bims-tubesc 2022-10-09 papers

bims-tubesc

Biomed News

on Molecular mechanisms in tuberous sclerosis

Issue of 2022–10–09
eight papers selected by

Tubers and Tumors Are CLIPped Together in Tuberous Sclerosis Complex.
Rapamycin Cannot Reduce Seizure Susceptibility in Infantile Rats with Malformations of Cortical Development Lacking mTORC1 Activation.
Pulmonary lymphangioleiomyomatosis and renal angiomyolipoma in a patient with systemic lupus erythematosus: A case report.
Absence of TSC1 Accelerates CD8+ T cell-mediated Acute Cardiac Allograft Rejection.
Comparison of outcomes after stereoelectroencephalography and subdural grid monitoring in pediatric tuberous sclerosis complex.
Low-grade oncocytic tumor of the kidney is characterized by genetic alterations of TSC1, TSC2, MTOR, or PIK3CA and consistent GATA3 positivity.
MRI diagnosed cardiac lipoma in tuberous sclerosis: a case report with a very rare association.
Cystine induced-mTORC2 activation through promoting Sin1 phosphorylation to suppress cancer cell ferroptosis.

Epilepsy Curr. 2022 Jul-Aug;22(4):22(4): 255-257

Tubers and Tumors Are CLIPped Together in Tuberous Sclerosis Complex.

Louis Dang.

DOI: https://doi.org/10.1177/15357597221101278
Mol Neurobiol. 2022 Oct 04.

Rapamycin Cannot Reduce Seizure Susceptibility in Infantile Rats with Malformations of Cortical Development Lacking mTORC1 Activation.

Minyoung Lee, Eun-Jin Kim, Min-Jee Kim, Mi-Sun Yum.

  The mechanistic target of the rapamycin (mTOR) pathway is involved in cortical development. However, the efficacy of mTOR inhibitors in malformations of cortical dysplasia (MCD) outside of the tuberous sclerosis complex is unknown. We selected the MCD rat model with prenatal MAM exposure to test the efficacy of mTOR inhibitors in MCDs. We explored the early cortical changes of mTOR pathway protein expression in rats aged P15. We also monitored the early treatment effect of the mTOR inhibitor, rapamycin, on N-methyl-D-aspartate (NMDA)-induced spasms at P15 and their behavior in the juvenile stage. In vivo MR spectroscopy was performed after rapamycin treatment and compared with vehicle controls. There was no difference in mTORC1 pathway protein expression between MAM-exposed MCD rats and controls at P15, and prolonged treatment of rapamycin had no impact on NMDA-induced spasms despite poor weight gain. Prenatal MAM-exposed juvenile rats treated with rapamycin showed increased social approaching and freezing behavior during habituation. MR spectroscopy showed altered neurometabolites, including Gln, Glu+Gln, Tau, and Cr. Despite behavioral changes and in vivo neurometabolic alteration with early prolonged rapamycin treatment, rapamycin had no effect on spasms susceptibility in prenatal MAM-exposed infantile rats with MCD without mTORC1 activation. For MAM-exposed MCD rats without mTORC1 activation, treatment options outside of mTOR pathway inhibitors should be explored.

Keywords:  Malformations of cortical development (MCD); Methylazoxymethanol (MAM); N-methyl-D-aspartate (NMDA); Rapamycin; mTOR

DOI:  https://doi.org/10.1007/s12035-022-03033-9
Medicine (Baltimore). 2022 Sep 23. 101(38): e30554

Pulmonary lymphangioleiomyomatosis and renal angiomyolipoma in a patient with systemic lupus erythematosus: A case report.

Jeong Suk Koh, Sina Oh, Chaeuk Chung.

