bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2022–02–13
fourteen papers selected by
  1. Genotype-phenotype correlation of renal lesions in the tuberous sclerosis complex.
  2. Spectrum of Presentations and Management Strategies in Renal Angiomyolipoma.
  3. Diagnosis and genotype-phenotype correlation in patients with PKD1/TSC2 contiguous gene deletion syndrome.
  4. Disruption of Amygdala Tsc2 in Adolescence Leads to Changed Prelimbic Cellular Activity and Generalized Fear Responses at Adulthood in Rats.
  5. Renal angiomyolipoma presenting as acute abdomen in a previously undiagnosed patient of tuberous sclerosis.
  6. Tuberous Sclerosis Complex Gene Products, Tuberin and Hamartin, Control mTOR Signaling by Acting as a GTPase-Activating Protein Complex toward Rheb.
  7. Srebf1c preserves hematopoietic stem cell function and survival as a switch of mitochondrial metabolism.
  8. NPRL3 loss alters neuronal morphology, mTOR localization, cortical lamination, and seizure threshold.
  9. Rap_GAP Domain of TSC2 Contributes to Tumor Suppression Through mTOR Signaling in Human Hepatocellular Carcinoma.
  10. Role of mTORC1 activity during early retinal development and lamination in human-induced pluripotent stem cell-derived retinal organoids.
  11. mTOR inhibition by TAK-228 is effective against growth, survival and angiogenesis in preclinical retinoblastoma models.
  12. mTOR inhibition prevents angiotensin II-induced aortic rupture and pseudoaneurysm but promotes dissection in Apoe-deficient mice.
  13. Efficacy of mTOR inhibitors (sirolimus) in isolated limb overgrowth: a systematic review.
  14. The RB1CC1 Claw-binding motif: a new piece in the puzzle of autophagy regulation.
  1. Hum Genome Var. 2022 Feb 10. 9(1): 5
    Genotype-phenotype correlation of renal lesions in the tuberous sclerosis complex.
    Yoshinari Muto, Hitomi Sasaki, Makoto Sumitomo, Hidehito Inagaki, Maki Kato, Takema Kato, Shunsuke Miyai, Hiroki Kurahashi, Ryoichi Shiroki.
      Tuberous sclerosis complex (TSC) is an autosomal dominant disease caused by loss-of-function mutations in either of two tumor suppressor genes, TSC1 and TSC2. These mutations lead to the growth of benign tumors and hamartomas in many organs, including those of the central nervous system, the skin, and the kidneys. To investigate the genotype-phenotype correlation, we performed sequence analysis of the TSC1/2 genes using next-generation sequencing. We classified 30 patients with TSC whose pathogenic variants were identified into two groups: those with mutations producing premature termination codons (PTCs) and those with missense mutations. Then, we compared the phenotypes between the two groups. Patients with a PTC were significantly more likely to manifest the major symptoms of the diagnostic criteria than those without a PTC (P = 0.035). The frequencies of subependymal nodules (P = 0.026), cortical tubers (P = 0.026), and renal cysts (P = 0.026) were significantly higher in PTC-containing variants than in cases without a PTC. When the analyses were limited to renal angiomyolipoma (AML) cases with TSC2 mutations, there was no difference in tumor size between cases with and without a PTC. However, the cases with a PTC showed a trend toward disease onset at a younger age and multiple tumors, and bilateral disease was observed in their AML lesions. TSC patients with PTC-producing mutations might potentially manifest more severe TSC phenotypes than those with missense mutations. A larger-scale study with appropriate samples deserves further investigation.
    DOI:  https://doi.org/10.1038/s41439-022-00181-1
  2. J Kidney Cancer VHL. 2022 ;9(1): 42-47
    Spectrum of Presentations and Management Strategies in Renal Angiomyolipoma.
    Sinan Khaddam, Shuchi Gulati.
