Materiały źródłowe

• #1 Tuberous Sclerosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK538492/

  Tuberous sclerosis complex (TSC) is a genetic disorder inherited in an autosomal dominant fashion and is characterized by an increased predisposition to hamartoma formation. TSC results from mutations in the genes TSC1 and TSC2 and is known for causing neurological disorders, including epilepsy and intellectual disability. […] Tuberous sclerosis involves mutations in genes TSC1 or TSC2, which are responsible for the production of proteins that regulate cell division and growth in the body. When gene mutations disrupt this balance, hamartomas may grow in the brain, skin, heart, kidney, liver, and lungs, affecting the function of these organs. […] TSC1/TSC2 mutations inactivate the inhibitory TSC protein complex, allowing aberrant activation of the mTOR pathways. The role of mTOR is to regulate cell growth and metabolism through the multimeric complexes mTORC1 and mTORC2. The complex mTORC1 integrates inputs from growth factors, amino acids, energy status, and hypoxia stressors to phosphorylate p70S6K and 4E-BP1 and promote cell proliferation. Without the TSC protein complex, the RAS homolog Rheb hyperactivates mTORC1. This reprogramming inhibits autophagy and favors anaerobic glycolysis. Therefore, mTORC1 aids solid tumor formation. […] Hamartin and tuberin play a role in a complex that controls cell growth and division in the body. These proteins modulate gene transcription and suppress tumor growth.

• #2 Tuberous sclerosis – Wikipedia

  https://en.wikipedia.org/wiki/Tuberous_sclerosis

  Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant genetic disease that causes non-cancerous tumours to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs and skin. […] TSC is caused by a mutation of either of two genes, TSC1 and TSC2, which code for the proteins hamartin and tuberin, respectively, with TSC2 mutations accounting for the majority and tending to cause more severe symptoms. […] These proteins act as tumor growth suppressors, agents that regulate cell proliferation and differentiation. […] Hamartin and tuberin function as a complex which is involved in the control of cell growth and cell division. The complex appears to interact with RHEB GTPase, thus sequestering it from activating mTOR signalling, part of the growth factor (insulin) signalling pathway. Thus, mutations at the TSC1 and TSC2 loci result in a loss of control of cell growth and cell division, and therefore a predisposition to forming tumors.

• #3 TSC/Facial Angiofibroma – HYFTOR® HCP Site

  https://hcp2024.hyftor.com/tuberous-sclerosis-complex/

  Tuberous sclerosis complex (TSC) is a genetic multisystemic disease that affects approximately 1 in 6,000 live births. It causes noncancerous tumors, or hamartomas, to form throughout the body. These benign tumors can develop in many organs, including the brain, eyes, kidneys, liver, lungs, heart, and skin. TSC is an autosomal dominant disorder. It is caused by abnormalities in the TSC1 and TSC2 genes. However, symptoms and severity may differ substantially even among members of the same family. The distribution, number, size, and location of tumors can vary. TSC can be so mild that individuals go undiagnosed, or it can cause significant complications and may even be life-threatening. […] Facial angiofibromas are made up of blood vessels and fibrous tissue and can coalesce to form patches. They can bleed, obstruct the nasal openings, and cause disfigurement. Facial angiofibroma occurs in approximately 75%-80% of TSC patients, making it one of the most predominant skin manifestations of this disease.

• #3 TSC/Facial Angiofibroma – HYFTOR® HCP Site

  https://hcp2024.hyftor.com/tuberous-sclerosis-complex/

  These tumors are sometimes treated with invasive modalities. However, these procedures may require anesthesia. Invasive treatments can also be difficult to administer in patients with extensive angiofibroma or severe intellectual impairments. […] HYFTOR is an mTOR inhibitor immunosuppressant indicated for the treatment of facial angiofibroma associated with tuberous sclerosis in adults and pediatric patients 6 years of age and older.

• #4 Tuberous Sclerosis Complex: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1177711-overview

  Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder affecting cellular differentiation, proliferation, and migration early in development, resulting in a variety of hamartomatous lesions that may affect virtually every organ system of the body. It is associated with two genetic loci: TSC1, located on chromosome 9q34, and TSC2, located on chromosome 16p13. Mutations in either of these genes can lead to the clinical phenotype. […] Clinically, tuberous sclerosis complex (TSC) exhibits an autosomal-dominant inheritance pattern, with a high spontaneous mutation rate. Two distinct genetic loci responsible for TSC have been identified: one on chromosome band 9q34 (also referred to as TSC1) and another on chromosome band 16p13 (TSC2). […] TSC2’s protein product tuberin has GTPase-activating properties and seems to function as a tumor suppressor. The highest levels of tuberin are found in adult human brain, heart, and kidney; tuberin also has been localized to arterioles of kidney, skin, and heart, as well as to pyramidal neurons and cerebellar Purkinje cells. Its exact function, particularly during neurogenesis, remains unknown. Individual tubers are thought to arise developmentally when mutated neural progenitor cells in the subependymal germinal matrix give rise to abnormally migrating daughter cells that in turn produce tubers. The tubers may undergo cystic degeneration or calcification, or exhibit contrast enhancement on neuroimaging, but these features do not necessarily imply malignant transformation.