BACKGROUND: The co-incidence of systemic lupus erythematosus (SLE) and tuberous sclerosis with pulmonary lymphangioleiomyomatosis (LAM) and renal angiomyolipoma (AML) is rare. In such patients, the rupture of renal AML may result in fatal circumstances, but this may be preventable.
METHODS: A 22-year-old Asian woman with SLE was admitted to our hospital with severe left-flank pain. Imaging studies showed the bilateral rupture of multiple renal AMLs.
RESULTS: The patient underwent emergency selective transcatheter embolization (TE) of the left renal artery. After TE and massive hydration, the patient complained of dyspnea and postembolization syndrome with fever. The chest computed tomography (CT) revealed pulmonary LAM, pulmonary edema with bilateral pleural effusions, and pneumonic consolidation. After the emergency procedure, the patient was treated with intravenous administration of antibiotics, diuretics, and nonsteroidal anti-inflammatory drugs for 10 days. The patient recovered favorably and was discharged 20 days after the treatment. She was diagnosed with renal AML and pulmonary LAM along with facial angiofibromas as well as tuberous sclerosis complex (TSC), although she had no TSC1 or TSC2 gene mutations.
CONCLUSION: Although rare, SLE may coexist with TSC, along with LAM and AML, with a risk of AML rupture. The activation of the mTOR signaling pathway is shared between SLE and TSC. Thus, in patients with SLE, clinicians should consider imaging studies, such as kidney sonography and chest CT, to screen for possible manifestation of AML and LAM.

DOI: https://doi.org/10.1097/MD.0000000000030554
Aging Dis. 2022 Oct 01. 13(5): 1562-1575

Absence of TSC1 Accelerates CD8+ T cell-mediated Acute Cardiac Allograft Rejection.

Liang Tan, Yanan Xu, Gongbin Lan, Hongxia Wang, Zhanfeng Liang, Zhaoqi Zhang, Qianchuan Tian, Yangxiao Hou, Yong Zhao, Xubiao Xie.

  Tuberous sclerosis complex (TSC) is an autosomal dominant disease caused by inactivating mutations in TSC1 or TSC2.Patients with TSC often require organ transplantation after organ failure. TSC1 serves as an important control node in immune cell development and responses; however, its effect on T cells in transplant immunity has not yet been explored. Here, we characterized the effect of TSC1 deficiency in T cells on acute allograft rejection using a mouse cardiac transplantation model. We observed compromised allograft survival in mice with TSC1-deficient T cells. Notably, the allografts in mice transferred with TSC1-deficient CD8+T cells showed accelerated acute allograft rejection. TSC1 deficiency triggered the increased accumulation of CD8+ T cells in allografts due to augmented infiltration caused by increased CXCR3 expression levels and elevated in-situ proliferation of TSC1-deficient CD8+ T cells. Compared to CD8+ T cells from wild-type (WT) mice, TSC1-deficient CD8+ T cells exhibited enhanced cell proliferation and increased expression levels of interferon-γ and granzyme B after alloantigen stimulation. Rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), is used to treat patients with TSC and prevent rejection after solid-organ transplantation. Although rapamycin induced most cardiac allografts to survive beyond 100 d in WT mice, rapamycin-treated cardiac allografts in TSC1-deficient mice were rejected within 60 d. These results suggest that TSC1-deficient recipients may be more resistant to rapamycin-mediated immunosuppression during organ transplantation. Collectively, TSC1 significantly accelerates acute allograft rejection by enhancing the alloreactivity of CD8+ T cells, making them more resistant to mTOR inhibitor-mediated immunosuppression.

Keywords:  acute rejection; cardiac transplantation; tuberous sclerosis complex 1

DOI:  https://doi.org/10.14336/AD.2022.0224
Neurosurg Focus. 2022 Oct;53(4): E5

Comparison of outcomes after stereoelectroencephalography and subdural grid monitoring in pediatric tuberous sclerosis complex.

Thomas Larrew, Jesse Skoch, S Katie Z Ihnen, Ravindra Arya, Katherine D Holland, Jeffrey R Tenney, Paul S Horn, James L Leach, Darcy A Krueger, Hansel M Greiner, Francesco T Mangano.

