ArticleNeurology2010
Biallelic TSC gene inactivation in tuberous sclerosis complex.
Article in Neurology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 91 papers.
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Who cites it
91 citing papers in PubMed, 149 citations in OpenAlex.
- Article
- The phosphoproteomic landscape of the neurological manifestations in tuberous sclerosis complex.Acta neuropathologica · 2026Article
- Tuberous sclerosis complex.Nature reviews. Disease primers · 2026Review
- Comparative Evaluation of CT and MRI in Detecting Intracranial and Extracranial Manifestations of Tuberous Sclerosis Complex.Neuropsychiatric disease and treatment · 2026Article
- Late diagnosis and effective everolimus treatment in a familial case of tuberous sclerosis complex: a case report.Frontiers in genetics · 2026Article
- Neuronal hyperactivity becomes mTORC1 independent due to transcriptional changes in tuberous sclerosis complex disease models.Cell reports · 2025Article
- Human TSC2 mutant cells exhibit aberrations in early neurodevelopment accompanied by changes in the DNA Methylome.Human molecular genetics · 2025Article
- Neuronal cell type specific roles for Nprl2 in neurodevelopmental disorder-relevant behaviors.Neurobiology of disease · 2025Article
- The molecular genetics of PI3K/PTEN/AKT/mTOR pathway in the malformations of cortical development.Genes & diseases · 2024Review
- Transcriptome-Wide Association Study Reveals New Molecular Interactions Associated with Melanoma Pathogenesis.Cancers · 2024Article
- Using cortical organoids to understand the pathogenesis of malformations of cortical development.Frontiers in neuroscience · 2024Review
- Utility of droplet digital polymerase chain reaction for studying somatic mosaicism: brain malformations and beyond.Neural regeneration research · 2023Article
- Observation of a Possible Successful Treatment of DEPDC5-Related Epilepsy with mTOR Inhibitor.Neuropediatrics · 2023Article
- Cerebral organoids as an in vitro model to study autism spectrum disorders.Gene therapy · 2023Review
- Specific Features of Focal Cortical Dysplasia in Tuberous Sclerosis Complex.Current issues in molecular biology · 2023Review
- Modeling genetic mosaicism of the mammalian target of rapamycin pathway in the cerebral cortex.Frontiers in mammal science · 2023Article
- Mechanistic target of rapamycin signaling in human nervous system development and disease.Frontiers in molecular neuroscience · 2022Review
- Hyperactivation of mTORC1 in a double hit mutant zebrafish model of tuberous sclerosis complex causes increased seizure susceptibility and neurodevelopmental abnormalities.Frontiers in cell and developmental biology · 2022Article
- Performing Single-Cell Clonal Analysis in the Mouse Brain Using Mosaic Analysis with Double Markers (MADM).Methods in molecular biology (Clifton, N.J.) · 2022Article
- Upregulation of the pathogenic transcription factor SPI1/PU.1 in tuberous sclerosis complex and focal cortical dysplasia by oxidative stress.Brain pathology (Zurich, Switzerland) · 2021Article
31 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
backgroundA pivotal developmental question is whether tubers in tuberous sclerosis complex (TSC) form by germline and somatic TSC1 or TSC2 gene mutations. Loss of TSC1 or TSC2 in vitro and in vivo leads to mTORC1 cascade activation and ribosomal protein S6 phosphorylation (P-S6). Giant cells (GCs) in tubers exhibit S6 phosphorylation, suggesting cell-specific loss of TSC gene function.
methodsTSC1 and TSC2 gene mutations were investigated in DNA extracted from tuber sections (n = 6) and microdissected P-S6-labeled GCs by sequencing and loss of heterozygosity (LOH) analysis to define germline and somatic mutations.
resultsA germline TSC1 mutation was defined in 1 case and TSC2 mutations were defined in 5 cases. LOH was not detected in whole tuber sections or microdissected P-S6-labeled GCs. TSC1 and TSC2 were sequenced in microdissected P-S6-immunolabeled GCs. In 5 specimens, a somatic mutation was identified in single GCs that was not detected in whole tuber sections or leukocyte DNA. Four somatic mutations were novel variants (1 nonsense and 3 missense mutations) and 1 additional nonsense somatic mutation was previously reported as a germline mutation. In 1 case, no somatic mutation was identified. There was reduced expression of TSC1 or TSC2 transcripts in the TSC1 or TSC2 associated specimens. In the cases containing a nonsense mutation, no transcript mRNA was detected, suggesting nonsense-mediated degradation.
conclusionsWe provide evidence to support the hypothesis that tubers form by biallelic TSC1 or TSC2 gene inactivation reflecting a "2-hit" mechanism of germline and somatic mutational events. AML = angiomyolipoma; DN = dysplastic neuron; FFPE = formalin fixed, paraffin embedded; GC = giant cell; H-E = hematoxylin and eosin; LOH = loss of heterozygosity; TSC = tuberous sclerosis complex.
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