• #4 Tuberous Sclerosis Complex: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1177711-overview

  Hamartin, the TSC1 product, was identified in 1997 and may also function as a tumor suppressor. Rather than having completely separate functions, both hamartin and tuberin have been shown to have „coiled-coil” domains that interact with each other. Hamartin and tuberin together form a tumor suppressor complex, which, through the GTPase activating function of tuberin, drives the small GTPase (termed Ras, homolog enhanced in brain) or Rheb into the inactive GDP-bound state. Rheb in the GTP-bound, active state is a positive effector of mTOR. […] Mutations in either hamartin or tuberin drive Rheb into the GTP-bound state, which results in constitutive mTOR signaling. mTOR appears to mediate many of its effects on cell growth through the phosphorylation of the ribosomal protein S6 kinases (S6Ks) and the repressors of protein synthesis initiation factor eIF4E, the 4EBPs. The S6Ks act to increase cell growth and protein synthesis, whereas the 4EBPs serve to inhibit these processes. mTOR interacts with the S6Ks and the 4EBPs through an associated protein, Raptor. When mTOR is constitutively activated through mutations in either hamartin or tuberin this results in the hamartomatous lesions of tuberous sclerosis in the brain, kidneys, heart, lungs, and other organs.

• #4 Tuberous Sclerosis Complex: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1177711-overview

  The high incidence of sporadic TSC, coupled with a probable „second hit” phenomenon, seems a likely explanation for the marked phenotypic variability observed. The second hit hypothesis suggests that in addition to an inherited or sporadic autosomal mutation in one allele of either TSC1 or TSC2, clinical signs and/or symptoms manifest only after a further mutation or inactivating event in the second, unaffected allele (second hit). This allows considerable potential for diversity, not only among various deletions and mutations between two genetic loci, but also with regard to possible interactions between protein products of varying functionality arising from different mutations on each allele. Thereby adjacent tubers, angiomyolipomas, even facial angiofibromas can have different second hits and different genotypes within the same organ of the same patient.

• #5 Tuberous sclerosis complex: Genetics and pathogenesis – UpToDate

  https://www.uptodate.com/contents/tuberous-sclerosis-complex-genetics-and-pathogenesis

  Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder that is characterized by pleomorphic features involving many organ systems, including multiple benign hamartomas of the brain, eyes, heart, lung, liver, kidney, and skin. […] The genetics and pathogenesis of TSC will be reviewed here. […] TSC is an autosomal dominant genetic disorder caused by heterozygous pathogenic variants in either the TSC complex subunit 1 (TSC1) or the TSC complex subunit 2 (TSC2) tumor suppressor genes. These variants cause overactivation of the mechanistic target of rapamycin (mTOR) pathway and tumor formation in multiple organs. […] Hamartin forms a complex with the tuberin protein that is encoded by the TSC2 gene.

• #6 Tuberous Sclerosis Complex: New Insights into Pathogenesis and Therapeutic Breakthroughs

  https://www.mdpi.com/2075-1729/15/3/368

  Tuberous sclerosis complex (TSC) is a rare, autosomal dominant genetic disorder caused by mutations in the TSC1 and TSC2 genes, which disrupt the regulation of the mammalian target of rapamycin (mTOR) pathway, a critical regulator of cellular growth. […] The underlying pathology is attributed to pathogenic variants in two critical genes: TSC1, located on chromosome 9, and TSC2, located on chromosome 16. These genes encode the proteins hamartin (TSC1) and tuberin (TSC2), which play pivotal roles in regulating cell growth and proliferation by acting as inhibitors of the mechanistic target of rapamycin (mTOR) signaling pathway. […] The two proteins encoded by the TSC1 and TSC2 genes play a main role in the mTOR signaling pathway, acting as inhibitors of the signaling cascade. The mTOR pathway, interconnected with the PI3K/AKT pathway, is essential for regulating cellular growth, metabolism, and cell survival.

• #6 Tuberous Sclerosis Complex: New Insights into Pathogenesis and Therapeutic Breakthroughs

  https://www.mdpi.com/2075-1729/15/3/368

  Genetic variants in the TSC1 or TSC2 genes disrupt this pathway, leading to the uncontrolled activation of mTOR signaling, which results in excessive cellular division and proliferation. This abnormal proliferation enhances angiogenesis, explaining the development of cutaneous and renal angiofibromas and renal angiomyolipomas. […] The introduction of mTOR inhibitors (mTORis), such as sirolimus and everolimus, has provided new insights into the management of the tumor-related forms of TSC, significantly improving patient quality of life by controlling tumor growth and reducing systemic complications. […] mTOR inhibitors have become the standard treatment for tumor-related manifestations of TSC. The TSC1 and TSC2 genes regulate the mTOR signaling pathway, which is critical for integrating growth signals and transmitting them downstream to mTOR. This pathway’s dysregulation leads to the pathogenesis of TSC, and mTOR inhibitors, such as sirolimus (rapamycin) and everolimus, are used to target these abnormalities.