   OBJECTIVE: Patients with tuberous sclerosis complex (TSC) epilepsy present with unique clinical challenges such as early seizure onset and high rates of intractability and multifocality. Although there are numerous studies about the safety and efficacy of stereoelectroencephalography (SEEG), this topic has not been studied in TSC patients who have distinct epilepsy profiles. The authors investigated subdural grid (SDG) and SEEG monitoring to determine whether these procedures lead to similar seizure and safety outcomes and to identify features unique to this pediatric population.
METHODS: TSC patients who underwent SDG or SEEG placement and a second epilepsy surgery during the period from 2007 to 2021 were included in this single-center retrospective cohort analysis. Various patient, hospitalization, and epilepsy characteristics were collected.
RESULTS: A total of 50 TSC patients were included in this study: 30 were included in the SDG cohort and 20 in the SEEG cohort. Baseline weekly seizure count did not significantly differ between the 2 groups (p = 0.412). The SEEG group had a greater mean baseline number of antiepileptic drugs (AEDs) (3.0 vs 2.0, p = 0.003), higher rate of previous surgical interventions (25% vs 0%, p = 0.007), and larger proportion of patients who underwent bilateral monitoring (50% vs 13.3%, p = 0.005). Despite this, there was no significant difference in seizure freedom between the SDG and SEEG cohorts. The mean reduction in seizure count was 84.9% and 47.8% of patients were seizure free at last follow-up (mean 79.4 months). SEEG trended toward being a safer procedure than SDG monitoring, with a shorter mean ICU stay (0.7 days vs 3.9 days, p < 0.001), lower blood transfusion rate (0% vs 13.3%, p = 0.140), and lower surgical complication rate (0% vs 10%, p = 0.265).
CONCLUSIONS: In the comparison of the SDG and SEEG cohorts, the SEEG group included patients who appeared to receive more aggressive management and have a higher rate of multifocality, more prior surgical interventions, more AEDs at baseline, and a higher rate of bilateral invasive monitoring. Despite this, the SEEG cohort had similar seizure outcomes and a trend toward increased safety. Based on these findings, SEEG appears to allow for monitoring of a wider breadth of TSC patients given its minimally invasive nature and its relative simplicity for monitoring numerous regions of the brain.

Keywords:  SEEG; pediatric epilepsy; seizure outcomes; subdural grids; tuberous sclerosis complex

DOI:  https://doi.org/10.3171/2022.7.FOCUS22335
Histopathology. 2022 Oct 08.

Low-grade oncocytic tumor of the kidney is characterized by genetic alterations of TSC1, TSC2, MTOR, or PIK3CA and consistent GATA3 positivity.

Sean R Williamson, Ondrej Hes, Kiril Trpkov, Aditi Aggarwal, Abhishek Satapathy, Sourav Mishra, Shivani Sharma, Ankur Sangoi, Liang Cheng, Mahmut Akgul, Muhammad Idrees, Albert Levin, Sudha Sadasivan, Pilar San Miguel Fraile, Joanna Rogala, Eva Comperat, Daniel M Berney, Stela Bulimbasic, Jesse K McKenney, Shilpy Jha, Nakul Y Sampat, Sambit K Mohanty.

