bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2021‒09‒05
eleven papers selected by
Marti Cadena Sandoval

  1. Biochem Cell Biol. 2021 Aug 31. 1-8
      Tuberous sclerosis complex (TSC), an inherited neurocutaneous disease, is caused by mutations in either the TSC1 or TSC2 gene. This genetic disorder is characterized by the growth of benign tumors in the brain, kidneys, and other organs. As a member of the orphan nuclear receptor family, nuclear receptor related 1 (Nurr1) plays a vital role in some neuropathological diseases and several types of benign or malignant tumors. Here, we explored the potential regulatory role of TSC1/2 signaling in Nurr1 and the effect of Nurr1 in TSC-related tumors. We found that Nurr1 expression was drastically decreased by the disruption of the TSC1/2 complex in Tsc2-null cells, genetically modified mouse models of TSC, cortical tubers of TSC patients, and kidney tumor tissue obtained from a TSC patient. Deficient TSC1/2 complex downregulated Nurr1 expression in an mTOR-dependent manner. Moreover, hyperactivation of mTOR reduced Nurr1 expression via suppression of autophagy. In addition, Nurr1 overexpression inhibited cell proliferation and suppressed cell cycle progression. Therefore, TSC/mTOR/autophagy/Nurr1 signaling is partially responsible for the tumorigenesis of TSC. Taken together, Nurr1 may be a novel therapeutic target for TSC-associated tumors, and Nurr1 agonists or reagents that induce Nurr1 expression may be used for the treatment of TSC.
    Keywords:  Nurr1; autophagie; autophagy; cell proliferation; cible de la rapamycine mTOR; mechanistic target of rapamycin; prolifération cellulaire; sclérose tubéreuse de Bourneville; tuberous sclerosis complex
  2. Lancet Respir Med. 2021 Aug 27. pii: S2213-2600(21)00228-9. [Epub ahead of print]
      Lymphangioleiomyomatosis (LAM) is a slowly progressive, low-grade, metastasising neoplasm of women, characterised by infiltration of the lung parenchyma with abnormal smooth muscle-like cells, resulting in cystic lung destruction. The invading cell in LAM arises from an unknown source and harbours mutations in tuberous sclerosis complex (TSC) genes that result in constitutive activation of the mechanistic target of rapamycin (mTOR) pathway, dysregulated cellular proliferation, and a programme of frustrated lymphangiogenesis, culminating in disordered lung remodelling and respiratory failure. Over the past two decades, all facets of LAM basic and clinical science have seen important advances, including improved understanding of molecular mechanisms, novel diagnostic and prognostic biomarkers, effective treatment strategies, and comprehensive clinical practice guidelines. Further research is needed to better understand the natural history of LAM; develop more powerful diagnostic, prognostic, and predictive biomarkers; optimise the use of inhibitors of mTOR complex 1 in the treatment of LAM; and explore novel approaches to the development of remission-inducing therapies.
  3. Mol Genet Genomic Med. 2021 Sep 04. e1802
      BACKGROUND: Fetal cardiac rhabdomyoma (CR) is strongly associated with tuberous sclerosis complex (TSC), which is caused by variants in TSC1 and TSC2. However, in 10%-15% of patients with clinically confirmed TSC, no TSC1/TSC2 variants are identified by panel sequencing or multiplex ligation-dependent probe amplification (MLPA).METHODS: We analyzed eight fetuses with CR and their families. No TSC1/TSC2 variants had previously been identified for six of these fetuses, and we suspected the other two families of gonadal mosaicism. We performed next-generation sequencing (NGS) using CR tissue, umbilical cord tissue, and parental blood. All positive results, involving two paternal semen, were verified by droplet digital polymerase chain reaction (ddPCR).
    RESULTS: Four fetuses carried low-level mosaic variants (0.05%-14.89%), and two only exhibited somatic mosaic variants in the CR tissue (15.76% and 37.69%). Two fathers had gonadal mosaicism (9.07% and 4.86%). We identified nine pathogenic variants in eight fetuses, including one fetus with a second-hit variant.