• #7 Tuberous Sclerosis Complex | Plastic Surgery Key

  https://plasticsurgerykey.com/tuberous-sclerosis-complex/

  TSC is caused by mutations in a tumor suppressor gene, either TSC1 or TSC2. Mutations in TSC2 are observed in about three-fourths of patients, and even more commonly in de novo cases. Patients with mutations in TSC2 tend to exhibit a more severe phenotype. […] Typical of mutations in tumor suppressor genes, the mutations observed in patients with TSC are inactivating mutations located anywhere along the sequence of TSC1 or TSC2. Consistent with Knudsons two-hit hypothesis, most TSC tumors show a second somatic mutation that inactivates the wild-type allele. TSC1 and TSC2 form a complex that inhibits signaling through the mammalian target of rapamycin (mTOR) pathway. Loss of TSC1/TSC2 function leads to increased mTOR signaling and increased cell growth. Rapamycin is a drug that inhibits mTOR and may be useful for the treatment of internal tumors in TSC.

• #8 SciELO Brazil – Tuberous sclerosis complex Tuberous sclerosis complex

  https://www.scielo.br/j/abd/a/QBWN3yJXCd4YCbzcf6wLjVp/

  Studies show that changes in TSC2 are five times more frequent than changes in TSC1 in sporadic cases. This relationship becomes 1:1 in cases of familial transmission. Changes in the TSC2 gene result in more severe pathology, when compared to TSC resulting from mutations in TSC1. Cases of familial transmission, which show higher frequency of changes in the TSC1 gene, result in mild to moderate disease, sometimes not meeting the various diagnostic criteria. […] […] For several years, the „two-hit” hypothesis, proposed by Knudson in the 70’s, explained the etiopathogenesis of hamartoma formation in TSC. According to that hypothesis, patients with TSC would already present a defective tumor suppressor gene in one of the alleles of TSC1 or TSC2 during germ-cell division. This stage would be the „first hit”. However, this previous change would not be enough to trigger phenotypic findings, since both alleles must be lost or deficient so that clinical manifestation occurs. Thus, a second change involving the normal allele and leading to loss of heterozygosity is necessary for the development of a hamartoma in TSC. This would be the „second hit”, which occurs during somatic cell proliferation. Knudson believes that the presence of the anomalous allele creates genomic instability or induces epigenetic phenomena (genetic changes caused by non-mutational factors, such as DNA methylation), which trigger loss of heterozygosity and disrupt the function of the tumor suppressor gene. This genetic change would lead to absence of the hamartin-tuberin complex, resulting in uncontrolled cell growth. […]

• #8 SciELO Brazil – Tuberous sclerosis complex Tuberous sclerosis complex

  https://www.scielo.br/j/abd/a/QBWN3yJXCd4YCbzcf6wLjVp/

  Tuberous sclerosis complex is an autosomal dominant disease with high penetrance. It is caused by inactivating mutations of TSC1 and TSC2 tumor suppressor genes, located on chromosomes 9q34 and 16p13.3, respectively. The TSC1 gene is responsible for encoding a protein called hamartin and TSC2 for encoding for tuberin. The hamartin-tuberin complex is an important inhibitor of tumor growth. Its absence triggers loss of inhibition on cell proliferation and migration. […] […] Numerous genetic changes are observed, such as deletions, insertions, nonsense, and missense mutations, basically involving all exons of the genes involved. In spite of verification of such changes, mutations are not identified in 15% of the cases. The familial forms of TSC arise from germline mutations and, although their transmission can be hereditary, 70% of the cases are a result of somatic mutations, especially when the mutant gene is TSC2. Somatic mutations are responsible for sporadic cases of the disease. The great variety of mutations and the possibility of involvement of different genes explain, in part, the phenotypic diversity of the disease. Another factor that may explain why clinical manifestations of TSC are unpredictable is the presence of mosaicism. […]

• #8 SciELO Brazil – Tuberous sclerosis complex Tuberous sclerosis complex

  https://www.scielo.br/j/abd/a/QBWN3yJXCd4YCbzcf6wLjVp/

  The mechanism through which these mutations lead to cellular hyperproliferation and appearance of numerous hamartomas anywhere in the human body is not fully understood. Some of the stages of this proliferation pathway have already been discovered. The cells of the human body continuously respond to a wide variety of integrated biological stimuli. Defects in this signaling mechanism result in proliferative diseases such as cancer and TSC. The TSC1 and TSC2 genes have an important role in regulating cell growth, via the phosphoinositide 3-kinase signaling pathway, inhibiting the mammalian target of rapamycin (mTOR). mTOR is a major sensor of energy and nutrient availability, thus regulating cell growth, differentiation and proliferation. […] […] The hamartin-tuberin complex forms a heterodimer that inhibits the signaling protein, known as „RAS homolog enriched in brain” (Rheb). mTOR, in turn, following stimulation by Rheb, regulates the phosphorylation of ribosomal protein S6 kinase 1 and 2 (S6K1 and S6K2) isoforms and of the protein inhibiting translation initiation, 4E-BP1 (also known as PHAS-1). The Loss of inhibitory function of the hamartin-tuberin complex on Rheb allows mTOR to stimulate the S6K and 4E-BP1 proteins, leading to an increase in ribosomal biogenesis, with increased production of proteins, which ultimately culminates in uncontrolled cell proliferation and tissue growth, with the emergence of tumors observed in tuberous sclerosis. […]

