Retracted Tuberous sclerosis complex: molecular pathogenesis and animal models

Mutations in one of two genes, TSC1 and TSC2, result in a similar disease phenotype by disrupting the normal interaction of their protein products, hamartin and tuberin, which form a functional signaling complex. Disruption of these genes in the brain results in abnormal cellular differentiation, migration, and proliferation, giving rise to the characteristic brain lesions of tuberous sclerosis complex (TSC) called cortical tubers. The most devastating complications of TSC affect the central nervous system and include epilepsy, mental retardation, autism, and glial tumors. Relevant animal models, including conventional and conditional knockout mice, are valuable tools for studying the normal functions of tuberin and hamartin and the way in which disruption of their expression gives rise to the variety of clinical features that characterize TSC. In the future, these animals will be invaluable preclinical models for the development of highly specific and efficacious treatments for children affected with TSC.

Download Full-text

Cerebral organoid model reveals excessive proliferation of human caudal late interneuron progenitors in Tuberous Sclerosis Complex

10.1101/2020.02.27.967802 ◽

2020 ◽

Author(s):

Oliver L. Eichmüller ◽

Nina S. Corsini ◽

Ábel Vértesy ◽

Theresa Scholl ◽

Victoria-Elisabeth Gruber ◽

...

Keyword(s):

Animal Models ◽

Human Brain ◽

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Developmental Disorders ◽

Neutral Loss ◽

Egfr Signaling ◽

Cortical Tubers ◽

Opening Up ◽

Excessive Proliferation

SummaryAlthough the intricate and prolonged development of the human brain critically distinguishes it from other mammals1, our current understanding of neurodevelopmental diseases is largely based on work using animal models. Recent studies revealed that neural progenitors in the human brain are profoundly different from those found in rodent animal models2–5. Moreover, post-mortem studies revealed extensive migration of interneurons into the late-gestational and post-natal human prefrontal cortex that does not occur in rodents6. Here, we use cerebral organoids to show that overproduction of mid-gestational human interneurons causes Tuberous Sclerosis Complex (TSC), a severe neuro-developmental disorder associated with mutations in TSC1 and TSC2. We identify a previously uncharacterized population of caudal late interneuron progenitors, the CLIP-cells. In organoids derived from patients carrying heterozygous TSC2 mutations, dysregulation of mTOR signaling leads to CLIP-cell over-proliferation and formation of cortical tubers and subependymal tumors. Surprisingly, second-hit events resulting from copy-neutral loss-of-heterozygosity (cnLOH) are not causative for but occur during the progression of tumor lesions. Instead, EGFR signaling is required for tumor proliferation, opening up a promising approach to treat TSC lesions. Our study demonstrates that the analysis of developmental disorders in organoid models can lead to fundamental insights into human brain development and neuropsychiatric disorders.

Download Full-text

Aspects of tuberous sclerosis complex (TSC) protein function in the brain

Biochemical Society Transactions ◽

10.1042/bst0310579 ◽

2003 ◽

Vol 31 (3) ◽

pp. 579-583 ◽

Cited By ~ 15

Author(s):

V. Ramesh

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Protein Function ◽

Direct Interaction ◽

Wild Type ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Dominant Disease ◽

The Central Nervous System ◽

Cortical Tubers

Tuberous sclerosis complex (TSC), an autosomal dominant disease caused by mutations in either TSC1 or TSC2, is characterized by the development of hamartomas in a variety of organs. Concordant with the tumour-suppressor model, loss of heterozygosity (LOH) is known to occur in these hamartomas at both TSC1 and TSC2 loci. LOH has been documented in renal angiomyolipomas, but loss of the wild-type allele in cortical tubers appears very uncommon. We analysed 24 hamartomas from 10 patients for second-hit mutations by several methods, and found no evidence for the inactivation of the second allele in many of the central nervous system (CNS) lesions, including tumours that appear to be clonally derived. We believe that somatic mutations in TSC1 and TSC2 resulting in the loss of wild-type alleles may not be necessary in some tumour types, and other mechanisms may contribute to tumorigenesis in this setting. We have shown that hamartin interacts with neurofilament light chain (NF-L) and could integrate the neuronal cytoskeleton through its direct interaction with NF-L and ERM (ezrin/radixin/moeisin) proteins. Our unpublished work further documents the binding of tuberin with Pam, a protein associated with c-Myc, which is enriched in brain. All these observations suggest that the tuberin–hamartin complex is likely to have distinct functions in the CNS.

Download Full-text

Expression and cellular distribution of FGF13 in cortical tubers of the tuberous sclerosis complex

Neuroscience Letters ◽

10.1016/j.neulet.2021.135714 ◽

2021 ◽

Vol 749 ◽

pp. 135714

Author(s):

Kefu Wu ◽

Jiong Yue ◽

Kaifeng Shen ◽

Jiaojiang He ◽

Gang Zhu ◽

...

