bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2021‒08‒29
six papers selected by
Marti Cadena Sandoval

  1. J Int Med Res. 2021 Aug;49(8): 3000605211035895
      OBJECTIVE: Tuberous sclerosis (TSC) is an autosomal dominant disorder, often detected during childhood. We present the results of genetic testing in a newborn with suspected TSC.METHODS: A newborn with no specific clinical manifestations of TSC showed evidence of TSC on magnetic resonance imaging and echocardiography. Next-generation sequencing (NGS) and multiple ligation-dependent probe amplification (MLPA) of the TSC1 and TSC2 gene exons were carried out to confirm the diagnosis.
    RESULTS: The results of MLPA were negative, but NGS showed a heterozygous mutation in the TSC1 gene comprising insertion of a T residue at c.2165 (exon 17) to c.2166 (exon 17), indicating a loss of function mutation. These results were verified by Sanger sequencing. This genetic change was present in the newborn but the parental genotypes were wild-type, indicating a de novo mutation.
    CONCLUSIONS: In this case, a case of TSC caused by a heterozygous mutation in the TSC1 gene was confirmed by NGS sequencing. This indicates the suitability of genetic testing for the early diagnosis of clinically rare and difficult-to-diagnose diseases, to guide clinical treatment.
    Keywords:  Gene; TSC1; intensive care unit; neonate; next-generation sequencing; tuberous sclerosis
  2. Cancer Discov. 2019 Dec;9(12): 1642
      Structures of components of cancer-associated mTORC1 bound to regulators reveal mechanisms.
  3. J Biol Chem. 2021 Aug 19. pii: S0021-9258(21)00906-6. [Epub ahead of print] 101103
      Heterodimeric Rag GTPases play a critical role in relaying fluctuating levels of cellular amino acids to the sensor mTOR complex 1 (mTORC1). Important mechanistic questions remain unresolved, however, regarding how guanine nucleotide binding enables Rag GTPases to transition dynamically between distinct Yoga-like structural poses that control activation state. Egri et al. identify a critical interdomain hydrogen bond within RagA and RagC that stabilizes their GDP-bound states. They demonstrate that this long-distance interaction controls Rag structure and function to confer appropriate amino acid sensing by mTORC1.
  4. J Thorac Dis. 2021 Jul;13(7): 4054-4062
      Background: Activation of the mTOR pathway has been implicated in the development of several malignancies and alterations in TSC1, TSC2, STK11 and NF1, can lead to the dysregulation of this pathway. Furthermore, mutations in TSC1 and NF2 are known to confer sensitivity to everolimus-an mTOR inhibitor. Based on these data, a single-arm, open label, single-institution phase II basket study was designed to assess the activity of everolimus in patients with solid malignancies whose tumors harbored mutations in TSC1, TSC2, NF1, NF2, or STK11.Methods: A total of 12 patients with histologically confirmed diagnosis of advanced solid tumors (metastatic, recurrent, or unresectable) with mutations in TSC1, TSC2, NF1, NF2 or STK11 genes, who had failed at least one line of standard of care systemic therapy, were enrolled to this open label, single-arm study. Presence of mutations in TSC1, TSC2, NF1, NF2 or STK11 genes was assessed using targeted-next generation sequencing (NGS). All eligible patients were treated with everolimus at an initial dose of 10 mg orally once daily in cycles of 28 days. The primary endpoint of this study was overall response rate (ORR).
    Results: Of 12 patients enrolled, 8 were evaluable for response at the end of 2 cycles. One complete response (CR) was observed (12.5%) and one patient (12.5%) had stable disease (SD), while six (75%) patients showed disease progression. Everolimus was overall well tolerated with anemia, decreased neutrophil and lymphocyte counts, peripheral edema and hyperglycemia representing the most common adverse events. One patient discontinued treatment due to a treatment related grade 4 pericardial effusion. Both patients with CR or SD had a diagnosis of lung adenocarcinoma with NF1 or STK11 mutations, respectively.
    Conclusions: Although this study failed to meet its prespecified ORR threshold for success of 30% or higher, exploratory analyses suggest potential activity for everolimus in a subset of patients with lung adenocarcinomas with STK11 or NF1 mutations. Further studies are necessary to systematically explore the clinical activity of everolimus, potentially as a combination therapy, in these patients.
    Keywords:  Mammalian target of rapamycin (mTOR); NF1; STK11; everolimus; solid tumor
  5. Int J Mol Sci. 2021 Aug 09. pii: 8564. [Epub ahead of print]22(16):
      Sporadic lymphangioleiomyomatosis (S-LAM) is a rare lung disease characterized by the proliferation of smooth muscle-like LAM cells and progressive cystic destruction. Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has a proven efficacy in patients with LAM. However, the therapeutic mechanisms of sirolimus in LAM remain unclear. We aimed to evaluate sirolimus-related lung parenchymal changes and the potential effect in LAM cells and modulating pathological cystic destruction. Lung specimens were examined for histopathological changes by HMB45 staining and compared the LAM patients treated with and without sirolimus. We detected the overexpression of mTOR, HMB45, and phosphorylation of cofilin (p-cofilin) in LAM patients. Sirolimus showed efficacy in patients with LAM, who exhibited a reduced expression of mTOR and p-cofilin as well as reduced interstitial septal thickness. In addition, sirolimus suppresses mTOR and p-cofilin, thus suppressing the migration and proliferation of LAM cells isolated from the patient's lung tissue. This study demonstrates that interstitial septal thickness, as determined by histological structural analysis. Sirolimus effectively reduced the expression of p-cofilin and interstitial septal thickness, which may be a novel mechanism by sirolimus. Moreover, we develop a new method to isolate and culture the LAM cell, which can test the possibility of medication in vitro and impact this current study has on the LAM field. The development of approaches to interfere with mTOR-cofilin1-actin signaling may result in an option for S-LAM therapy.
    Keywords:  interstitial septal thickness; lymphangioleiomyomatosis; mTOR; p-cofilin; sirolimus
  6. Cell Death Dis. 2021 Aug 24. 12(9): 805
      Denervation of skeletal muscles results in a rapid and programmed loss of muscle size and performance, termed muscle atrophy, which leads to a poor prognosis of clinical nerve repair. Previous researches considered this process a result of multiple factors, such as protein homeostasis disorder, mitochondrial dysfunction, endoplasmic reticulum stress (ERS), and apoptosis, while their intrinsic association remains to be explored. In this study, Sestrin2 (SESN2), a stress-inducible protein, was shown to act as a key protective signal involved in the crosstalk therein. SESN2 expression was induced in the gastrocnemius two weeks post denervation, which was accompanied by ERS, mitochondrial dysfunction, and apoptosis. Knockdown of SESN2 aggravated this situation and resulted in severer atrophy. Similar results were also found in rotenone-treated C2C12 cells. Furthermore, SESN2 was demonstrated to be induced by an ERS-activated transcription factor CCAAT-enhancer-binding protein beta (C/EBPβ). Once induced, SESN2 halted protein synthesis by inhibiting the mammalian target of rapamycin complex 1 (mTORC1), thereby attenuating ERS. Moreover, increased SESN2 activated the specific autophagic machinery and facilitated the aggregation of sequestosome 1 (SQSTM1, p62) on the mitochondrial surface, which promoted the clearance of damaged mitochondria through mitophagy. Collectively, the SESN2-mediated unfolded protein response (UPR) and mitophagy play a critical role in protecting against denervated muscle atrophy, which may provide novel insights into the mechanism of skeletal muscle atrophy following denervation.