• #8 SciELO Brazil – Tuberous sclerosis complex Tuberous sclerosis complex

  https://www.scielo.br/j/abd/a/QBWN3yJXCd4YCbzcf6wLjVp/

  The role of TSC1 and TSC2 in regulating biological processes is not yet fully understood, and some of its properties are the subject of considerable interest. One example is the finding that the hamartin-tuberin complex acts in the biology of the cell cycle by regulating cyclin-dependent kinase inhibitor p27, playing a major role in the stages of cell differentiation. Loss of inhibition of the mTOR signaling pathway also has an important role in the insulin-dependent cellular metabolism. Activation of mTOR induces endoplasmic reticulum stress, resulting in severe insulin and IGF1 resistance, besides making the cell more susceptible to apoptosis. […]

• #9 Tuberous Sclerosis Complex

  https://biology.kenyon.edu/slonc/bio38/howell/tsc.htm

  Tuberous Sclerosis Complex (TSC) was discovered in the 1880’s by a French physician named Bourneville. TSC, also known as Bourneville’s Disease and Epilola, is an incurable multisystem genetic disorder which can have a wide range of effects. Approximately one in 8,000 adults and one in 6,000 newborns are affected by TSC. Although TSC is often inherited, new mutations have been implicated in up to 75% of all cases (TSA of Greece). Males and females of equally likely to have Tuberous Sclerosis and the chance of passing it on to offspring is 50%. […] Tuberous Sclerosis Complex is an autosomal dominant disorder caused by a mutation in one of two known genes. The TSC1 gene is located on chromosome 9q34 and the TSC2 gene on chromosome 16p13. The precise location of the TSC2 gene was found in 1993 and it is now known to be responsible for the production of the protein tuberin which suppresses the growth of tumors. Mutations in this gene prevent the production of tuberin and allow certain tissues to grow unchecked.

• #9 Tuberous Sclerosis Complex

  https://biology.kenyon.edu/slonc/bio38/howell/tsc.htm

  Another study by Henske et. al., 1996, also investigated loss of heterozygosity in lesions, focusing on the difference between the TSC1 and TSC2 genes and the different organs where the lesions are found. Testing of lesions from 47 patients revealed that loss of heterozygosity is more frequently seen in relation to TSC2 than TSC1. The researchers also found that loss of heterozygosity was seen in 56% of renal and cardiac lesions but in only 4% of brain lesions. The study concluded that brain lesions must form by a different mechanism that other hamartomas. […] The search for specific mutations which lead to TSC is a major topic of current research. A paper by Vrtel et. al., 1996, identified a point mutation which caused TSC in a father and son. A genomic phage library of the TSC2 gene was prepared and analyzed by polymerase chain reaction (PCR) and single strand confirmation polymorphism (SSCP) analysis. The mutation was detected in the first exon of the 5′ end of the gene. Several large deletions were detected in other patients as well. The relatively mild cases of this father and son and the lack of tumors in the family suggested that perhaps this mutation only caused a partial loss of tuberin producing ability.

• #10 Renal disease in tuberous sclerosis complex: pathogenesis and therapy | Nature Reviews Nephrology

  https://www.nature.com/articles/s41581-018-0059-6

  Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by hamartomatous tumours of the brain, heart, skin, lung and kidney. […] TSC is caused by inactivating mutations in TSC1 and TSC2, which encode hamartin and tuberin, respectively. These two proteins form a complex that negatively regulates mechanistic target of rapamycin complex 1 (mTORC1), a master regulator of cellular growth and metabolism. […] Activation of mechanistic target of rapamycin complex 1 (mTORC1) promotes TSC by accelerating cell growth and inhibiting autophagy. […] mTORC1 hyperactivation increases oxidative stress, rendering TSC-related tumour cells vulnerable to agents that increase oxidative stress or inhibit antioxidant biosynthesis. […] Critical knowledge gaps include the angiomyolipoma cell of origin, aggressive behaviour of renal cell carcinomas and molecular mechanisms underlying early-onset cystic disease in PKD1 TSC2 contiguous gene deletion syndrome. […] Loss of tuberin in both subependymal giant cell astrocytomas and angiomyolipomas supports a two-hit model for the pathogenesis of tuberous sclerosis tumors.

• #11 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Tuberous-Sclerosis-Pathophysiology.aspx

  Hamartin and tuberin are thought to play a role in a complex that controls cell growth and division in the body. To date, the exact mechanism of pathology that leads to unregulated cell growth and the appearance of tumors is not known, although it is thought to be due to changes in the signaling of mTOR. Thus, the proteins hamartin and tuberin are considered to modulate gene transcription and suppress tumor growth. […] The 2-hit model of tumorigenesis by Knudson specifies that the formation of the tumor requires a second mutation and a loss of heterozygosity (LOH). This suggestion follows from the presence of LOH in several hamartomas around the body in people with tuberous sclerosis.

