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Background: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder affecting multiple organ systems, with a prevalence of 1:6,760-1:13,520 live births in Germany. On the molecular level, TSC is caused by heterozygous loss-of-function variants in either of the genes TSC1 or TSC2, encoding the Tuberin-Hamartin complex, which acts as a critical upstream suppressor of the mammalian target of rapamycin (mTOR), a key signaling pathway controlling cellular growth and metabolism. Despite the therapeutic success of mTOR inhibition in treating TSC-associated manifestations, studies with mTOR inhibitors in children with TSC above two years of age have failed to demonstrate beneficial effects on disease-related neuropsychological deficits.

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Article Synopsis
  • There is a significant sex bias in autism spectrum disorder (ASD), with 80% of cases diagnosed in males, making it challenging to uncover the biological reasons behind this difference.
  • Loss of function mutations leading to dysregulated mTORC1 signaling are prevalent in individuals with tuberous sclerosis (TSC), and over 50% of those with TSC are also diagnosed with ASD, indicating a strong genetic link.
  • In experiments with mice, it was found that while motor coordination deficits are similar in both male and female mice, social interaction impairments are significantly worse in males, suggesting that certain behavioral issues in ASD may vary based on sex.
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Genetic and pharmacological targeting of mTORC1 in mouse models of arteriovenous malformation expose non-cell autonomous signalling in HHT.

Angiogenesis

December 2024

Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, 171 77, Sweden.

Article Synopsis
  • Arteriovenous malformations (AVMs) are abnormal connections between arteries and veins that negatively affect the cardiovascular system and can be caused by mutations in the endoglin gene, leading to the disease HHT1.
  • Research indicates that mTORC1 signaling is activated in the retinal vasculature of HHT mouse models and is influenced by the loss of endoglin, showing a complex interaction with AVM biology.
  • While inhibiting mTORC1 in endothelial cells only slightly reduced AVM severity, increasing its activity surprisingly led to less severe AVMs, suggesting a need for balanced mTORC1 signaling; total inhibition with rapamycin was the most effective treatment, raising questions about other pathways involved.
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Article Synopsis
  • Pathogenic mutations in genes associated with tuberous sclerosis complex (TSC) affect various types of kidney tumors like eosinophilic solid and cystic renal cell carcinoma (ESC RCC) and oncocytic tumors.
  • A study validated a TSC2 immunohistochemistry (IHC) assay on tissues from renal tumors to assess the presence of TSC2 mutations, achieving high predictive values for diagnosing these tumors.
  • The findings highlight that TSC2 IHC can help identify renal tumors linked to TSC/mTOR pathway mutations, supporting its use in diagnostic processes.
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Structure of the human TSC:WIPI3 lysosomal recruitment complex.

Sci Adv

November 2024

Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.

Tuberous sclerosis complex (TSC) is targeted to the lysosomal membrane, where it hydrolyzes RAS homolog-mTORC1 binding (RHEB) from its GTP-bound to GDP-bound state, inhibiting mechanistic target of rapamycin complex 1 (mTORC1). Loss-of-function mutations in TSC cause TSC disease, marked by excessive tumor growth. Here, we overcome a high degree of continuous conformational heterogeneity to determine the 2.

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