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Gene expression analysis of tuberous sclerosis complex cortical tubers reveals increased expression of adhesion and inflammatory factors.

ABSTRACT: Cortical tubers in patients with tuberous sclerosis complex are associated with disabling neurological manifestations, including intractable epilepsy. While these malformations are believed to result from the effects of TSC1 or TSC2 gene mutations, the molecular mechanisms leading to tuber formation, as well as the onset of seizures, remain largely unknown. We used the Affymetrix Gene Chip platform to provide the first genome-wide investigation of gene expression in surgically resected tubers, compared with histological normal perituberal tissue from the same patients or autopsy control tissue. We identified 2501 differentially expressed genes in cortical tubers compared with autopsy controls. Expression of genes associated with cell adhesion, for example, VCAM1, integrins and CD44, or with the inflammatory response, including complement factors, serpinA3, CCL2 and several cytokines, was increased in cortical tubers, whereas genes related to synaptic transmission, for example, the glial glutamate transporter GLT-1, and voltage-gated channel activity, exhibited lower expression. Gene expression in perituberal cortex was distinct from autopsy control cortex suggesting that even in the absence of tissue pathology the transcriptome is altered in TSC. Changes in gene expression yield insights into new candidate genes that may contribute to tuber formation or seizure onset, representing new targets for potential therapeutic development.

SUBMITTER: Boer K

PROVIDER: S-EPMC2888867 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Cell-specific alterations of glutamate receptor expression in tuberous sclerosis complex cortical tubers.

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Suppressed expression of autophagosomal protein LC3 in cortical tubers of tuberous sclerosis complex.

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Gene expression analysis of TSC-tubers reveals increased expression of adhesion and inflammatory factors

Project description:Cortical tubers in patients with tuberous sclerosis complex (TSC) are associated with cognitive disability and intractable epilepsy. While these developmental malformations are believed to result from the effects of TSC1 or TSC2 Gene mutations, the molecular mechanisms leading to tuber formation during brain development as well as the onset of seizures remain largely unknown. We used the Affymetrix Gene Chip platform as a genome-wide strategy to define the Gene expression profile of cortical tubers resected during epilepsy surgery compared to histologically normal perituberal tissue (adjacent to the cortical tuber) from the same patients or autopsy control tissue.

2010-02-02 | GSE16969 | GEO

Coding and small non-coding transcriptional landscape of tuberous sclerosis complex cortical tubers: implications for pathophysiology and treatment.

Project description:Tuberous Sclerosis Complex (TSC) is a rare genetic disorder that results from a mutation in the TSC1 or TSC2 genes leading to constitutive activation of the mechanistic target of rapamycin complex 1 (mTORC1). TSC is associated with autism, intellectual disability and severe epilepsy. Cortical tubers are believed to represent the neuropathological substrates of these disabling manifestations in TSC. In the presented study we used high-throughput RNA sequencing in combination with systems-based computational approaches to investigate the complexity of the TSC molecular network. Overall we detected 438 differentially expressed genes and 991 differentially expressed small non-coding RNAs in cortical tubers compared to autopsy control brain tissue. We observed increased expression of genes associated with inflammatory, innate and adaptive immune responses. In contrast, we observed a down-regulation of genes associated with neurogenesis and glutamate receptor signaling. MicroRNAs represented the largest class of over-expressed small non-coding RNA species in tubers. In particular, our analysis revealed that the miR-34 family (including miR-34a, miR-34b and miR-34c) was significantly over-expressed. Functional studies demonstrated the ability of miR-34b to modulate neurite outgrowth in mouse primary hippocampal neuronal cultures. This study provides new insights into the TSC transcriptomic network along with the identification of potential new treatment targets.

| S-EPMC5556011 | biostudies-literature

Increased expression of complement components in tuberous sclerosis complex and focal cortical dysplasia type 2B brain lesions.