      Renal angiomyolipoma (rAML) occurs rarely sporadically but is commonly encountered in patients with tuberous sclerosis complex and lymphangioleiomyomatosis. rAML is a rare entity, not seen regularly in daily practice; however, is commonly encountered and diagnosed by clinicians who approach and treat kidney masses. Basic knowledge of this entity is necessary to recognize that despite being benign, these tumors can rarely cause deadly complications such as hemorrhage or severe renal dysfunction or may have malignant components associated with them.
    Keywords:  PEComa; angiomyolipoma; epithelioid renal angiomyolipoma; mTOR inhibitors
    DOI:  https://doi.org/10.15586/jkcvhl.v9i1.221
  3. Clin Nephrol. 2022 Feb 10.
    Diagnosis and genotype-phenotype correlation in patients with PKD1/TSC2 contiguous gene deletion syndrome.
    Shunlai Shang, Yan Mei, Tao Wang, Xinyi Zheng, Keng Chen, Shishi Xiong, Yu Dong, Yuanyuan Chang, Xiaoyuan Wu, Xiangdong Kong, Mei Tan, Li Wu, Yingjie Zhang, Yunming Xiao, Yuansheng Xie, Guangyan Cai, Xiangmei Chen, Qinggang Li.
      Deletions involving the TSC2 and PKD1 genes lead to tuberous sclerosis complex (TSC) and autosomal dominant polycystic kidney disease (ADPKD), which is known as TSC2-PKD1 contiguous gene deletion syndrome (PKDTS). PKDTS leads to severe symptoms and death. There are few reported cases of PKDTS, the phenotypic descriptions are poor, and detailed statistics and descriptions of the time of onset and prognosis of PKDTS are lacking. This is the first study to report on the clinical data of PKDTS patients in China. We analyzed all cases including Chinese individuals and summarized the clinical manifestations and genetic characteristics. Our study was the first to use a combination of exome sequencing and multiplex ligation-dependent probe amplification (MLPA) to screen and diagnose PKDTS. We found that many PKDTS patients have the following: multiple renal cysts; angiofibromas (≥ 3) or fibrous cephalic plaque; subependymal nodules; seizures; intellectual disability. PKDTS develops into polycystic kidney disease from before birth to 17 years old and the time of occurrence of end-stage renal disease or dialysis was 21.62 ± 12.87 years of age, which was significantly earlier than in ADPKD caused by PKD1 mutation. Compared with non-Chinese individuals of diverse ancestry, Chinese people have significant differences in the clinical characteristics, including ungual fibromas (≥ 2), and shagreen patch. Five novel large deletions were identified in Chinese. We found no relationship between the clinical phenotype and the genotype. We combined exome sequencing with MLPA to develop a diagnostic method for PKDTS.
    DOI:  https://doi.org/10.5414/CN110476
  4. Cereb Cortex. 2022 Feb 12. pii: bhab506. [Epub ahead of print]
    Disruption of Amygdala Tsc2 in Adolescence Leads to Changed Prelimbic Cellular Activity and Generalized Fear Responses at Adulthood in Rats.
    Fanny Joly, Pauline Jeckel, Martin Kriebel, Sanket Raut, Nicole El Massioui, Cyrille Vaillend, Luke R Johnson, Hansjürgen Volkmer, Valérie Doyère.
      Adolescence constitutes a period of vulnerability in the emergence of fear-related disorders (FRD), as a massive reorganization occurs in the amygdala-prefrontal cortex network, critical to regulate fear behavior. Genetic and environmental factors during development may predispose to the emergence of FRD at the adult age, but the underlying mechanisms are poorly understood. In the present study, we tested whether a partial knock-down of tuberous sclerosis complex 2 (Tsc2, Tuberin), a risk gene for neurodevelopmental disorders, in the basolateral amygdala (BLA) from adolescence could alter fear-network functionality and create a vulnerability ground to FRD appearance at adulthood. Using bilateral injection of a lentiviral vector expressing a miRNA against Tsc2 in the BLA of early (PN25) or late adolescent (PN50) rats, we show that alteration induced specifically from PN25 resulted in an increased c-Fos activity at adulthood in specific layers of the prelimbic cortex, a resistance to fear extinction and an overgeneralization of fear to a safe, novel stimulus. A developmental dysfunction of the amygdala could thus play a role in the vulnerability to FRD emergence at adulthood. We propose our methodology as an alternative to model the developmental vulnerability to FRD, especially in its comorbidity with TSC2-related autism syndrome.