• #12 SciELO Brazil – TSC1 and TSC2 gene mutations and their implications for treatment in Tuberous Sclerosis Complex: a review TSC1 and TSC2 gene mutations and their implications for

  https://www.scielo.br/j/gmb/a/YGnxnhRTwWJHYVHVBbP8YBg/?lang=en

  Tuberous sclerosis is caused by the mutation of one of two tumor suppressor genes, TSC1 or TSC2. […] Tuberous sclerosis is caused by mutations in one of two tumor suppressor genes: TSC1 (9q34) and TSC2 (16p13.3). […] Loss of function mutations in TSC1 or TSC2 lead to deregulated expression patterns in this pathway, abnormal production of the end products, and ultimately promote tumorigenesis. […] It is suggested that tumor formation is initiated as a consequence of at least two hits: as TSC1 and TSC2 are tumor suppressor genes, the inactivation of both TSC1 or both TSC2 alleles is necessary for benign or malignant tumor formation. […] There are multiple possible mechanisms for somatic inactivation of the wild-type alleles of TSC1 and TSC2, including loss of heterozygosity, mutation and promoter methylation.

• #13 The genomic landscape of tuberous sclerosis complex | Nature Communications

  https://www.nature.com/articles/ncomms15816

  Tuberous sclerosis complex (TSC) is a rare genetic disease causing multisystem growth of benign tumours and other hamartomatous lesions, which leads to diverse and debilitating clinical symptoms. Patients are born with TSC1 or TSC2 mutations, and somatic inactivation of wild-type alleles drives MTOR activation; however, second hits to TSC1/TSC2 are not always observed. […] While TSC lesions may develop by somatic inactivation of TSC1/TSC2, second hits (mutations) are not always observed, especially in brain lesions, suggesting that additional mechanisms may contribute to their growth. Moreover, the collective molecular changes underlying TSC tumour growth are unknown, yet essential to understanding disease aetiology and developing therapies. […] We find that unlike a majority of RAs and SEN/SEGAs, only one-third of cortical tubers are driven by somatic TSC1/TSC2 inactivation, suggesting monoallelic mutation may be sufficient to cause cortical malformation. Further, we discover that most TSC lesions have a low somatic mutational burden, in contrast to malignant tumours. Instead, large arm-level chromosomal aberrations are found in tumours from a subset of patients (11%). […] Taken together, this study provides a comprehensive genomic landscape of TSC, knowledge around cell-of-origin, and unifies the molecular signatures of these complex tumours.

• #14 Genetics of Tuberous Sclerosis: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/951002-overview

  Hamartin and tuberin are believed to have a role in growth and differentiation of cells. Both proteins are found throughout the body and interact with each other. Little attention has been given to the recently discovered role of the TSC1/TSC2 complex in gene transcription via the Wnt signaling pathway; hamartin and tuberin have been found to modulate gene transcription via beta-catenin. […] Evidence also suggests that extracellular signal-regulated kinase (ERK) is specifically implicated in the pathogenesis of hamartomas. Jozwiak et al postulate that ERK activation consistently detected in different tuberous sclerosis-associated tumors is a molecular trigger for the development of these neoplasms. […] More than 450 different disease-causing mutations are known for TSC1, and more than 1300 for TSC2, with most of TSC1 mutations being truncating comprising frameshift, nonsense, and splice mutations. […] Molecular studies suggest that tumor development relies on second-hit events, ie, a storm of them, to produce multifocal renal cell carcinoma in tuberous sclerosis complex.

• #14 Genetics of Tuberous Sclerosis: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/951002-overview

  Tuberous sclerosis complex has a broad clinical spectrum and affects almost every organ system. Tuberous sclerosis complex is an inherited disorder characterized by hamartomas in different body organs, mainly in the brain, skin, kidney, liver, lung, and heart. […] The genes responsible for tuberous sclerosis complex have been identified. In 1993, TSC2, located on chromosome 16, was the first gene discovered to be involved in tuberous sclerosis complex. TSC1 is located on chromosome 9 and was identified in 1997. TSC1 encodes for the protein hamartin; TSC2, encodes for the protein tuberin. Mutations in either TSC1 or TSC2, which are tumor suppressor genes that work together to facilitate tumor suppression, cause tuberous sclerosis complex. […] The function and interaction of hamartin and tuberin are not yet fully understood, although they may function as tumor suppressors. Knudson’s 2-hit model of tumorigenesis mandates that a second-hit mutation and resulting loss of heterozygosity (LOH) of a tumor suppressor gene is necessary for tumor formation. LOH is commonly found in several types of hamartomas formed in the process of tuberous sclerosis, but not in brain lesions that contain characteristic giant cells.

• #15 Does the Coexistence of Tuberous Sclerosis and of Multiple Sclero

  https://www.iomcworld.org/open-access/does-the-coexistence-of-tuberous-sclerosis-and-of-multiple-sclerosis-in-a-young-woman-have-a-common-pathogenic-mechanism-101457.html

  A common pathogenic mechanism can be suggested in the present case as dysregulation of the Mammalian Target of Rapamycin (mTOR) pathway is implicated in TSC pathology and in immuno-modulatory mechanisms. […] In TSC, mutations of the TSC 1 and TSC 2 genes leads to an abnormally activated mammalian target of rapamycin pathway, which is one of the main pathways regulating development, differentiation, metabolism, and function of T and B cell. […] Subsequently, dysregulation of B and T lymphocytes may cause abnormal responses with an increased risk of autoimmunity. […] The association between TSC and autoimmune diseases or abnormal production of autoantibodies could have a common pathogenesis.