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Cellular Distribution ◽

Cortical Tubers

Download Full-text

Neuron–Glia Interactions in Tuberous Sclerosis Complex Affect the Synaptic Balance in 2D and Organoid Cultures

Cells ◽

10.3390/cells10010134 ◽

2021 ◽

Vol 10 (1) ◽

pp. 134

Author(s):

Stephanie Dooves ◽

Arianne J. H. van Velthoven ◽

Linda G. Suciati ◽

Vivi M. Heine

Keyword(s):

Tuberous Sclerosis ◽

Glial Cells ◽

Tuberous Sclerosis Complex ◽

Neuronal Development ◽

Transmembrane Proteins ◽

Significant Burden ◽

Epidermal Growth ◽

And Control ◽

Egf Signaling ◽

The Brain

Tuberous sclerosis complex (TSC) is a genetic disease affecting the brain. Neurological symptoms like epilepsy and neurodevelopmental issues cause a significant burden on patients. Both neurons and glial cells are affected by TSC mutations. Previous studies have shown changes in the excitation/inhibition balance (E/I balance) in TSC. Astrocytes are known to be important for neuronal development, and astrocytic dysfunction can cause changes in the E/I balance. We hypothesized that astrocytes affect the synaptic balance in TSC. TSC patient-derived stem cells were differentiated into astrocytes, which showed increased proliferation compared to control astrocytes. RNA sequencing revealed changes in gene expression, which were related to epidermal growth factor (EGF) signaling and enriched for genes that coded for secreted or transmembrane proteins. Control neurons were cultured in astrocyte-conditioned medium (ACM) of TSC and control astrocytes. After culture in TSC ACM, neurons showed an altered synaptic balance, with an increase in the percentage of VGAT+ synapses. These findings were confirmed in organoids, presenting a spontaneous 3D organization of neurons and glial cells. To conclude, this study shows that TSC astrocytes are affected and secrete factors that alter the synaptic balance. As an altered E/I balance may underlie many of the neurological TSC symptoms, astrocytes may provide new therapeutic targets.

Download Full-text

A novel TSC1 variant associated with tuberous sclerosis and sacrococcygeal teratoma

Human Genome Variation ◽

10.1038/s41439-020-00124-8 ◽

2020 ◽

Vol 7 (1) ◽

Author(s):

Saba Ahmad ◽

Luis Manon ◽

Gifty Bhat ◽

Jerry Machado ◽

Alice Zalan ◽

...

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Cellular Differentiation ◽

Autosomal Dominant ◽

De Novo ◽

Autosomal Dominant Disease ◽

Sacrococcygeal Teratoma ◽

Dominant Disease ◽

The Brain

AbstractTuberous sclerosis complex (TSC) is an autosomal dominant disease associated with tumors and malformed tissues in the brain and other vital organs. We report a novel de novo frameshift variant of the TSC1 gene (c.434dup;p. Ser146Valfs*8) in a child with TSC who initially presented with a sacral teratoma. This previously unreported association between TSC and teratoma has broad implications for the pathophysiology of embryonic tumors and mechanisms underlying cellular differentiation.

Download Full-text

Lymphangioleiomyomatosis (LAM) presenting as recurrent pneumothorax in an infant with tuberous sclerosis: treated successfully with sirolimus

BMJ Case Reports ◽

10.1136/bcr-2018-226244 ◽

2018 ◽

pp. bcr-2018-226244

Author(s):

Lalit Takia ◽

Kana Ram Jat ◽

Anirban Mandal ◽

Sushil Kumar Kabra

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Right Atrial ◽

Age Group ◽

Bilateral Pneumothorax ◽

General Physical Examination ◽

Paediatric Age ◽

Cortical Tubers ◽

General Physical ◽

Multiple Cysts

Lymphangioleiomyomatosis (LAM) either sporadic or a part of tuberous sclerosis complex is rare in paediatric age group. Here, we report a case of LAM with tuberous sclerosis in an infant. She was referred to our institute at the age of 4 months as a case of recurrent bilateral pneumothorax requiring intercostal tube drainage. Detailed history revealed that patient was symptomatic since 1 month of age in the form of seizures. She had respiratory symptoms for last 15 days. General physical examination revealed whitish macular patches. Brain imaging was suggestive of cortical tubers and subependymal nodules. The echocardiography showed right atrial rhabdomyoma. Chest CT revealed multiple cysts suggesting LAM. On the basis of above findings, a diagnosis of tuberous sclerosis complex with LAM was made. The infant was started on sirolimus and there was significant clinical and radiological improvement over a period of 2 and half years without any side effects.

