bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2021‒10‒10
thirteen papers selected by
Marti Cadena Sandoval
metabolic-signalling.eu
  1. Cardiac findings in tuberous sclerosis complex.
  2. Primary cells derived from Tuberous Sclerosis Complex patients show autophagy alteration in the haploinsufficiency state.
  3. Autophagy deficiency activates rDNA transcription.
  4. Evolution of electroencephalogram in infants with tuberous sclerosis complex and neurodevelopmental outcome: a prospective cohort study.
  5. Prenatal Sirolimus Treatment for Rhabdomyomas in Tuberous Sclerosis.
  6. Resolving the biological paradox of aneurysm formation in children with tuberous sclerosis complex.
  7. Precision Therapy for Epilepsy Related to Brain Malformations.
  8. 18F-FDG Positron Emission Tomography/Computed Tomography (PET/CT) for Distinguishing Tuberous Sclerosis Complex Lesions from Colon Cancer Metastases.
  9. Growth Curves of Subependymal Giant Cell Tumors in Tuberous Sclerosis Complex.
  10. mTOR-Activating Mutations in RRAGD are Causative for Kidney Tubulopathy and Cardiomyopathy.
  11. PTEN mutations in autism spectrum disorder and congenital hydrocephalus: developmental pleiotropy and therapeutic targets.
  12. Monomethyl branched-chain fatty acid mediates amino acid sensing upstream of mTORC1.
  13. Mapping of mTOR drug targets: Featured platforms for anti-cancer drug discovery.
  1. Lancet. 2021 Oct 02. pii: S0140-6736(21)01855-9. [Epub ahead of print]398(10307): 1256
    Cardiac findings in tuberous sclerosis complex.
    Sjoerd Bouwmeester, Irene E G van Hellemond, Pieter-Jan Vlaar, Johannes C Post.
      
    DOI:  https://doi.org/10.1016/S0140-6736(21)01855-9
  2. Genet Mol Biol. 2021 ;pii: S1415-47572021000600701. [Epub ahead of print]44(4): e20200475
    Primary cells derived from Tuberous Sclerosis Complex patients show autophagy alteration in the haploinsufficiency state.
    Clévia Rosset, Mariane da Cunha Jaeger, Eduardo Filippi-Chiela, Larissa Brussa Reis, Ivaine Taís Sauthier Sartor, Cristina Brinckmann Oliveira Netto, Caroline Brunetto de Farias, Rafael Roesler, Patricia Ashton-Prolla.
      Tuberous sclerosis complex (TSC) is an autosomal dominant cancer predisposition disorder caused by heterozygous mutations in TSC1 or TSC2 genes and characterized by mTORC1 hyperactivation. TSC-associated tumors develop after loss of heterozygosity mutations and their treatment involves the use of mTORC1 inhibitors. We aimed to evaluate cellular processes regulated by mTORC1 in TSC cells with different mutations before tumor development. Flow cytometry analyses were performed to evaluate cell viability, cell cycle and autophagy in non-tumor primary TSC cells with different heterozygous mutations and in control cells without TSC mutations, before and after treatment with rapamycin (mTORC1 inhibitor). We did not observe differences in cell viability and cell cycle between the cell groups. However, autophagy was reduced in mutated cells. After rapamycin treatment, mutated cells showed a significant increase in the autophagy process (p=0.039). We did not observe differences between cells with distinct TSC mutations. Our main finding is the alteration of autophagy in non-tumor TSC cells. Previous studies in literature found autophagy alterations in tumor TSC cells or knock-out animal models. We showed that autophagy could be an important mechanism that leads to TSC tumor formation in the haploinsufficiency state. This result could guide future studies in this field.
    DOI:  https://doi.org/10.1590/1678-4685-GMB-2020-0475
  3. Autophagy. 2021 Oct 06. 1-12
    Autophagy deficiency activates rDNA transcription.
    Yinfeng Xu, Yaosen Wu, Lei Wang, Zhuo Ren, Lijiang Song, Hui Zhang, Chuying Qian, Qian Wang, Zhengfu He, Wei Wan.