• #16 Brain Symptoms of Tuberous Sclerosis Complex: Pathogenesis and Treatment

  https://www.mdpi.com/1422-0067/22/13/6677

  The mammalian target of the rapamycin (mTOR) system plays multiple, important roles in the brain, regulating both morphology, such as cellular size, shape, and position, and function, such as learning, memory, and social interaction. Tuberous sclerosis complex (TSC) is a congenital disorder caused by a defective suppressor of the mTOR system, the TSC1/TSC2 complex. Almost all brain symptoms of TSC are manifestations of an excessive activity of the mTOR system. […] In TSC, a decrease in the regulatory function of TSC1/TSC2 causes the chronic hyperactivation of the downstream mTOR system, which affects cellular proliferation, migration, glucose uptake/metabolism, and angiogenesis, leading to tumorigenesis and dysgenesis. […] The TSC1/TSC2 complex is located in the midstream of the mTOR pathway and negatively regulates the activity of the system.

• #16 Brain Symptoms of Tuberous Sclerosis Complex: Pathogenesis and Treatment

  https://www.mdpi.com/1422-0067/22/13/6677

  The genetic mechanisms of TSC-associated focal dysplasia (hamartias) largely remain to be elucidated. In cerebral dysplastic lesions, namely cortical tubers, loss of heterozygosity (LOH) has not been found. […] The interaction of both cell types may account for the epileptogenicity of cortical tubers. […] The pathologic orchestration of the “haploinsufficient cells” and “null cells” may create a synaptic network with a tendency toward a distorted E/I balance. […] Recent advances in the studies of TSC have provided clinicians with candidates for robust therapeutic measures to escape from the vicious cycle, such as vigabatrin, mTOR inhibitors, and epilepsy surgery.

• #17

  https://www.jci.org/articles/view/41897

  Tuberous sclerosis complex (TSC) is caused by mutations that inactivate the TSC1 or TSC2 genes, which normally function to inhibit activation of mammalian target of rapamycin signaling. […] In this issue of the JCI, two studies reported by Karbowniczek et al. and Ma et al. link TSC inactivation with activated Notch signaling. […] Both studies show that inactivation of TSC leads to Notch1 activation. […] The TSC and Rheb regulate Notch-dependent cell-fate decision in Drosophila and Notch activity in mammalian cells and that Notch dysregulation may underlie some of the distinctive clinical and pathologic features of TSC. […] TSC loss promotes Rheb-dependent Notch activation in flies, rodents, and humans. […] The TSC/Rheb/Notch pathway is TORC1 independent. […] Together, the work from both Karbowniczek et al. and Ma et al. provides strong evidence that Notch signaling is activated as a consequence of TSC loss. […] The precise reasons for the different conclusions are not clear; however, they may result from studying the effects of TSC loss in different model systems. […] The new findings will undoubtedly catalyze these studies.

• #18 Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. | BioGRID

  https://thebiogrid.org/77853/publication/phosphorylation-and-functional-inactivation-of-tsc2-by-erk-implications-for-tuberous-sclerosis-and-cancer-pathogenesis.html

  Tuberous sclerosis (TSC) is a tumor syndrome caused by mutation in TSC1 or TSC2 genes. […] Recently, extracellular signal-regulated kinase (Erk) has been found activated in TSC lesions lacking TSC1 or TSC2 LOH. […] Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. […] Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. […] Our findings position the Ras/MAPK pathway upstream of the TSC complex and suggest that Erk may modulate mTOR signaling and contribute to disease progression through phosphorylation and inactivation of TSC2.

• #19 Two independent mechanisms are involved in tuberous sclerosis

  https://medicalxpress.com/news/2019-02-independent-mechanisms-involved-tuberous-sclerosis.html

  Two independent mechanisms are involved in tuberous sclerosis. The current idea about how tuberous sclerosis occurs places mTORC1, a protein complex that regulates cell metabolism, as the major driving force behind the disease. But according to a new study published in the Proceedings of the National Academy of Sciences by researchers at Baylor College of Medicine and Texas Children’s Hospital, the development of this rare condition also involves a second mechanism that is independent of mTORC1. […] Tuberous sclerosis is caused by mutations in the genes TSC1 and TSC2. The current thought is that the dysfunctional proteins produced by these mutated genes fail to regulate mTORC1, which then becomes hyperactive and leads to the development of the disease. How the disease actually develops is still not clear.

