Alternative titles; symbols
HGNC Approved Gene Symbol: TSC2
Cytogenetic location: 16p13.3 Genomic coordinates (GRCh38): 16:2,047,985-2,089,491 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.3 | ?Focal cortical dysplasia, type II, somatic | 607341 | 3 | |
| Lymphangioleiomyomatosis, somatic | 606690 | 3 | ||
| Tuberous sclerosis-2 | 613254 | Autosomal dominant | 3 |
Using pulsed field gel electrophoresis (PFGE), the European Chromosome 16 Tuberous Sclerosis Consortium (1993) identified 5 deletions at 16p13.3 in patients with tuberous sclerosis-2 (613254). These were mapped to a 120-kb region that was cloned in cosmids and from which 4 genes were isolated. One gene, designated TSC2, was interrupted by all 5 PFGE deletions, and closer examination revealed several intragenic mutations, including 1 de novo deletion. In this case, Northern blot analysis identified a shortened transcript, while reduced expression was observed in another TSC family, confirming TSC2 as the chromosome 16 TSC gene. The 5.5-kb TSC2 transcript was found to be widely expressed, and its protein product, designated tuberin, to have a region of homology to the GTPase-activating protein GAP3.
The TSC gene on chromosome 16 was originally designated TSC4. With the consensus that there is no locus for tuberous sclerosis on chromosome 11 or chromosome 12, the TSC gene on chromosome 16 was designated TSC2.
The TSC2 gene has 41 small exons spanning 45 kb of genomic DNA and encodes a 5.5-kb mRNA (van Bakel et al., 1997).
Using tuberous sclerosis families in which linkage to chromosome 9 (TSC1) had been excluded, Kandt et al. (1992) demonstrated linkage with D16S283, the closest marker on the proximal side of the locus for polycystic kidney disease type 1 (173900), on chromosome 16p13. A lod score of 9.50 at theta = 0.02 was observed; 1 family independently presented a lod score of 4.44 at theta = 0.05.
Using a positional cloning strategy, the European Chromosome 16 Tuberous Sclerosis Consortium (1993) mapped the TSC2 gene to chromosome 16p13.3.
Brook-Carter et al. (1994) stated that the TSC2 gene lies immediately adjacent to the PKD1 gene (601313) on chromosome 16p13.3 in a tail-to-tail orientation.
Imai et al. (1998) determined that the TSC2 gene lies immediately adjacent to the NTHL1 gene (602656) on chromosome 16p13.3 in a head-to-head orientation.
Wienecke et al. (1995) generated antisera against the N-terminal and C-terminal portions of tuberin, and found that these antisera specifically recognize a 180-kD protein in immunoprecipitation and immunoblotting analyses. A wide variety of human cell lines expressed the 180-kD tuberin protein, and subcellular fractionation showed that most tuberin is found in a membrane/particulate fraction. They found that immunoprecipitates of native tuberin contain an activity that specifically stimulated the intrinsic GTPase activity of the RAS-related protein RAP1A (179520). Tuberin did not stimulate the GTPase activity of RAP2 (179540), HRAS (190020), Rac, or RHO (165370). These results suggested to the authors that the loss of tuberin leads to constitutive activation of RAP1 in tumors of patients with tuberous sclerosis.
Xiao et al. (1997) reported that tuberin exhibits substantial GAP activity towards RAB5 (179512), a critical and rate-limiting component of the docking and fusion process of the endocytic pathway. An intermediate adaptor-like molecule, rabaptin-5 (603616), mediates the tuberin association with RAB5. The authors suggested that tuberin functions as a RAB5GAP in vivo to regulate RAB5-GTP activity negatively in endocytosis. They speculated that loss of the RAB5GAP activity encoded by the tumor suppressor gene TSC2 might interfere with the endocytic pathway, leading to missorting of internalized growth factor receptors or other molecules that would otherwise undergo lysosomal degradation.
Imai et al. (1998) performed promoter analysis of the TSC2 gene, which indicated that multiple transcription-initiation sites are present in exons 1, 1a, and 1b and that TATA and CAAT boxes are lacking. Northern blot analysis revealed ubiquitous but variable expression of a 5.5-kb transcript.
Nellist et al. (2001) studied the ability of tuberin to act as a chaperone for hamartin (TSC1; 605284) by cotransfecting native hamartin- and tuberin-containing missense mutations into COS cells. A domain within tuberin necessary for the chaperone function was identified in the vicinity of residues 611-769. Although mutations that prevented tuberin tyrosine phosphorylation also inhibited tuberin-hamartin binding and the chaperone function, the authors concluded that only hamartin is phosphorylated in the tuberin-hamartin complex.
Hodges et al. (2001) used a series of hamartin and tuberin constructs to assay for interaction in the yeast 2-hybrid system. Hamartin (amino acids 302-430) and tuberin (amino acids 1-418) interacted strongly with one another. A region of tuberin encoding a putative coiled-coil (amino acids 346-371) was necessary but not sufficient to mediate the interaction with hamartin, as more N-terminal residues were also required. A region of hamartin (amino acids 719-998) predicted to encode coiled-coils was capable of oligomerization but was not important for the interaction with tuberin. Subtle, non-truncating mutations identified in patients with tuberous sclerosis and located within the putative binding regions of hamartin or tuberin abolished or dramatically reduced interaction of the proteins.