Project description:ObjectiveIncreasing evidence supports the contribution of inflammatory mechanisms to the neurological manifestations of epileptogenic developmental pathologies linked to mammalian target of rapamycin (mTOR) pathway dysregulation (mTORopathies), such as tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD). In this study, we aimed to investigate the expression pattern and cellular distribution of the complement factors C1q and C3 in resected cortical tissue of clinically well-characterized patients with TSC and FCD2B.MethodsWe applied immunohistochemistry in TSC (n = 29) and FCD2B (n = 32) samples and compared them to autopsy and biopsy controls (n = 27). Furthermore, protein expression was observed via Western blot, and for descriptive colocalization studies immunofluorescence double labeling was performed.ResultsProtein expression for C3 was significantly upregulated in TSC and FCD2B white and gray matter lesions compared to controls. Staining of the synaptic vesicle protein synaptophysin showed a remarkable increase in the white matter of both TSC and FCD2B. Furthermore, confocal imaging revealed colocalization of complement factors with astroglial, microglial, neuronal, and abnormal cells in various patterns.SignificanceOur results demonstrate that the prominent activation of the complement pathway represents a common pathological hallmark of TSC and FCD2B, suggesting that complement overactivation may play a role in these mTORopathies.

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Deep learning in rare disease. Detection of tubers in tuberous sclerosis complex.

Project description:OBJECTIVE:To develop and test a deep learning algorithm to automatically detect cortical tubers in magnetic resonance imaging (MRI), to explore the utility of deep learning in rare disorders with limited data, and to generate an open-access deep learning standalone application. METHODS:T2 and FLAIR axial images with and without tubers were extracted from MRIs of patients with tuberous sclerosis complex (TSC) and controls, respectively. We trained three different convolutional neural network (CNN) architectures on a training dataset and selected the one with the lowest binary cross-entropy loss in the validation dataset, which was evaluated on the testing dataset. We visualized image regions most relevant for classification with gradient-weighted class activation maps (Grad-CAM) and saliency maps. RESULTS:114 patients with TSC and 114 controls were divided into a training set, a validation set, and a testing set. The InceptionV3 CNN architecture performed best in the validation set and was evaluated in the testing set with the following results: sensitivity: 0.95, specificity: 0.95, positive predictive value: 0.94, negative predictive value: 0.95, F1-score: 0.95, accuracy: 0.95, and area under the curve: 0.99. Grad-CAM and saliency maps showed that tubers resided in regions most relevant for image classification within each image. A stand-alone trained deep learning App was able to classify images using local computers with various operating systems. CONCLUSION:This study shows that deep learning algorithms are able to detect tubers in selected MRI images, and deep learning can be prudently applied clinically to manually selected data in a rare neurological disorder.

| S-EPMC7190137 | biostudies-literature

Giant cyst-like cortical tubers in an adult with tuberous sclerosis presenting as spastic tetraplegia.

Project description:Introduction and importanceTuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by inactivating mutations in TSC1 or TSC2 genes, resulting in benign lesions that involve multiple organs including the central nerves system.Case presentationA 39-year-old male of known TSC presented with inability to walk for two months. On physical examination, he was consciously oriented and cooperative, but he had spastic tetraparesis in the muscle-motor examination. On brain imaging, cystic lesions of various sizes in the supra and infratentorial regions were observed, consistent with giant cyst-like tubers. However, they could not differentiate from TSC related brain tumors based on the imaging findings. He underwent surgical intervention to resect/evacuate the large cystic lesion, which had the mass effects on the brain stem. The pathologic examinations revealed no malignant changes.Clinical discussionAlthough the cyst-like lesions in the cortex and white matter have been reported in several previous studies of TSC, they usually had a small size and similar intensity to CSF on T2- weighted MRI and low intensity on FLAIR images.ConclusionGiant cyst-like cortical tubers are exceedingly rare and atypical findings of tuberous sclerosis complex, which are usually associated with epilepsy and neurological deficits. Though many authors recommend the brain MRI as a screening tool for patients with TSC once every 1-3 years until the age of 25, our report showed that the brain lesions may develop in patients with TSC even after the age of 25. Thus, the MRI should be used periodically in all patients with TSC to timely detect the brain lesions and prevent the patient's disability. Surgical resection is the mainstay of treatment for the symptomatic cystic-like cortical tuber; however, it may recur after resection.

| S-EPMC9289415 | biostudies-literature

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