• #19 Two independent mechanisms are involved in tuberous sclerosis

  https://medicalxpress.com/news/2019-02-independent-mechanisms-involved-tuberous-sclerosis.html

  Further investigations showed that the second mTORC1-independent mechanism involved defects in the formation of lysosomes and in the process that digests cellular materials, including glycogen. And this led to the accumulation of glycogen inside the cells. […] Current treatments are focused on modifying only mTORC1 activity. This work suggests that further studies are needed to systematically analyze the TSC mutations carried by each patient. Some patients may be carrying TSC mutations that affect mTORC1. But in other patients TSC mutations may be affecting the second mechanism without disrupting mTORC1.

• #20

  https://aesnet.org/abstractslisting/ferroptosis-as-a-potential-disease-mechanism-in-tuberous-sclerosis-complex

  Ferroptosis is an iron-dependent form of regulated cell death driven by iron accumulation and the excessive production of lipid reactive oxygen species (ROS). […] However, the role of ferroptosis in Tuberous Sclerosis Complex (TSC), a genetic disorder manifesting with early life epilepsy, cognitive dysfunction and autism has not been investigated. […] Since previous studies have demonstrated increased levels of neuronal ROS and lipid peroxidation in TSC, we hypothesized that the ferroptosis cascade might be activated and therefore may contribute to disease pathology. […] We found that the TFRC expression was significantly increased in the TSC mice (p 0.0001), while both FHC and FLC were significantly downregulated (p 0.01), suggesting an excessive deposition of non-transferrin bound iron. […] In addition, GPX4 was significantly downregulated in the TSC mouse cortex (p 0.001), consistent with diminished cellular antioxidant capacity in these mice.

• #21 Tuberous sclerosis complex: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/tuberous-sclerosis-complex/

  Tuberous sclerosis complex is a genetic disorder characterized by the growth of numerous noncancerous (benign) tumors in many parts of the body. […] Variants (also known as mutations) in the TSC1 or TSC2 gene can cause tuberous sclerosis complex. The TSC1 and TSC2 genes provide instructions for making the proteins hamartin and tuberin, respectively. Within cells, these two proteins work together to help regulate cell growth and division (proliferation) and cell size. The proteins act as tumor suppressors, which normally prevent cells from growing and dividing too fast or in an uncontrolled way. […] For tumors to develop in tuberous sclerosis complex, a second change involving the other copy of the TSC1 or TSC2 gene must occur in cells during a person’s lifetime. […] The absence of hamartin or tuberin in different types of cells leads to the growth of tumors in many different organs and tissues, as seen in tuberous sclerosis complex.

• #22 Tuberous sclerosis complex exhibits a new renal cystogenic mechanism.

  http://bridgeslab.sph.umich.edu/papers/tuberous-sclerosis-complex-exhibits-a-new-renal-cystogenic-mechanism

  Tuberous sclerosis complex (TSC) is a tumor predisposition syndrome with significant renal cystic and solid tumor disease. While the most common renal tumor in TSC, the angiomyolipoma, exhibits a loss of heterozygosity associated with disease, we have discovered that the renal cystic epithelium is composed of type A intercalated cells that have an intact Tsc gene that have been induced to exhibit Tsc?mutant disease phenotype. This mechanism appears to be different than that for ADPKD. […] The induction signaling driving cystogenesis may be mediated by extracellular vesicle trafficking.

• #23 Tuberous sclerosis protein – Wikipedia

  https://en.wikipedia.org/wiki/Tuberous_sclerosis_protein

  Tuberous sclerosis proteins 1 and 2, also known as TSC1 (hamartin) and TSC2 (tuberin), form a protein-complex. The complex is known as a tumor suppressor. Mutations in these genes can cause tuberous sclerosis complex. […] The TSC1/TSC2-complex integrates environmental signals such as stress and energy status in yeast and stress, energy status and growth factors in mammals into TOR signalling. […] Defects in its genes result in less control of cell growth and may cause tuberous sclerosis or tuberous sclerosis complex (TSC). […] The TSC1 and TSC2 proteins form a heterodimeric complex which acts as an important integrator of different signaling pathways controlling mTOR signaling, by regulating especially mTORC1 activity. […] TSC2 contains a GTPase Activating Protein (GAP) domain which has been shown to stimulate (down regulate) the GTPase activity of the small GTPase Rheb, which is in its GTP bound form an activator of mTORC1. […] The activity of the TSC1-TSC2 complex is regulated by phosphorylation of different Ser and Thr sites mediated by the following Pathways:

• #24 Tuberous sclerosis

  https://dermnetnz.org/topics/tuberous-sclerosis

  Tuberous sclerosis is a genetic disorder due to a mutation in one of two genes: TSC1, which produces a protein called hamartin (1030% of cases) […] TSC2, which produces a protein called tuberin. About one-third of all cases of tuberous sclerosis are inherited from an affected parent. All other cases are due to sporadic new mutations occurring in the early stages of life, most often mutations of TSC2. Epilepsy is present in about 70% of patients with tuberous sclerosis. The greater the number of tumours (cortical tubers) in the brain, the greater the severity of seizures. Developmental delay and behavioural problems may also occur. Symptoms include mild to severe intellectual disability, autism, attention deficit disorder (ADD), anxiety, depression, paranoia and schizophrenia. Tuberous sclerosis is a multisystem disorder, so treatment from a team of specialist doctors is usually necessary.