      Macroautophagy/autophagy, a highly conserved lysosome-dependent degradation pathway, has been intensively studied in regulating cell metabolism by degradation of intracellular components. In this study, we link autophagy to RNA metabolism by uncovering a regulatory role of autophagy in ribosomal RNA (rRNA) synthesis. Autophagy-deficient cells exhibit much higher 47S precursor rRNA level, which is caused by the accumulation of SQSTM1/p62 (sequestosome 1) but not other autophagy receptors. Mechanistically, SQSTM1 accumulation potentiates the activation of MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) signaling and promotes the assembly of RNA polymerase I pre-initiation complex at ribosomal DNA (rDNA) promoters, which leads to an increase of 47S rRNA transcribed from rDNA. Functionally, autophagy deficiency promotes protein synthesis, cell growth and cell proliferation, both of which are dependent on SQSTM1 accumulation. Taken together, our findings suggest that autophagy deficiency is involved in RNA metabolism by activating rDNA transcription and provide novel mechanisms for the reprogramming of cell metabolism in autophagy-related diseases including multiple types of cancers.Abbreviations: 5-FUrd: 5-fluorouridine; AMPK: AMP-activated protein kinase; ATG: autophagy related; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; ChIP: chromatin immunoprecipitation; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK/ERK: mitogen-activated protein kinase; MTOR: mechanistic target of rapamycin kinase; NBR1: NBR1 autophagy cargo receptor; NFKB/NF-κB: nuclear factor kappa B; NFE2L2/NRF2: nuclear factor, erythroid 2 like 2; OPTN: optineurin; PIC: pre-initiation complex; POLR1: RNA polymerase I; POLR1A/RPA194: RNA polymerase I subunit A; POLR2A: RNA polymerase II subunit A; rDNA: ribosomal DNA; RPS6KB1/S6K1: ribosomal protein S6 kinase B1; rRNA: ribosomal RNA; RUBCN/Rubicon: rubicon autophagy regulator; SQSTM1/p62: sequestosome 1; STX17: syntaxin 17; SUnSET: surface sensing of translation; TAX1BP1: Tax1 binding protein 1; UBTF/UBF1: upstream binding transcription factor; WIPI2: WD repeat domain, phosphoinositide interacting 2; WT: wild-type.
    Keywords:  Autophagy; MTORC1; SQSTM1/p62; rDNA; rRNA
    DOI:  https://doi.org/10.1080/15548627.2021.1974178
  4. Dev Med Child Neurol. 2021 Oct 02.
    Evolution of electroencephalogram in infants with tuberous sclerosis complex and neurodevelopmental outcome: a prospective cohort study.
    Jessie De Ridder, Katarzyna Kotulska, Paolo Curatolo, Anna C Jansen, Eleonora Aronica, David J Kwiatkowski, Floor E Jansen, Sergiusz Jóźwiak, Lieven Lagae, .
      AIM: To describe the evolution of electroencephalogram (EEG) characteristics in infants with tuberous sclerosis complex (TSC) and the relationship with neurodevelopmental outcome at 24 months.METHOD: Eighty-three infants were enrolled in the EPISTOP trial and underwent serial EEG follow-up until the age of 24 months (males n=45, females n=37, median age at enrolment 28d, interquartile range 14-54d). Maturation of the EEG background and epileptiform discharges were compared between the TSC1 and TSC2 variants and between preventive and conventional groups respectively.
    RESULTS: Children with TSC2 more frequently had a slower posterior dominant rhythm (PDR) at 24 months (51% vs 11%, p=0.002), a higher number of epileptiform foci (median=8 vs 4, p=0.003), and a lower fraction of EEGs without epileptiform discharges (18% vs 61%, p=0.001) at follow-up. A slower PDR at 24 months was significantly associated with lower cognitive (median=70 vs 80, p=0.028) and motor developmental quotients (median=70 vs 79, p=0.008). A higher fraction of EEGs without epileptiform discharges was associated with a lower probability of autism spectrum disorder symptoms (odds ratio=0.092, 95% confidence interval=0.009-0.912, p=0.042) and higher cognitive (p=0.004), language (p=0.002), and motor (p=0.001) developmental quotients at 24 months.
    INTERPRETATION: TSC2 is associated with more abnormal EEG characteristics compared to TSC1, which are predictive for neurodevelopmental outcome.