    CONCLUSION: The fetuses assessed in this study carried low-level and somatic mosaic variants, and CR tissue from one fetus exhibited a second-hit variant. Heterozygous gonadal variants can exist in patients with low-level mosaicism. Combining NGS with ddPCR improves the accuracy of prenatal TSC diagnosis.
    Keywords:  TSC1/TSC2; cardiac rhabdomyoma; hybrid-capture next-generation sequencing; mosaic variants
  4. Epilepsy Behav Rep. 2021 ;16 100473
      Tuberous sclerosis complex (TSC) is a rare autosomal dominant disease due to pathogenic variants in TSC1 or TSC2 genes. In the brain, TSC is associated with multiple cortical and subcortical malformations including tubers and abnormalities of radial neuronal migration. Approximately 80% of patients develop epilepsy in the first two years of life, most often focal seizures and infantile spasms. As with all seizure disorders, systemic illness and fever can trigger a seizure, and result in status epilepticus or even refractory status epilepticus. Infantile Hemiconvulsion-Hemiplegia and Epilepsy (IHHE) is considered a subcategory of new-onset refractory status epilepticus (NORSE) and presents with hemiclonic seizures in the setting of fever, unihemispheric brain imaging abnormality and hemiparesis. Here, we present an 18-month-old boy with TSC who developed IHHE. His extensive brain malformations and neuronal hyperexcitability in peri-tuberal tissue could have predisposed him to IHHE. In addition to these factors, we postulate that another prerequisite for IHHE is likely a genetic predisposition for an excessive inflammatory response that is yet to be elucidated.
    Keywords:  Infantile Hemiconvulsion-Hemiplegia and Epilepsy; New-Onset Refractory Status Epilepticus; Tuberous sclerosis complex
  5. Exp Ther Med. 2021 Oct;22(4): 1183
      Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with multisystemic involvement usually resulting from mutations in the tuberous sclerosis 1 (TSC1) or TSC2 genes. However, 10 to 25% of patients do not exhibit these mutations. Cerebral cavernous malformations (CCMs) are capillary-venous malformations that can be asymptomatic or cause variable neurological manifestations, including seizures. Familial CCMs are recognized. In both conditions, specific dermatological lesions are associated. We present the case of a 31-year-old female with TSC diagnosed at the age of 18 years who presented with negative genetic testing. She was admitted to our department in 2019 for a sudden increased frequency of focal seizures. Patient examination revealed multiple facial and intraoral angiofibroma, diplopia, right hemihypoesthesia, brisk deep tendon reflexes, and distal leg paresthesia. VideoEEG indicated a frontal paramedian epileptogenic focus. Cerebral magnetic resonance imaging (MRI) and angioMRI identified multiple fronto-parietal cortical tubers, as well as multiple CCMs, with evidence of bleeding in one. Under antiepileptic drug (AED) and mTOR inhibitor treatment, the seizure frequency significantly improved in a short period of time. This is the first reported case of tuberous sclerosis with negative genetic testing associated with multiple cerebral cavernoma. Such complex patients require multidisciplinary management and detailed genetic testing for increasing knowledge on neuro-cutaneous disorders.
    Keywords:  epilepsy; multiple cerebral cavernous malformations; neuro-cutaneous diseases; seizures; skin lesions; tuberous sclerosis with negative genetic testing
  6. Diagn Pathol. 2021 Aug 31. 16(1): 83
      BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by hamartomas in multiple organs associated with germline mutations in TSC1 and TSC2, including exonic, intronic, or mosaic mutations. Gastrointestinal (GI) tract Lymphangioleiomyomatosis (LAM) is an extremely rare manifestation of TSC, with few reported cases. Herein, we aimed to determine the driver mutation, pathogenesis, and relationship of germline and somatic mutations of LAM through whole-genome sequencing (WGS) of the tumor and blood samples and whole transcriptome sequencing (WTS) analysis.CASE PRESENTATION: A nine-year-old girl with a full-blown TSC presented with abdominal masses detected during a routine check-up. Resected intestinal masses were diagnosed as LAM by thorough pathological examination. Interestingly, the LAM presented a somatic TSC2 gene mutation in exon 24 (p.R905W, c.C2713T), and the patient had intron retention by a novel germline mutation in the intron region of TSC2 (chr16:2126489, C > G).