• #25 2015 Tuberous Sclerosis Complex Highlight – Elucidating the Role of the mTOR Pathway in Tuberous Sclerosis, Tuberous Sclerosis Complex Research Program, Congressionally Directed Medical Research Programs

  https://cdmrp.health.mil/tscrp/research_highlights/15guan_highlight

  Dr. Guan’s results were among the first to demonstrate that TSC1 regulates TORC2 function. […] Dr. Guan was able to demonstrate that AMPK contributes to p53 stabilization, which he also showed is required for energy-starvation induced programmed cell death in cells lacking functional TSC2 proteins. […] Taken together, these results explained the sensitivity of TSC-deficient cells to energy starvation that can lead to misregulated p53 activation, causing the increased likelihood of tumor growth in patients with TSC disease. […] Dr. Guan’s research has led to many breakthroughs in the field of mTOR signaling, its involvement with TSC proteins, and its crosstalk with other well-known signaling mediators, as noted above. […] This understanding may lead to new therapeutic targets that will help alleviate some of the manifestations of tuberous sclerosis.

• #26

  https://www.omim.org/entry/191100

  Liang et al. (2014) generated a mosaic Tsc1-knockout mouse model in which mutant mice developed renal mesenchymal lesions that recapitulated perivascular epithelioid cell tumors (PEComas) found in patients with TSC. […] The authors found that YAP (YAP1; 606608) was upregulated by MTOR (601231) in mouse and human PEComas. […] Genetic or pharmacologic inhibition of Yap blunted abnormal proliferation and induced apoptosis of mouse Tsc1/Tsc2-deficient cells in culture and in mosaic Tsc1-knockout mice. […] Yap accumulated in cells lacking Tsc1/Tsc2 due to impaired degradation of Yap by autophagy in an Mtor-dependent manner. […] Liang et al. (2014) proposed that YAP is a potential therapeutic target for TSC and other disease with dysregulated MTOR activity.

• #27 The Neurodevelopmental Pathogenesis of Tuberous Sclerosis Complex (TSC)

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7381175/

  The TSC1 and TSC2 genes encode for the proteins hamartin and tuberin that form a GTPase activating protein (GAP) complex and inhibit RAS homologue enriched in brain (RHEB). […] Therefore, mutations that inhibit hamartin/tuberin function increase mTORC1 activity. […] mTOR partitions into two molecular complexes, mTORC1 and mTORC2. […] In this way, mutations in TSC1/2 increase mTORC1 and notably, cell growth. […] The role of inflammation and immune invasion in the pathogenesis of TSC is unclear but it is certainly a component of hot tubers. […] The cellular heterogeneity and mosaic patterning of abnormal cells surrounded by normal cells in tubers complicate both the analysis and conclusions based on surgically resected tubers. […] The absence of an identified mutation in 10-15% of patients with a clinical diagnosis spurred studies that examined TSC1/2 methylation and genetic modifiers and even the possibility of a TSC3 gene. […] Somatic mutations resulting in dominant-negative function would only require a single allele to be mutated to cause phenotypic changes.

• #28 Two independent mechanisms involved in tuberous sclerosis

  https://www.bcm.edu/news/two-mechanisms-involved-in-tuberous-sclerosis

  But when the researchers tested samples from patients carrying two particular TSC2 mutations that do not completely eliminate the gene but just change the protein, they observed that mTORC1 was working normally, yet glycogen accumulated inside the cells. […] This suggested that there was another glycogen-clearing mechanism at play and that it was independent of mTORC1. […] Further investigations showed that the second mTORC1-independent mechanism involved defects in the formation of lysosomes and in the process that digests cellular materials, including glycogen. […] Our findings put forward a new perspective on this disease that can have implications for patient treatment. […] Current treatments are focused on modifying only mTORC1 activity. […] This work suggests that further studies are needed to systematically analyze the TSC mutations carried by each patient.

• #29 New insights into the pathogenesis and prevention… | F1000Research

  https://f1000research.com/articles/6-859

  Tuberous sclerosis complex (TSC) is a multi-system disorder resulting from mutations in either the TSC1 or TSC2 genes leading to hyperactivation of mechanistic target of rapamycin (mTOR) signaling. […] The neurobiology of TSC has been linked to mutations in the TSC1 or TSC2 genes leading to dysfunction of the TSC1 or TSC2 proteins, which form a complex that usually inhibits mechanistic target of rapamycin (mTOR). […] Dis-inhibition of this pathway caused by loss-of-function mutations in TSC1 or TSC2 leads to generally benign overgrowth or tumors in brain, kidney, skin, eye, and other organs that are the clinical hallmarks of the disorder. […] The concept of TAND also encompasses the psychosocial impact of the individuals condition on the rest of the family. […] Recognition that early onset of seizures, especially infantile spasms, are common in infants with TSC and that early onset of infantile spasms and associated hypsarrhythmia may have a malignant effect on brain development in infants with TSC has stimulated the search for ways to anticipate the onset of infantile spasms before they become apparent as seizures. […] This information, combined with an understanding of the genetics and neurobiology of TSC, is leading to a deeper understanding of pathogenesis and possibly better therapies.

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