    DOI:  https://doi.org/10.1111/dmcn.15073
  5. Pediatr Neurol. 2021 Sep 25. pii: S0887-8994(21)00207-1. [Epub ahead of print]125 26-31
    Prenatal Sirolimus Treatment for Rhabdomyomas in Tuberous Sclerosis.
    Daniel Ebrahimi-Fakhari, Gabrielle Stires, Eunice Hahn, Darcy Krueger, David Neal Franz.
      BACKGROUND: In tuberous sclerosis, most cardiac rhabdomyomas regress spontaneously. In some cases, the tumors can cause life-threatening hemodynamic compromise requiring subsequent surgical resection. The mechanistic target of rapamycin inhibitors everolimus and sirolimus have shown to be effective treatments for multiple conditions. There are four reports of off-label treatment with transplacental sirolimus for fetal rhabdomyomas due to tuberous sclerosis complex. The optimal dosing regimen is unknown.METHODS: We reviewed the medical records of all patients treated prenatally with sirolimus for rhabdomyomas. All fetuses had a clinical and molecular diagnosis of tuberous sclerosis complex (2012 Consensus Diagnostic Criteria, including a positive genetic test). Clinical history, mechanistic target of rapamycin inhibitor dosing and levels, outcome, and adverse events were reviewed after initiation of sirolimus treatment.
    RESULTS: Three fetuses were treated with maternal sirolimus. Dosing regimens and subsequent trough levels differed from 1 mg/day to 6 mg/day and <1.0 ng/mL to 12.2 ng/mL. Cardiac rhabdomyomas gradually shrank in all patients. Growth restriction was noted in one patient. No severe adverse events occurred during the treatment period.
    CONCLUSIONS: Maternal sirolimus appears to be a safe treatment option in prenatally detected rhabdomyomas with possible need for intervention. Follow-up visits with fetal ultrasound, echocardiography, and laboratory work should be performed weekly during the treatment period. The optimal dosing and trough level timepoints remain unclear. Based on our results, we recommend a sirolimus starting dose of at least 2 mg/m2/day, preferably 3-3.5 mg/m2/day to achieve a target trough level of 10-12 ng/mL.
    Keywords:  Cardiac tumor; Fetal; Maternal; Rapamycin; Sirolimus; Transplacental; Tuberous sclerosis; mTOR inhibitor
    DOI:  https://doi.org/10.1016/j.pediatrneurol.2021.09.014
  6. JVS Vasc Sci. 2021 ;2 72-78
    Resolving the biological paradox of aneurysm formation in children with tuberous sclerosis complex.
    Ulf Hedin, Hans Brunnström, Maria Dahlin, Torbjörn Backman, Valeria Perez de Sa, Phan-Kiet Tran.
      Aortic aneurysms are rare manifestations in children with tuberous sclerosis complex (TSC) with life threating implications. Although an association between TSC, aortic and other aneurysms has been recognized, mechanistic insights explaining the pathophysiology behind aneurysm development and genetic aberrations in TSC have so far been lacking. Here, we summarize existing knowledge on aneurysms in TSC and present a case of a 2-year-old boy with an infrarenal aortic aneurysm, successfully treated with open aortic reconstruction. Histologic examination of the excised aneurysm wall showed distortion of vessel wall structure with loss of elastin and a pathologic accumulation of smooth muscle cells. Until now, these pathologic features have puzzled researchers as proliferating smooth muscle cells would rather be expected to preserve vessel wall integrity. Recent reports exploring the biological consequences of the dysregulated intracellular signaling pathways in patients with TSC provide plausible explanations to this paradox, which may support the development of future therapeutic strategies.
    Keywords:  Aortic aneurysms; Smooth muscle cell phenotype; Tuberous sclerosis; mTOR signaling
    DOI:  https://doi.org/10.1016/j.jvssci.2021.05.003
  7. Neurotherapeutics. 2021 Oct 04.
    Precision Therapy for Epilepsy Related to Brain Malformations.
    Alissa M D'Gama, Annapurna Poduri.