Download Full-text

Extraventricular subependymal giant cell tumor in a child with tuberous sclerosis complex

Journal of Neurosurgery Pediatrics ◽

10.3171/2009.3.peds08225 ◽

2009 ◽

Vol 4 (1) ◽

pp. 85-90 ◽

Cited By ~ 10

Author(s):

Robert J. Bollo ◽

Jonathan L. Berliner ◽

Ingeborg Fischer ◽

Daniel K. Miles ◽

Elizabeth A. Thiele ◽

...

Keyword(s):

Tuberous Sclerosis ◽

Giant Cell ◽

Tuberous Sclerosis Complex ◽

Rapid Growth ◽

Neonatal Period ◽

Cell Tumor ◽

Giant Cell Tumors ◽

Neurological Morbidity ◽

Cortical Tubers ◽

The Right

Subependymal giant cell tumors (SGCTs) are observed in 5–20% of patients with tuberous sclerosis complex (TSC) but account for ~ 25% of neurological morbidity. The authors report the case of a 7-year-old girl with TSC and multiple cortical tubers who presented with worsening seizures in the context of the rapid growth of a cystic, calcified, extraventricular SGCT in the right frontal lobe, initially thought to represent a cortical tuber. The tumor and surrounding tubers were excised, and clinical seizures resolved. This is the first report of an extraventricular SGCT in a child with TSC outside the neonatal period.

Download Full-text

Early white matter development is abnormal in tuberous sclerosis complex patients who develop autism spectrum disorder

Journal of Neurodevelopmental Disorders ◽

10.1186/s11689-019-9293-x ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 10

Author(s):

Anna K. Prohl ◽

◽

Benoit Scherrer ◽

Xavier Tomas-Fernandez ◽

Peter E. Davis ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

White Matter ◽

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Neural Circuits ◽

Diffusion Tensor ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Fiber Bundles ◽

The Brain

Abstract Background Autism spectrum disorder (ASD) is prevalent in tuberous sclerosis complex (TSC), occurring in approximately 50% of patients, and is hypothesized to be caused by disruption of neural circuits early in life. Tubers, or benign hamartomas distributed stochastically throughout the brain, are the most conspicuous of TSC neuropathology, but have not been consistently associated with ASD. Widespread neuropathology of the white matter, including deficits in myelination, neuronal migration, and axon formation, exist and may underlie ASD in TSC. We sought to identify the neural circuits associated with ASD in TSC by identifying white matter microstructural deficits in a prospectively recruited, longitudinally studied cohort of TSC infants. Methods TSC infants were recruited within their first year of life and longitudinally imaged at time of recruitment, 12 months of age, and at 24 months of age. Autism was diagnosed at 24 months of age with the ADOS-2. There were 108 subjects (62 TSC-ASD, 55% male; 46 TSC+ASD, 52% male) with at least one MRI and a 24-month ADOS, for a total of 187 MRI scans analyzed (109 TSC-ASD; 78 TSC+ASD). Diffusion tensor imaging properties of multiple white matter fiber bundles were sampled using a region of interest approach. Linear mixed effects modeling was performed to test the hypothesis that infants who develop ASD exhibit poor white matter microstructural integrity over the first 2 years of life compared to those who do not develop ASD. Results Subjects with TSC and ASD exhibited reduced fractional anisotropy in 9 of 17 white matter regions, sampled from the arcuate fasciculus, cingulum, corpus callosum, anterior limbs of the internal capsule, and the sagittal stratum, over the first 2 years of life compared to TSC subjects without ASD. Mean diffusivity trajectories did not differ between groups. Conclusions Underconnectivity across multiple white matter fiber bundles develops over the first 2 years of life in subjects with TSC and ASD. Future studies examining brain-behavior relationships are needed to determine how variation in the brain structure is associated with ASD symptoms.

Download Full-text

Tuberous Sclerosis Complex

10.1093/med/9780199937837.003.0050 ◽

2017 ◽

Author(s):

Tanjala T. Gipson ◽

Andrea Poretti ◽

Rebecca McClellan ◽

Michael V. Johnston

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Scientific Discovery ◽

Skin Lesions ◽

Benign Tumors ◽

Behavioral Difficulties ◽

Future Directions ◽

Neurocutaneous Disorder ◽

The Status ◽

The Brain

Tuberous sclerosis complex (TSC) is a disease, commonly classified as a neurocutaneous disorder, which may result in benign tumors throughout the brain and body, skin lesions, epilepsy, and cognitive/behavioral difficulties. Scientific discovery in TSC has resulted in the availability of treatments designed to target the neurobiological core of TSC in children. However, research is needed to determine if these treatments are effective for multiple aspects of the TSC phenotype in children. Current pediatric research studies have focused on the effects of early treatment of epilepsy as well as identification of potential biomarkers. This chapter reviews the aspects of TSC unique to pediatric patients, the status of current research, and future directions.

Download Full-text