    Keywords:  adolescence; amygdala; fear conditioning; medial prefrontal cortex; tuberous sclerosis complex 2
    DOI:  https://doi.org/10.1093/cercor/bhab506
  5. BMJ Case Rep. 2022 Feb 07. pii: e248328. [Epub ahead of print]15(2):
    Renal angiomyolipoma presenting as acute abdomen in a previously undiagnosed patient of tuberous sclerosis.
    Arun Prabhahar Rajarajen, Alan Shaji, Jasmine Sethi, Sudheer Kumar Devana.
      
    Keywords:  acute renal failure; renal intervention; renal system
    DOI:  https://doi.org/10.1136/bcr-2021-248328
  6. Curr Biol. 2022 Feb 07. pii: S0960-9822(22)00038-0. [Epub ahead of print]32(3): 733-734
    Tuberous Sclerosis Complex Gene Products, Tuberin and Hamartin, Control mTOR Signaling by Acting as a GTPase-Activating Protein Complex toward Rheb.
    Andrew R Tee, Brendan D Manning, Philippe P Roux, Lewis C Cantley, John Blenis.
      
    DOI:  https://doi.org/10.1016/j.cub.2022.01.027
  7. Stem Cell Reports. 2022 Feb 01. pii: S2213-6711(22)00055-8. [Epub ahead of print]
    Srebf1c preserves hematopoietic stem cell function and survival as a switch of mitochondrial metabolism.
    Yukai Lu, Zihao Zhang, Song Wang, Yan Qi, Fang Chen, Yang Xu, Mingqiang Shen, Mo Chen, Naicheng Chen, Lijing Yang, Shilei Chen, Fengchao Wang, Yongping Su, Mengjia Hu, Junping Wang.
      Mitochondria are fundamental but complex determinants for hematopoietic stem cell (HSC) maintenance. However, the factors involved in the regulation of mitochondrial metabolism in HSCs and the underlying mechanisms have not been fully elucidated. Here, we identify sterol regulatory element binding factor-1c (Srebf1c) as a key factor in maintaining HSC biology under both steady-state and stress conditions. Srebf1c knockout (Srebf1c-/-) mice display increased phenotypic HSCs and less HSC quiescence. In addition, Srebf1c deletion compromises the function and survival of HSCs in competitive transplantation or following chemotherapy and irradiation. Mechanistically, SREBF1c restrains the excessive activation of mammalian target of rapamycin (mTOR) signaling and mitochondrial metabolism in HSCs by regulating the expression of tuberous sclerosis complex 1 (Tsc1). Our study demonstrates that Srebf1c plays an important role in regulating HSC fate via the TSC1-mTOR-mitochondria axis.
    Keywords:  Srebf1c; TSC1; hematopoietic stem cell; mTOR; mitochondrial metabolism
    DOI:  https://doi.org/10.1016/j.stemcr.2022.01.011
  8. Brain. 2022 Feb 08. pii: awac044. [Epub ahead of print]
    NPRL3 loss alters neuronal morphology, mTOR localization, cortical lamination, and seizure threshold.
    Philip H Iffland, Mariah E Everett, Katherine M Cobb-Pitstick, Lauren E Bowser, Allan E Barnes, Janice K Babus, Andrea J Romanowski, Marianna Baybis, Soad Elziny, Erik G Puffenberger, Claudia Gonzaga-Jauregui, Alexandros Poulopoulos, Vincent J Carson, Peter B Crino.