      Malformations of cortical development (MCDs) represent a range of neurodevelopmental disorders that are collectively common causes of developmental delay and epilepsy, especially refractory childhood epilepsy. Initial treatment with antiseizure medications is empiric, and consideration of surgery is the standard of care for eligible patients with medically refractory epilepsy. In the past decade, advances in next generation sequencing technologies have accelerated progress in understanding the genetic etiologies of MCDs, and precision therapies for focal MCDs are emerging. Notably, mutations that lead to abnormal activation of the mammalian target of rapamycin (mTOR) pathway, which provides critical control of cell growth and proliferation, have emerged as a common cause of malformations. These include tuberous sclerosis complex (TSC), hemimegalencephaly (HME), and some types of focal cortical dysplasia (FCD). TSC currently represents the best example for the pathway from gene discovery to relatively safe and efficacious targeted therapy for epilepsy related to MCDs. Based on extensive pre-clinical and clinical data, the mTOR inhibitor everolimus is currently approved for the treatment of focal refractory seizures in patients with TSC. Although clinical studies are just emerging for FCD and HME, we believe the next decade will bring significant advancements in precision therapies for epilepsy related to these and other MCDs.
    Keywords:  Epilepsy; Malformations of cortical development (MCDs); Mammalian target of rapamycin (mTOR); Precision therapy; Somatic mosaicism
    DOI:  https://doi.org/10.1007/s13311-021-01122-6
  8. Am J Case Rep. 2021 Oct 07. 22 e933320
    18F-FDG Positron Emission Tomography/Computed Tomography (PET/CT) for Distinguishing Tuberous Sclerosis Complex Lesions from Colon Cancer Metastases.
    Andrzej Mazurek, Mirosław Dziuk, Ewa Witkowska-Patena, Agnieszka Gizewska, Stanisław Piszczek.
      BACKGROUND Tuberous sclerosis complex (TSC; Bourneville-Pringle disease) is a multisystem genetic disorder manifesting as benign tumors that can affect any system. Malignant neoplasm may coexist in patients with TSC. In such cases, there are diagnostic difficulties in distinguishing between metastatic lesions and benign changes. We show the usefulness of positron emission tomography (PET) in resolving these difficulties. CASE REPORT The purpose of this article is to present the usefulness of metabolic imaging using 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in distinguishing benign from neoplastic lesions in a patient with TSC. A 17-year-old female patient with TSC was referred for 18F-FDG PET/CT with suspected lung and bone metastases. The patient underwent a bilateral nephrectomy because of multiple cysts and angiomyolipomas. A colonoscopy - performed in preparation for kidney transplantation - revealed sevearal colon polyps, one of which was found to be cancerous upon histopathologic examination. A diagnosis of adenocarcinoma G3 was made and a CT scan of the chest and abdomen performed afterwards showed multiple pulmonary nodules and sclerotic bone lesions suggestive of metastases. Two 18F-FDG PET/CT scans (performed within 6 months) showed multiple nodules of 7-15 mm in diameter and changes typical of multifocal micronodular pneumocyte hyperplasia in both lungs. In the bones, we found multiple sclerotic lesions. All of the above findings showed FDG uptake at the level of the background activity which contradicted the lesions' metastatic origin. CONCLUSIONS Using the example of a 17-year-old patient with TSC, we present the usefulness of metabolic imaging using 18F-FDG PET/CT in distinguishing benign from neoplastic lesions.
    DOI:  https://doi.org/10.12659/AJCR.933320
  9. AJNR Am J Neuroradiol. 2021 Oct;42(10): 1891-1897
    Growth Curves of Subependymal Giant Cell Tumors in Tuberous Sclerosis Complex.
    J R Barnett, J H Freedman, H Zheng, E A Thiele, P Caruso.
      BACKGROUND AND PURPOSE: Growth of subependymal giant cell tumor and subependymal nodules has not been well-characterized. The purpose of this study was to determine whether growth curves can differentiate subependymal giant cell tumors from subependymal nodules.MATERIALS AND METHODS: Brain MR imaging of patients with tuberous sclerosis complex were retrospectively reviewed from 2002 to 2018. All lesions in the region of the foramen of Monro were measured. Lesions were categorized on the basis of maximal diameter at the most recent scan: small lesions (<1 cm), indeterminate lesions (>1 cm), and resected lesions (>1 cm and surgically resected). Growth velocity and acceleration on serial imaging were analyzed, and growth rates were calculated between 0 and 20 years of age and compared among the 3 categories.