    CONCLUSION: Our case suggests that intron retention by a single nucleotide intronic mutation of TSC2 is sufficient to develop severe manifestations of TSC, but the development of LAM requires an additional somatic oncogenic mutation of TSC2.
    Keywords:  Germline mutation; Intron retention; Lymphangioleiomyomatosis; Perivascular epithelioid cell tumor (PEComa); Somatic mutation; Tuberous sclerosis complex
  7. Pediatr Cardiol. 2021 Sep 01.
      Aortic aneurysm in children is rare, but has been described in the tuberous sclerosis complex (TSC) population. While surgical repair has been utilized as the primary means of intervention, we present the first known case reporting exclusion of a descending thoracic aortic aneurysm with percutaneous covered stent implantation in a pediatric patient with TSC. A review of the literature is also included herein.
    Keywords:  Aortic aneurysm; Covered stent; Tuberous sclerosis
  8. Life Sci. 2021 Aug 31. pii: S0024-3205(21)00907-3. [Epub ahead of print] 119920
      AIMS: The sustained activation of intestinal mechanistic target of rapamycin complex 1 (mTORC1) brought about by repeated mucosal insult or injury has been linked to escalation of gut inflammatory response, which may progress to damage the epithelium if not controlled. This study investigated the role of mTORC1 in the response of macrophage and enterocyte to inflammatory stimuli.MATERIALS AND METHODS: We genetically manipulated human THP-1 monocytes and epithelial intestinal Caco-2 cells to generate stable cell lines with baseline, low or high mTORC1 kinase activity. The effects of THP-1 macrophage secretions onto Caco-2 cells were investigated by means of conditioned media transfer experiments.
    KEY FINDINGS: The priming of mTORC1 for activation promoted lipopolysaccharide (LPS)-mediated THP-1 macrophage immune response as evidenced by the stimulation of inflammatory mediators (TNFα, IL-6, IL-8, IL-1β and IL-10). The treatment of THP-1 macrophages with LPS more than the manipulated level of mTORC1 activity of macrophages determined whether cytokine gene expression was induced in Caco-2 cells. LPS carry over was not responsible for the stimulation of Caco-2 cells' cytokine response. Knocking down Raptor in Caco-2 cells or treating Caco-2 cells with rapamycin enhanced Caco-2 TNFα gene expression revealing the anti-inflammatory role of a functional mTORC1 in intestinal epithelial cells exposed to macrophage-derived pro-inflammatory stimuli.
    SIGNIFICANCE: Taken together, mTORC1 differentially impacts the immune responses of THP-1-derived macrophages and Caco-2 epithelial cells when placed in a pro-inflammatory microenvironment.
    Keywords:  Cell differentiation; Endotoxin; Gut innate immunity; Interleukin; Rapamycin; Tuberous sclerosis complex
  9. Childs Nerv Syst. 2021 Aug 29.
      OBJECTIVE: Recent evidence favors a network concept in tuberous sclerosis (TSC) with seizure generation and propagation related to changes in global and regional connectivity between multiple, anatomically distant tubers. Direct exploration of network dynamics in TSC has been made possible through intracranial sampling with stereoelectroencephalography (sEEG). The objective of this study is to define epileptic networks in TSC using quantitative analysis of sEEG recordings. We also discuss the impact of the definition of these epileptic networks on surgical decision-making.METHODS: Intracranial sEEG recordings were obtained from four pediatric patients who presented with medically refractory epilepsy secondary to TSC and subjected to quantitative signal analysis methods. Cortical connectivity was quantified by calculating pairwise coherence between all contacts and constructing an association matrix. The global coherence, defined as the ratio of the largest eigenvalue to the sum of all the eigenvalues, was calculated for each frequency band (delta, theta, alpha, beta, gamma). Spatial distribution of the connectivity was identified by plotting the leading principal component (product of the largest eigenvalue and its corresponding eigenvector).
