Aspects of tuberous sclerosis complex (TSC) protein function in the brain

2003 ◽  
Vol 31 (3) ◽  
pp. 579-583 ◽  
Author(s):  
V. Ramesh
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Protein Function ◽  
Direct Interaction ◽  
Wild Type ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Dominant Disease ◽  
The Central Nervous System ◽  
Cortical Tubers

Tuberous sclerosis complex (TSC), an autosomal dominant disease caused by mutations in either TSC1 or TSC2, is characterized by the development of hamartomas in a variety of organs. Concordant with the tumour-suppressor model, loss of heterozygosity (LOH) is known to occur in these hamartomas at both TSC1 and TSC2 loci. LOH has been documented in renal angiomyolipomas, but loss of the wild-type allele in cortical tubers appears very uncommon. We analysed 24 hamartomas from 10 patients for second-hit mutations by several methods, and found no evidence for the inactivation of the second allele in many of the central nervous system (CNS) lesions, including tumours that appear to be clonally derived. We believe that somatic mutations in TSC1 and TSC2 resulting in the loss of wild-type alleles may not be necessary in some tumour types, and other mechanisms may contribute to tumorigenesis in this setting. We have shown that hamartin interacts with neurofilament light chain (NF-L) and could integrate the neuronal cytoskeleton through its direct interaction with NF-L and ERM (ezrin/radixin/moeisin) proteins. Our unpublished work further documents the binding of tuberin with Pam, a protein associated with c-Myc, which is enriched in brain. All these observations suggest that the tuberin–hamartin complex is likely to have distinct functions in the CNS.

scholarly journals Retracted Tuberous sclerosis complex: molecular pathogenesis and animal models

2006 ◽  
Vol 20 (1) ◽  
pp. 1-6 ◽  
Author(s):  
Leandro R. Piedimonte ◽  
Ian K. Wailes ◽  
Howard L. Weiner
Keyword(s):  
Animal Models ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Conditional Knockout ◽  
Signaling Complex ◽  
Normal Functions ◽  
Similar Disease ◽  
The Central Nervous System ◽  
Cortical Tubers ◽  
The Brain

Mutations in one of two genes, TSC1 and TSC2, result in a similar disease phenotype by disrupting the normal interaction of their protein products, hamartin and tuberin, which form a functional signaling complex. Disruption of these genes in the brain results in abnormal cellular differentiation, migration, and proliferation, giving rise to the characteristic brain lesions of tuberous sclerosis complex (TSC) called cortical tubers. The most devastating complications of TSC affect the central nervous system and include epilepsy, mental retardation, autism, and glial tumors. Relevant animal models, including conventional and conditional knockout mice, are valuable tools for studying the normal functions of tuberin and hamartin and the way in which disruption of their expression gives rise to the variety of clinical features that characterize TSC. In the future, these animals will be invaluable preclinical models for the development of highly specific and efficacious treatments for children affected with TSC.

Expression and cellular distribution of FGF13 in cortical tubers of the tuberous sclerosis complex

2021 ◽  
Vol 749 ◽  
pp. 135714
Author(s):  
Kefu Wu ◽  
Jiong Yue ◽  
Kaifeng Shen ◽  
Jiaojiang He ◽  
Gang Zhu ◽  
...  
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Cellular Distribution ◽  
Cortical Tubers

scholarly journals A novel TSC1 variant associated with tuberous sclerosis and sacrococcygeal teratoma

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Saba Ahmad ◽  
Luis Manon ◽  
Gifty Bhat ◽  
Jerry Machado ◽  
Alice Zalan ◽  
...  
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Cellular Differentiation ◽  
Autosomal Dominant ◽  
De Novo ◽  
Autosomal Dominant Disease ◽  
Sacrococcygeal Teratoma ◽  
Dominant Disease ◽  
The Brain

AbstractTuberous sclerosis complex (TSC) is an autosomal dominant disease associated with tumors and malformed tissues in the brain and other vital organs. We report a novel de novo frameshift variant of the TSC1 gene (c.434dup;p. Ser146Valfs*8) in a child with TSC who initially presented with a sacral teratoma. This previously unreported association between TSC and teratoma has broad implications for the pathophysiology of embryonic tumors and mechanisms underlying cellular differentiation.

scholarly journals Energy Stress-Mediated Cytotoxicity in Tuberous Sclerosis Complex 2-Deficient Cells with Nelfinavir and Mefloquine Treatment