    RESULTS: Forty-one patients were analyzed. The average age at the earliest scan was 5.9 (SD = 5.7) years. One hundred twenty-six small, 27 indeterminate, and 10 resected lesions were measured. Subependymal giant cell tumors grew faster than indeterminate lesions between 6 and 15 years of age. Indeterminate lesions grew faster than small lesions at 0-10 years of age. Resected lesions showed increased velocity and acceleration of growth compared with indeterminate lesions and small lesions on serial imaging.
    CONCLUSIONS: Growth differentiates subependymal nodules and subependymal giant cell tumors within the first 20 years of life, and the use of velocity and acceleration of growth may refine the diagnostic criteria of subependymal giant cell tumors. Additionally, 6-15 years of age may be an important period to monitor subependymal giant cell tumors at the foramen of Monro because increased growth may help to identify subependymal giant cell tumors that will continue to grow and result in obstructive hydrocephalus.
    DOI:  https://doi.org/10.3174/ajnr.A7231
  10. J Am Soc Nephrol. 2021 Oct 04. pii: ASN.2021030333. [Epub ahead of print]
    mTOR-Activating Mutations in RRAGD are Causative for Kidney Tubulopathy and Cardiomyopathy.
    Karl-Peter Schlingmann, François Jouret, Kuang Shen, Anukrati Nigam, Francisco Arjona, Claudia Dafinger, Pascal Houillier, Deborah Jones, Felix Kleinerüschkamp, Jun Oh, Nathalie Godefroid, Mehmet Eltan, Tülay Güran, Stéphane Burtey, Marie-Christine Parotte, Jens König, Alina Braun, Caro Bos, Maria Ibars Serra, Holger Rehmann, Fried Zwartkruis, Kirsten Renkema, Karin Klingel, Eric Schulze-Bahr, Bernhard Schermer, Carsten Bergmann, Janine Altmüller, Holger Thiele, Bodo Beck, Karin Dahan, David Sabatini, Max Liebau, Rosa Vargas-Poussou, Nine Knoers, Martin Konrad, Jeroen de Baaij.
      Background Over the last decade, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless, approximately 20% of all tubulopathy patients lack a genetic diagnosis. Methods We performed whole-exome and genome sequencings of a patient cohort with a novel inherited salt-losing tubulopathy, hypomagnesemia, and dilated cardiomyopathy. We also conducted subsequent functional analyses in vitro of identified variants of RRAGD, a gene that encodes a small Rag guanosine triphosphatase (GTPase). Results In eight children from unrelated families with a tubulopathy characterized by hypomagnesemia, hypokalemia, salt wasting, and nephrocalcinosis, we identified heterozygous missense variants in RRAGD that mostly occurred de novo Six of these patients also had dilated cardiomyopathy and three underwent heart transplantation. We identified a heterozygous variant in RRAGD that segregated with the phenotype in eight members of a large family with similar kidney manifestations. The GTPase RagD encoded by RRAGD plays a role in mediating amino acid signaling to the mechanistic target of rapamycin complex 1 (mTORC1). RagD expression along the mammalian nephron included the thick ascending limb and the distal convoluted tubule. The identified RRAGD variants were shown to induce a constitutive activation of mTOR signaling in vitro Conclusions Our findings establish a novel disease, which we call autosomal dominant kidney hypomagnesemia (ADKH-RRAGD), that combines an electrolyte-losing tubulopathy and dilated cardiomyopathy. The condition is caused by variants in the RRAGD gene, which encodes Rag GTPase D; these variants lead to an activation of mTOR signaling, suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function.
    DOI:  https://doi.org/10.1681/ASN.2021030333
  11. Trends Neurosci. 2021 Oct 05. pii: S0166-2236(21)00166-1. [Epub ahead of print]
    PTEN mutations in autism spectrum disorder and congenital hydrocephalus: developmental pleiotropy and therapeutic targets.
