Akt is a major mechanism controlling hamartin-tuberin function.Tuberous sclerosis complex (TSC) 1 is an autosomal dominant disorder and is characterized by the presence of hamartomas in many organs such as brain, skin, heart, lung, and kidney (1). It is caused by mutation of either the TSC1 or TSC2 tumor suppressor gene (2-5). TSC1 encodes a protein, hamartin, containing two coiled-coil domains that have been shown to mediate binding to hamartin (6). The TSC2 gene codes for tuberin, which contains a small region of homology to the rap1GTPase-activating protein, rap1GAP (7). These two proteins function within the same pathway(s) regulating cell cycle, cell growth, adhesion, and vesicular trafficking (4,5). However, the regulation of hamartin and tuberin in the context of physiologic role as tumor suppressor genes has not been documented.Among the various properties of these two proteins, the ability to interact and to form stable complex has been the most consistent finding. This led to the hypothesis that hamartin and tuberin function as a complex and that factors regulating their interaction are important in understanding physiologic roles. There is evidence to suggest that phosphorylation of tuberin may be a major mechanism of regulation of the hamartin-tuberin complex (8, 9). However, the kinases that are responsible for phosphorylation of this complex are currently unknown. Recent Drosophila genetic studies showed that dTsc1 and dTsc2 play an important role in the insulin/dPI3K/ dakt signal transduction pathway by demonstrating that reduced cell size and cell proliferation caused by either mutations in dINR and dakt or by overexpression of dPTEN are overridden by homozygous mutants of dTsc1 or dTsc2. This implies that dTsc1 and dTsc2 are either direct downstream targets of dakt or on a parallel pathway of the insulin cascade downstream from dakt (10 -13). Akt, also known as protein kinase B (PKB),...

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric Neurology published articles outlining updated diagnostic criteria and recommendations for surveillance and management of disease manifestations. Advances in knowledge and approvals of new therapies necessitated a revision of those criteria and recommendations. Methods: Chairs and working group cochairs from the 2012 International TSC Consensus Group were invited to meet face-to-face over two days at the 2018 World TSC Conference on July 25 and 26 in Dallas, TX, USA. Before the meeting, working group cochairs worked with group members via e-mail and telephone to (1) review TSC literature since the 2013 publication, (2) confirm or amend prior recommendations, and (3) provide new recommendations as required. Results: Only two changes were made to clinical diagnostic criteria reported in 2013: "multiple cortical tubers and/or radial migration lines" replaced the more general term "cortical dysplasias," and sclerotic bone lesions were reinstated as a minor criterion. Genetic diagnostic criteria were reaffirmed, including highlighting recent findings that some individuals with TSC are genetically mosaic for variants in TSC1 or TSC2. Changes to surveillance and management criteria largely reflected increased emphasis on early screening for electroencephalographic abnormalities, enhanced surveillance and management of TSCassociated neuropsychiatric disorders, and new medication approvals. Conclusions: Updated TSC diagnostic criteria and surveillance and management recommendations presented here should provide an improved framework for optimal care of those living with TSC and their families.

Major genes which cause tuberous sclerosis (TSC) and autosomal dominant polycystic kidney disease (ADPKD), known as TSC2 and PKD1 respectively, lie immediately adjacent to each other on chromosome 16p. Renal cysts are often found in TSC, but a specific renal phenotype, distinguished by the severity and infantile presentation of the cystic changes, is seen in a small proportion of cases. We have identified large deletions disrupting TSC2 and PKD1 in each of six such cases studied. Analysis of the deletions indicates that they inactivate PKD1, in contrast to the mutations reported in ADPKD patients, where in each case abnormal transcripts have been detected.

Uveal melanoma is a lethal cancer with a strong propensity to metastasize. Limited therapeutic options are available once the disease has disseminated. A strong predictor for metastasis is the loss of chromosome 3. Inactivating mutations in BAP1 encoding the BRCA1-associated protein 1 and located on chromosome 3p21.1, have been described in uveal melanoma and other types of cancer. In this study, we determined the prevalence of somatic BAP1 mutations and examined whether these mutations correlate with the functional expression of BAP1 in uveal melanoma tissue and with other clinical, histopathological and chromosomal parameters. We screened a cohort of 74 uveal melanomas for BAP1 mutations, using different deep sequencing methods. The frequency of BAP1 mutations in our study group was 47%. The expression of BAP1 protein was studied using immunohistochemistry. BAP1 staining was absent in 43% of the cases. BAP1 mutation status was strongly associated with BAP1 protein expression (Po0.001), loss of chromosome 3 (Po0.001), and other aggressive prognostic factors. Patients with a BAP1 mutation and absent BAP1 expression had an almost eightfold higher chance of developing metastases compared with those without these changes (P ¼ 0.002). We found a strong correlation between the immunohistochemical and sequencing data and therefore propose that, immunohistochemical screening for BAP1 should become routine in the histopathological work-up of uveal melanoma. Furthermore, our analysis indicates that loss of BAP1 may be particularly involved in the progression of uveal melanoma to an aggressive, metastatic phenotype.

Our systematic analysis confirms proposed relationships between tuber load, epilepsy and cognitive function in tuberous sclerosis complex (TSC), but also indicates that tuber/brain proportion is a better predictor of cognitive function than tuber number and that age at seizure onset is the only independent determinant of cognitive function. Seizure control should be the principal neurointervention in patients with TSC.