Cancers ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 375 ◽  
Author(s):  
Henry McCann ◽  
Charlotte Johnson ◽  
Rachel Errington ◽  
D. Davies ◽  
Elaine Dunlop ◽  
...  
Keyword(s):  
Cell Death ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Transcriptional Profiling ◽  
Cancer Drug ◽  
Wild Type ◽  
Cell Recovery ◽  
Energy Stress ◽  
Mtorc1 Pathway ◽  
Energy Deprivation

To find new anti-cancer drug therapies, we wanted to exploit homeostatic vulnerabilities within Tuberous Sclerosis Complex 2 (TSC2)-deficient cells with mechanistic target of rapamycin complex 1 (mTORC1) hyperactivity. We show that nelfinavir and mefloquine synergize to selectively evoke a cytotoxic response in TSC2-deficient cell lines with mTORC1 hyperactivity. We optimize the concentrations of nelfinavir and mefloquine to a clinically viable range that kill cells that lack TSC2, while wild-type cells tolerate treatment. This new clinically viable drug combination causes a significant level of cell death in TSC2-deficient tumor spheroids. Furthermore, no cell recovery was apparent after drug withdrawal, revealing potent cytotoxicity. Transcriptional profiling by RNA sequencing of drug treated TSC2-deficient cells compared to wild-type cells suggested the cytotoxic mechanism of action, involving initial ER stress and an imbalance in energy homeostatic pathways. Further characterization revealed that supplementation with methyl pyruvate alleviated energy stress and reduced the cytotoxic effect, implicating energy deprivation as the trigger of cell death. This work underpins a critical vulnerability with cancer cells with aberrant signaling through the TSC2-mTORC1 pathway that lack flexibility in homeostatic pathways, which could be exploited with combined nelfinavir and mefloquine treatment.

scholarly journals Lymphangioleiomyomatosis (LAM) presenting as recurrent pneumothorax in an infant with tuberous sclerosis: treated successfully with sirolimus

2018 ◽  
pp. bcr-2018-226244
Author(s):  
Lalit Takia ◽  
Kana Ram Jat ◽  
Anirban Mandal ◽  
Sushil Kumar Kabra
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Right Atrial ◽  
Age Group ◽  
Bilateral Pneumothorax ◽  
General Physical Examination ◽  
Paediatric Age ◽  
Cortical Tubers ◽  
General Physical ◽  
Multiple Cysts

Lymphangioleiomyomatosis (LAM) either sporadic or a part of tuberous sclerosis complex is rare in paediatric age group. Here, we report a case of LAM with tuberous sclerosis in an infant. She was referred to our institute at the age of 4 months as a case of recurrent bilateral pneumothorax requiring intercostal tube drainage. Detailed history revealed that patient was symptomatic since 1 month of age in the form of seizures. She had respiratory symptoms for last 15 days. General physical examination revealed whitish macular patches. Brain imaging was suggestive of cortical tubers and subependymal nodules. The echocardiography showed right atrial rhabdomyoma. Chest CT revealed multiple cysts suggesting LAM. On the basis of above findings, a diagnosis of tuberous sclerosis complex with LAM was made. The infant was started on sirolimus and there was significant clinical and radiological improvement over a period of 2 and half years without any side effects.

scholarly journals Cerebral organoid model reveals excessive proliferation of human caudal late interneuron progenitors in Tuberous Sclerosis Complex

2020 ◽  
Author(s):  
Oliver L. Eichmüller ◽  
Nina S. Corsini ◽  
Ábel Vértesy ◽  
Theresa Scholl ◽  
Victoria-Elisabeth Gruber ◽  
...  
Keyword(s):  
Animal Models ◽  
Human Brain ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Developmental Disorders ◽  
Neutral Loss ◽  
Egfr Signaling ◽  
Cortical Tubers ◽  
Opening Up ◽  
Excessive Proliferation