      Mutations in nitrogen permease regulator-like 3 (NPRL3), a component of the GATOR1 complex within the mechanistic target of rapamycin (mTOR) pathway, are associated with epilepsy and malformations of cortical development. Little is known about the effects of NPRL3 loss on neuronal mTOR signaling and morphology, or cerebral cortical development and seizure susceptibility. We report the clinical phenotypic spectrum of a founder NPRL3 pedigree (c.349delG, p.Glu117LysFS; n = 133) among Old Order Mennonites dating to 1727. Next, as a strategy to define the role of NPRL3 in cortical development, CRISPR/Cas9 Nprl3 knockout in Neuro2a cells in vitro and in fetal mouse brain in vivo was used to assess effects of Nprl3 knockout on mTOR activation, subcellular mTOR localization, nutrient signaling, cell morphology and aggregation, cerebral cortical cytoarchitecture, and network integrity. The NPRL3 pedigree exhibited an epilepsy penetrance of 28% and heterogeneous clinical phenotypes with a range of epilepsy semiologies i.e., focal or generalized onset, brain imaging abnormalities i.e., polymicrogyria, focal cortical dysplasia, or normal imaging, and EEG findings, e.g., focal, multi-focal, or generalized spikes, focal or generalized slowing. Whole exome analysis comparing a seizure-free group (n = 37) to those with epilepsy (n = 24) to search for gene modifiers for epilepsy did not identify a unique genetic modifier that explained the variability in seizure penetrance in this cohort. Nprl3 knockout in vitro caused mTOR pathway hyperactivation, cell soma enlargement, and the formation of cellular aggregates seen in time-lapse videos that were prevented with the mTOR inhibitors rapamycin or torin1. In Nprl3 KO cells, mTOR remained localized on the lysosome in a constitutively active conformation, as evidenced by phosphorylation of S6 and 4E-BP1 proteins, even under nutrient starvation (amino acid free) conditions, demonstrating that Nprl3 loss decouples mTOR activation from neuronal metabolic state. To model human malformations of cortical development associated with NPRL3 variants, we created a focal Nprl3 KO in fetal mouse cortex by in utero electroporation and found altered cortical lamination and white matter heterotopic neurons, effects which were prevented with rapamycin treatment. EEG recordings showed network hyperexcitability and reduced seizure threshold to pentylenetetrazol treatment. NPRL3 variants are linked to a highly variable clinical phenotype which we propose result from mTOR-dependent effects on cell structure, cortical development, and network organization.
    Keywords:  GATOR1; cortical malformations; epilepsy; focal cortical dysplasia; mTOR
    DOI:  https://doi.org/10.1093/brain/awac044
  9. DNA Cell Biol. 2022 Feb;41(2): 215-224
    Rap_GAP Domain of TSC2 Contributes to Tumor Suppression Through mTOR Signaling in Human Hepatocellular Carcinoma.
    Mengying Cui, Weibo Jiang, Jiyao Sheng, Jiacheng Wu, Xuewen Zhang.
      Hepatocellular carcinoma (HCC) is an aggressive disease with a high degree of tumor heterogeneity. Genetic lesions of mTOR-related genes, including TSC2 and hyperactivation of mTOR signaling, are common in HCC. However, the association of genetic alterations with hepatocarcinogenesis remains unclear. In this study, continuous truncating mutations occurred within or upstream of the TSC2 Rap_GAP domain in clinical HCC samples. To elucidate whether hyperactivation of mTOR signaling in HCC is caused by TSC2 truncating mutations, HCC cell models carrying the TSC2 deletion (CRISPR/Cas9) or the TSC2 truncating mutation (mutagenesis) were established. Our findings showed that either TSC2 deletion or TSC2 mutant could lead to TSC2 loss-of-function and hyperactivation of mTOR signaling. Furthermore, hyperactivation of mTOR signaling was relieved by rapamycin. Immunohistochemistry of clinical samples confirmed frequent TSC2 loss in HCC. Thus, our study revealed that genetic alterations cause TSC2 loss of function and result in the hyperactivation of mTOR, and high frequency of TSC2 truncating mutations around RAP_GAP domain may be one of the reasons for the hyperactivation of mTOR in HCC patients.
    Keywords:  HCC; Rap_GAP domain; TSC2; mTOR; truncating mutation
    DOI:  https://doi.org/10.1089/dna.2021.0769
  10. Cell Death Discov. 2022 Feb 08. 8(1): 56
    Role of mTORC1 activity during early retinal development and lamination in human-induced pluripotent stem cell-derived retinal organoids.