    Tyrone DeSpenza, Marina Carlson, Shreyas Panchagnula, Stephanie Robert, Phan Q Duy, Nell Mermin-Bunnell, Benjamin C Reeves, Adam Kundishora, Aladine A Elsamadicy, Hannah Smith, Jack Ocken, Seth L Alper, Sheng Chih Jin, Ellen J Hoffman, Kristopher T Kahle.
      The lack of effective treatments for autism spectrum disorder (ASD) and congenital hydrocephalus (CH) reflects the limited understanding of the biology underlying these common neurodevelopmental disorders. Although ASD and CH have been extensively studied as independent entities, recent human genomic and preclinical animal studies have uncovered shared molecular pathophysiology. Here, we review and discuss phenotypic, genomic, and molecular similarities between ASD and CH, and identify the PTEN-PI3K-mTOR (phosphatase and tensin homolog-phosphoinositide 3-kinase-mammalian target of rapamycin) pathway as a common underlying mechanism that holds diagnostic, prognostic, and therapeutic promise for individuals with ASD and CH.
    Keywords:  mTOR; macrocephaly; neurodevelopmental disorders; rapamycin; ventriculomegaly
    DOI:  https://doi.org/10.1016/j.tins.2021.08.007
  12. Dev Cell. 2021 Oct 01. pii: S1534-5807(21)00728-0. [Epub ahead of print]
    Monomethyl branched-chain fatty acid mediates amino acid sensing upstream of mTORC1.
    Mengnan Zhu, Fukang Teng, Na Li, Li Zhang, Shuxian Zhang, Fan Xu, Jing Shao, Haipeng Sun, Huanhu Zhu.
      Animals have developed various nutrient-sensing mechanisms for survival under fluctuating environmental conditions. Although extensive cell-culture-based analyses have identified diverse mediators of amino acid sensing upstream of mTOR, studies using animal models to examine intestine-initiated amino acid sensing mechanisms under specific physiological conditions are lacking. Here, we developed a Caenorhabditis elegans model to examine the impact of amino acid deficiency on development. We discovered a leucine-derived monomethyl branched-chain fatty acid and its downstream metabolite, glycosphingolipid, which critically mediates the overall amino acid sensing by intestinal and neuronal mTORC1, which in turn regulates postembryonic development at least partly by controlling protein translation and ribosomal biogenesis. Additional data suggest that a similar mechanism may operate in mammals. This study uncovers an amino-acid-sensing mechanism mediated by a lipid biosynthesis pathway.
    Keywords:  C. elegans; amino acid sensing; developmental arrest; developmental control; glucosylceramide; mTOR; mTORC1; mmBCFA; nutrient sensing; sphingolipid
    DOI:  https://doi.org/10.1016/j.devcel.2021.09.010
  13. Pharmacol Ther. 2021 Oct 05. pii: S0163-7258(21)00214-X. [Epub ahead of print] 108012
    Mapping of mTOR drug targets: Featured platforms for anti-cancer drug discovery.
    Raef Shams, Yoshihiro Ito, Hideyuki Miyatake.
      The mammalian/mechanistic target of rapamycin (mTOR) is a regulatory protein kinase involved in cell growth and proliferation. mTOR is usually assembled in two different complexes with different regulatory mechanisms, mTOR complex 1 (mTORC1) and mTORC2, which are involved in different functions such as cell proliferation and cytoskeleton assembly, respectively. In cancer cells, mTOR is hyperactivated in response to metabolic alterations and/or oncogenic signals to overcome the stressful microenvironments. Therefore, recent research progress for mTOR inhibition involves a variety of compounds that have been developed to disturb the metabolic processes of cancer cells through mTOR inhibition. In addition to competitive or allosteric inhibition, a new inhibition strategy that emerged mTOR complexes destabilization has recently been a concern. Here, we review the history of mTOR and its inhibition, along with the timeline of the mTOR inhibitors. We also introduce prospective drug targets to inhibit mTOR by disrupting the complexation of the components with peptides and small molecules.
    Keywords:  Cancer therapy; Drug target; mTOR; mTOR inhibitors generations; mTORC1/2 destabilizers
    DOI:  https://doi.org/10.1016/j.pharmthera.2021.108012
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