SummaryAlthough the intricate and prolonged development of the human brain critically distinguishes it from other mammals1, our current understanding of neurodevelopmental diseases is largely based on work using animal models. Recent studies revealed that neural progenitors in the human brain are profoundly different from those found in rodent animal models2–5. Moreover, post-mortem studies revealed extensive migration of interneurons into the late-gestational and post-natal human prefrontal cortex that does not occur in rodents6. Here, we use cerebral organoids to show that overproduction of mid-gestational human interneurons causes Tuberous Sclerosis Complex (TSC), a severe neuro-developmental disorder associated with mutations in TSC1 and TSC2. We identify a previously uncharacterized population of caudal late interneuron progenitors, the CLIP-cells. In organoids derived from patients carrying heterozygous TSC2 mutations, dysregulation of mTOR signaling leads to CLIP-cell over-proliferation and formation of cortical tubers and subependymal tumors. Surprisingly, second-hit events resulting from copy-neutral loss-of-heterozygosity (cnLOH) are not causative for but occur during the progression of tumor lesions. Instead, EGFR signaling is required for tumor proliferation, opening up a promising approach to treat TSC lesions. Our study demonstrates that the analysis of developmental disorders in organoid models can lead to fundamental insights into human brain development and neuropsychiatric disorders.

Extraventricular subependymal giant cell tumor in a child with tuberous sclerosis complex

2009 ◽  
Vol 4 (1) ◽  
pp. 85-90 ◽  
Author(s):  
Robert J. Bollo ◽  
Jonathan L. Berliner ◽  
Ingeborg Fischer ◽  
Daniel K. Miles ◽  
Elizabeth A. Thiele ◽  
...  
Keyword(s):  
Tuberous Sclerosis ◽  
Giant Cell ◽  
Tuberous Sclerosis Complex ◽  
Rapid Growth ◽  
Neonatal Period ◽  
Cell Tumor ◽  
Giant Cell Tumors ◽  
Neurological Morbidity ◽  
Cortical Tubers ◽  
The Right

Subependymal giant cell tumors (SGCTs) are observed in 5–20% of patients with tuberous sclerosis complex (TSC) but account for ~ 25% of neurological morbidity. The authors report the case of a 7-year-old girl with TSC and multiple cortical tubers who presented with worsening seizures in the context of the rapid growth of a cystic, calcified, extraventricular SGCT in the right frontal lobe, initially thought to represent a cortical tuber. The tumor and surrounding tubers were excised, and clinical seizures resolved. This is the first report of an extraventricular SGCT in a child with TSC outside the neonatal period.

scholarly journals In vivo optical properties of cortical tubers in children with tuberous sclerosis complex (TSC): a preliminary investigation

Epilepsia ◽  
2011 ◽  
Vol 52 (9) ◽  
pp. 1699-1704 ◽  
Author(s):  
Sanghoon Oh ◽  
Tara Stewart ◽  
Ian Miller ◽  
Sanjiv Bhatia ◽  
John Ragheb ◽  
...  
Keyword(s):  
Optical Properties ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Preliminary Investigation ◽  
Cortical Tubers

scholarly journals Tuberous sclerosis: a syndrome of incomplete tumor suppression

2006 ◽  
Vol 20 (1) ◽  
pp. 1-9 ◽  
Author(s):  
Todd McCall ◽  
Steven S. Chin ◽  
Karen L. Salzman ◽  
Daniel W. Fults
Keyword(s):  
Cell Growth ◽  
Tuberous Sclerosis ◽  
Signal Transduction Pathway ◽  
Loss Of Function ◽  
Cancer Cell Growth ◽  
Multiple Organs ◽  
The Central Nervous System ◽  
Neurocutaneous Syndrome ◽  
Cortical Tubers ◽  
Psychiatric Complications

Tuberous sclerosis (TS) is a congenital neurocutaneous syndrome (or phacomatosis) characterized by widespread development of hamartomas in multiple organs. For affected individuals, neurological and psychiatric complications are the most disabling and lethal features. Although the clinical phenotype of TS is complex, only three lesions characterize the neuropathological features of the disease: cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas. The latter is a benign brain tumor of mixed neuronal and glial origin. Tuberous sclerosis is caused by loss-of-function mutations in one of two genes, TSC1 or TSC2. The normal cellular proteins encoded by these genes, hamartin and tuberin, respectively, form a heterodimer that suppresses cell growth in the central nervous system by dampening the phosphatidylinositol 3–kinase signal transduction pathway. The authors review the clinical and neuropathological features of TS as well as recent research into the molecular biology of this disease. Through this work, investigators are beginning to resolve the paradoxical findings that malignant cancers seldom arise in patients with TS, even though the signaling molecules involved are key mediators of cancer cell growth.

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