    Si Hyung Lee, Jung Woo Han, Jin Young Yang, Hyoung Oh Jun, Ji Hong Bang, Heejeong Shin, Ji Hye Choi, Jongwoo Lee, Sanjar Batirovich Madrakhimov, Kyung Hwun Chung, Hun Soo Chang, Jungmook Lyu, Tae Kwann Park.
      Retinal organoids derived from human-induced pluripotent stem cells (hiPSC) are powerful tools for studying retinal development as they model spatial and temporal differentiation of retinal cell types. Vertebrate retinal development involves a delicate and coordinated process of retinal progenitor cell (RPC) differentiation, and the mammalian target of rapamycin complex 1 (mTORC1) has been reported to play a significant role in this complex process. Herein, using hiPSC-derived retinal organoids, we identify the time-dependent role of mTORC1 in retinal development, specifically in retinal ganglion cell (RGC) differentiation and the retinal lamination process, during the early stages of retinal organoid (RO) development. mTORC1 activity in ROs was the highest at 40 days of differentiation. MHY1485-induced hyperactivation of mTORC1 during this period resulted in a significant increase in the overall size of ROs compared to the untreated controls and rapamycin-treated Ros; there was also a marked increase in proliferative activity within the inner and outer layers of ROs. Moreover, the MHY1485-treated ROs showed a significant increase in the number of ectopic RGCs in the outer layers (indicating disruption of retinal laminar structure), with robust expression of HuC/D-binding proteins in the inner layers. These results demonstrate that mTORC1 plays a critical role in the development of hiPSC-derived ROs, especially during the early stages of differentiation.
    DOI:  https://doi.org/10.1038/s41420-022-00837-5
  11. Pharmacol Res Perspect. 2022 Feb;10(1): e00930
    mTOR inhibition by TAK-228 is effective against growth, survival and angiogenesis in preclinical retinoblastoma models.
    Lanlan Tang, Yu Fu, Jiarun Song, Taibing Hu, Kun Li, Zhi Li.
      We and others have shown that aberrant activation of the mammalian target of rapamycin (mTOR) signalling is essential for retinoblastoma progression and has potential therapeutic value. TAK-228 is a potent inhibitor of mTOR1 and 2 with preclinical activity in a variety of cancers. In this study, we report that TAK-228 is a dual inhibitor of retinoblastoma and angiogenesis. TAK-228 inhibits growth and induces apoptosis in a panel of retinoblastoma cell lines, with IC50 at ~0.2 μM. Under the same experimental conditions, TAK-228 was less effective in inhibiting growth and survival in normal retinal and fibroblast cells than retinoblastoma cells. In addition, TAK-228 inhibited retinal endothelial cell capillary network formation, migration, growth and survival. We further demonstrate that TAK-228 inhibits retinoblastoma and retinal angiogenesis through inhibiting mTOR signalling. Rescue studies confirm that mTOR is the target of TAK-228 in both retinoblastoma and retinal endothelial cells. Finally, we confirm the inhibitory effects of TAK-228 on tumor and angiogenesis in retinoblastoma xenograft mouse model. Our findings provide a preclinical rationale to explore TAK-228 as a strategy to treat retinoblastoma and highlight the therapeutic value of targeting mTOR in retinoblastoma.
    Keywords:  TAK-228; angiogenesis; mTOR; retinoblastoma
    DOI:  https://doi.org/10.1002/prp2.930
  12. JCI Insight. 2022 Feb 08. pii: e155815. [Epub ahead of print]7(3):
    mTOR inhibition prevents angiotensin II-induced aortic rupture and pseudoaneurysm but promotes dissection in Apoe-deficient mice.
    Changshun He, Bo Jiang, Mo Wang, Pengwei Ren, Sae-Il Murtada, Alexander W Caulk, Guangxin Li, Lingfeng Qin, Roland Assi, Constantinos J Lovoulos, Martin A Schwartz, Jay D Humphrey, George Tellides.