    RESULTS: Four pediatric subjects with TSC underwent invasive intracranial monitoring with sEEG, comprising 31 depth electrodes and 250 contacts, for localization of the epileptogenic focus and guidance of subsequent surgical intervention. Quantitative connectivity analysis revealed a change in global coherence during the ictal period in the beta/low gamma (14-30 Hz) and high gamma (31-80 Hz) bands. Our results corroborate findings from existing literature, which implicate higher frequencies as a driver of synchrony and desynchrony.
    CONCLUSIONS: Coordinated high-frequency activity in the beta/low gamma and high gamma bands among spatially distant sEEG define the ictal period in TSC. This time-dependent change in global coherence demonstrates evidence for intra-tuberal and inter-tuberal connectivity in TSC. This observation has surgical implications. It suggests that targeting multiple tubers has a higher chance of seizure control as there is a higher chance of disrupting the epileptic network. The use of laser interstitial thermal therapy (LITT) allowed us to target multiple disparately located tubers in a minimally invasive manner with good seizure control outcomes.
    Keywords:  Epileptic networks; Global coherence; Pediatric; Quantitative analysis; Stereoelectroencephalography (sEEG); Tuberous sclerosis complex (TSC)
  10. Autophagy. 2021 Sep 01. 1-3
      A progressive decline in the macroautophagic/autophagic flux is a hallmark of pancreatic β-cell failure in type 2 diabetes (T2D) but the responsible intrinsic factors and underlying molecular mechanisms are incompletely understood. A stress-sensitive multicomponent cellular loop of the Hippo pathway kinase LATS2 (large tumor suppressor 2), MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) and autophagy regulates β-cell survival and metabolic adaptation. Chronic metabolic stress leads to LATS2 hyperactivation which then induces MTORC1, subsequently impairing the cellular autophagic flux and consequently triggering β-cell death. Reciprocally, under physiological conditions, autophagy controls β-cell survival by lysosomal degradation of LATS2. These signaling cross-talks and the interaction between autophagy and LATS2 are important for the regulation of β-cell turnover and functional compensation under metabolic stress.
    Keywords:  Autophagy; LATS2; MTORC1; beta cells; diabetes; type 2 diabetes
  11. Biomol Ther (Seoul). 2021 Sep 01. 29(5): 506-518
      The imprinted tumour suppressor NOEY2 is downregulated in various cancer types, including ovarian cancers. Recent data suggest that NOEY2 plays an essential role in regulating the cell cycle, angiogenesis and autophagy in tumorigenesis. However, its detailed molecular function and mechanisms in ovarian tumours remain unclear. In this report, we initially demonstrated the inhibitory effect of NOEY2 on tumour growth by utilising a xenograft tumour model. NOEY2 attenuated the cell growth approximately fourfold and significantly reduced tumour vascularity. NOEY2 inhibited the phosphorylation of the signalling components downstream of phosphatidylinositol-3'-kinase (PI3K), including phosphoinositide-dependent protein kinase 1 (PDK-1), tuberous sclerosis complex 2 (TSC-2) and p70 ribosomal protein S6 kinase (p70S6K), during ovarian tumour progression via direct binding to vascular endothelial growth factor receptor-2 (VEGFR-2). Particularly, the N-terminal domain of NOEY2 (NOEY2-N) had a potent anti-angiogenic activity and dramatically downregulated VEGF and hypoxia-inducible factor-1α (HIF-1α), key regulators of angiogenesis. Since no X-ray or nuclear magnetic resonance structures is available for NOEY2, we constructed the threedimensional structure of this protein via molecular modelling methods, such as homology modelling and molecular dynamic simulations. Thereby, Lys15 and Arg16 appeared as key residues in the N-terminal domain. We also found that NOEY2-N acts as a potent inhibitor of tumorigenesis and angiogenesis. These findings provide convincing evidence that NOEY2-N regulates endothelial cell function and angiogenesis by interrupting the VEGFR-2/PDK-1/GSK-3β signal transduction and thus strongly suggest that NOEY2-N might serve as a novel anti-tumour and anti-angiogenic agent against many diseases, including ovarian cancer.
    Keywords:  Antiangiogenic activity; Homology modelling; NOEY2 N-terminal; Ovarian cancer; Tumour suppressor; VEGFR-2