  Low-grade oncocytic tumor (LOT) of the kidney has recently emerged as a potential novel tumor type. Despite similarity to oncocytoma or eosinophilic chromophobe renal cell carcinoma, it shows diffuse keratin 7 immunohistochemistry (IHC) and negative KIT (CD117), which differs from both. We aimed to identify the molecular characteristics of these tumors. Seventeen tumors (1 man, 16 women, 9 previously published) fitting the original description of this entity (solid eosinophilic cell morphology, often with areas of tumor cells loosely stretched in edematous stroma, and the above IHC features), were analyzed with a next-generation sequencing panel of 324 cancer-associated genes from formalin-fixed, paraffin-embedded tissue. All tumors harbored at least one alteration in either TSC1 (n= 7, 41%), TSC2 (n=2, 12%), MTOR (n=5, 29%), or PIK3CA (n=4, 24%). Four tumors harbored a second alteration, including two NF2, one each in conjunction with MTOR and TSC2 alterations, one PTEN with TSC1 alteration, and one tumor with both MTOR and TSC1 alterations. No other renal cancer-related or recurring gene alterations were identified. In addition to the previously described IHC findings, 16/16 were positive for GATA3. Eleven patients with follow-up had no metastases or recurrent tumors. Recurrent tuberous sclerosis / MTOR pathway gene alterations in LOT supports its consideration as a distinct morphologic, immunohistochemical, and genetic entity. PIK3CA is another pathway member that may be altered in these tumors. Further study will be necessary to determine whether tumor behavior or syndromic associations differ from those of oncocytoma and chromophobe carcinoma, warranting different clinical consideration.

Keywords:  MTOR; PIK3CA; TSC1; TSC2; low-grade oncocytic tumor; oncocytoma

DOI:  https://doi.org/10.1111/his.14816
Cardiol Young. 2022 Oct 03. 1-3

MRI diagnosed cardiac lipoma in tuberous sclerosis: a case report with a very rare association.

Balaban Ismail, Muzaffer Elmalı, Kemal Baysal.

  Tuberous sclerosis is a genetic multisystem disorder characterised by hamartomas in several organs. Cardiac rhabdomyomas are the main features of the disease but lipomas can very rarely be associated. Herein, we present a very rare association of tuberous sclerosis and cardiac lipoma detected by echocardiography and diagnosed as a lipoma via MRI and fat suppression technic, aim to report this very rare association, and emphasise usefulness of MRI in cardiac mass lesions.

Keywords:  Tuberous sclerosis; cardiac MRI; cardiac lipoma

DOI:  https://doi.org/10.1017/S1047951122003122
Mol Nutr Food Res. 2022 Oct 03. e2200186

Cystine induced-mTORC2 activation through promoting Sin1 phosphorylation to suppress cancer cell ferroptosis.

GuoYan Wang, Lei Chen, SenLin Qin, YiNing Zheng, Chao Xia, JunHu Yao, Ping Wang, Lu Deng.

   SCOPE: Mechanistic target of rapamycin (mTOR) serves as a central signaling node in the coordination of cell growth and metabolism, and it functions via two distinct complexes, namely, mTORC1 and mTORC2. mTORC1 plays a crucial role in sensing amino acids, whereas mTORC2 involves in sensing growth factors. However, it remains largely unclear whether mTORC2 can sense amino acids and the mechanism by which amino acids regulate mTORC2 has not been studied.
METHODS AND RESULTS: After treating cells with indicated concentration of amino acids for different time, it is found that the mTORC2 activation was significantly increased in response to amino acids stimulation, especially cystine. Particularly, knockdown SLC7A11 by siRNA showed that SLC7A11-mediated cystine uptake is responsible for activating mTORC2. Mechanistically, we found that p38 is activated in response to cystine stimulation, and co-immunoprecipitation experiments suggested that p38 regulated the assembly of components within mTORC2 by mediating the phosphorylation of the mTORC2 subunit Sin1 in a cystine-dependent manner. Finally, combined with inducers and inhibitors of ferroptosis and cell viability assay, we observed that cystine-mediated regulation of the p38-Sin1-mTOR-AKT pathway induced resistance to ferroptosis.
CONCLUSION: These results indicate that cystine-induced activation of the p38-Sin1-mTORC2-AKT pathway suppresses ferroptosis. This article is protected by copyright. All rights reserved.

Keywords:  Cystine; Ferroptosis; Sin1; mTORC2; p38

DOI:  https://doi.org/10.1002/mnfr.202200186