      Aortic dissection and rupture are triggered by decreased vascular wall strength and/or increased mechanical loads. We investigated the role of mTOR signaling in aortopathy using a well-described model of angiotensin II-induced dissection, aneurysm, or rupture of the suprarenal abdominal aorta in Apoe-deficient mice. Although not widely appreciated, nonlethal hemorrhagic lesions present as pseudoaneurysms without significant dissection in this model. Angiotensin II-induced aortic tears result in free rupture, contained rupture with subadventitial hematoma (forming pseudoaneurysms), dilatation, or healing, while the media invariably thickens regardless of mural tears. Medial thickening results from smooth muscle cell hypertrophy and extracellular matrix accumulation, including matricellular proteins. Angiotensin II activates mTOR signaling in vascular wall cells, and inhibition of mTOR signaling by rapamycin prevents aortic rupture but promotes dissection. Decreased aortic rupture correlates with decreased inflammation and metalloproteinase expression, whereas extensive dissection correlates with induction of matricellular proteins that modulate adhesion of vascular cells. Thus, mTOR activation in vascular wall cells determines whether aortic tears progress to dissection or rupture. Previous mechanistic studies of aortic aneurysm and dissection by angiotensin II in Apoe-deficient mice should be reinterpreted as clinically relevant to pseudoaneurysms, and mTOR inhibition for aortic disease should be explored with caution.
    Keywords:  Cardiovascular disease; Mouse models; Surgery; Vascular Biology
    DOI:  https://doi.org/10.1172/jci.insight.155815
  13. J Hand Surg Eur Vol. 2022 Feb 07. 17531934211073866
    Efficacy of mTOR inhibitors (sirolimus) in isolated limb overgrowth: a systematic review.
    Mohamed Badawy, Yangmyung Ma, Carla Baldrighi, Kerstin Oestreich, Andrea Jester.
      We systematically assessed the literature on the use of sirolimus for the treatment of isolated limb overgrowth conditions and its various modalities of administration in PubMed, Scopus, Ovid MEDLINE, Web of Science, Google Scholar, Cochrane Database of Systematic Reviews, references of journals and grey literature using pre-trialled Medical Subject Headings terms and articles. Eleven articles were included, and 39 patients were identified for review. Sirolimus was given orally in 38 patients and topically in one patient. Sirolimus was found to be highly effective in treatment of isolated limb overgrowth conditions with improvement of symptoms (physical, emotional, social) reported in all but one patient. Dosage and adverse effects seemed to be closely correlated. The result of our study suggests that sirolimus should be considered as an adjuvant or first-line management in isolated limb overgrowth in prospective trials.
    Keywords:  Isolated limb overgrowth; mTOR inhibitors; rapamycin; vascular malformation
    DOI:  https://doi.org/10.1177/17531934211073866
  14. Autophagy. 2022 Feb 08. 1-3
    The RB1CC1 Claw-binding motif: a new piece in the puzzle of autophagy regulation.
    Hana Popelka, Daniel J Klionsky.
      RB1CC1/FIP200 is a subunit of the ULK1 complex in more complex eukaryotes. This large polypeptide was proposed to be a functional homolog of the Atg17 and Atg11 scaffolding proteins in yeast. Previous studies showed that RB1CC1 can bind to various proteins of the macroautophagy/autophagy machinery, where the RB1CC1 Claw domain directly interacts with a short linear segment of its interactors. A mechanistic insight into how the small globular RB1CC1 Claw domain can interact with such an array of structurally variable proteins has been elusive. The recent study by Zhou et al., discussed here, yields structural data that not only provide a unifying mechanistic explanation of these interactions, but also reveals previously unknown RB1CC1 interactors and opens a new field for exploration of autophagy regulation.Abbreviations: FIR: FIP200-interacting region; LIR: LC3-interacting region; pS/p-S: phosphorylated serine.
    Keywords:  Analytical gel filtration chromatography; FIR motif; LIR motif; NMR spectroscopy; autophagy receptor; crystal structure; fluorescence polarization-based assay
    DOI:  https://doi.org/10.1080/15548627.2022.2029234
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