Using a combination of biochemistry and bioinformatics, Manning et al. (2002) identified substrates of S/T-protein kinases activated by phosphoinositide 3-kinase (PI3K; see 171833). This approach identified the TSC2 gene product, tuberin, as a potential target of AKT1 (164730). Upon activation of PI3K, tuberin was phosphorylated on consensus recognition sites for PI3K-dependent S/T kinases. Moreover, AKT1 could phosphorylate tuberin in vitro and in vivo. The authors determined that amino acid residues ser939 and thr1462 of tuberin are PI3K-regulated phosphorylation sites, and thr1462 was constitutively phosphorylated in PTEN (601728) -/- tumor-derived cell lines. A tuberin mutant lacking the major PI3K-dependent phosphorylation sites could block the activation of S6K1 (608938), suggesting a means by which the PI3K-AKT1 pathway regulates S6K1 activity.
Inoki et al. (2002) demonstrated that Tsc2 is inactivated, and its interaction with Tsc1 is disrupted, following phosphorylation by Akt. Potter et al. (2002) described a similar relationship between Tsc2 and Akt in Drosophila. Inoki et al. (2002) showed that the Tsc1-Tsc2 complex inhibits the mammalian target of rapamycin (MTOR; 601231), leading to inhibition of ribosomal S6K1 and activation of eukaryotic translation initiation factor 4E-binding protein-1 (EIF4EBP1; 602223).
Inoki et al. (2003) found that activation of AMPK (see 600497) by energy starvation of human embryonic kidney cells resulted in the phosphorylation of TSC2 on thr1227 and ser1345. Knockdown of TSC2 by RNA interference eliminated the ATP depletion-induced dephosphorylation of S6K. Tsc2 -/- mouse embryonic fibroblasts were defective in S6k dephosphorylation in response to energy starvation. Starvation-induced dephosphorylation of S6k was restored by expression of wildtype Tsc2, but not an Ampk phosphorylation mutant, in Tsc2 -/- cells. The authors determined that TSC2 controlled cell size in response to energy limitation and protected cells from glucose deprivation-induced apoptosis; these functions were also dependent on AMPK phosphorylation of TSC2. Inoki et al. (2003) concluded that TSC2 and AMPK phosphorylation is essential in the cellular energy response.
Zhang et al. (2003) determined that Drosophila Rheb (601293) is a direct target of Tsc2 GAP activity both in vivo and in vitro. Point mutations in the GAP domain of Tsc2 disrupted its ability to regulate Rheb without affecting the interaction between Tsc2 and Tsc1.
Stocker et al. (2003) found genetic and biochemical evidence that Drosophila Rheb functions downstream of Tsc1 and Tsc2 in the TOR signaling pathway to control cell growth.
Shumway et al. (2003) identified 14-3-3-beta (601289) as a TSC2-binding protein by yeast 2-hybrid screening of a HeLa cell cDNA library using rat Tsc2 and by immunoprecipitation of human embryonic kidney cells following ectopic expression of TSC2. Binding of 14-3-3-beta did not impair TSC1-TSC2 association, and phosphorylation of TSC2 on ser1210 was required for 14-3-3 binding. Shumway et al. (2003) noted that ser1210 is not 1 of the multiple sites phosphorylated by AKT. Binding of 14-3-3-beta to TSC2 at phosphorylated ser1210 reduced the ability of the TSC1-TSC2 complex to inhibit the phosphorylation of ribosomal protein S6 kinase, impairing the ability of the complex to inhibit cell growth.
Using transfected mouse embryo fibroblasts, Nellist et al. (2005) analyzed the effects of nontruncating TSC2 mutations on tuberin-hamartin interaction, on the phosphorylation of tuberin by PKB (see AKT1, 164730), and on the tuberin-dependent inhibition of S6 (RPS6; 180460) phosphorylation. Amino acid changes to the central region of TSC2 (outside the GAP domain) resulted in complete inactivation of tuberin. Nellist et al. (2005) concluded that this central domain is necessary for formation of the tuberin-hamartin complex.
Inoki et al. (2006) identified TSC2 as a physiologic substrate of GSK3 (606784) and showed that WNT (see 604663) stimulates the MTOR signaling pathway by inhibiting GSK3 phosphorylation of TSC2. The results revealed a function of TSC2/MTOR signaling in tumorigenesis caused by dysfunction of the WNT pathway and a mechanism for WNT stimulation of protein synthesis and cell growth.
Loss of the TSC genes leads to constitutive activation of MTOR and downstream signaling elements, resulting in tumor development, neurologic disorders, and severe insulin/IGF1 (147440) resistance. Ozcan et al. (2008) found that loss of TSC1 or TSC2 in cell lines and mouse or human tumors caused endoplasmic reticulum (ER) stress and activated the unfolded protein response. The resulting ER stress played a significant role in the MTOR-mediated negative feedback inhibition of insulin action and increased the vulnerability to apoptosis.
The majority of disease-associated TSC mutations result in substantial decreases in TSC1 or TSC2 protein levels, suggesting that protein turnover plays a critical role in TSC regulation. Hu et al. (2008) showed that FBW5 (609072), DDB1 (600045), CUL4A (CUL4A; 603137), and ROC1 (RBX1; 603814) formed an E3 ubiquitin ligase that regulated TSC2 protein stability and TSC complex turnover.
Choi et al. (2008) showed that Tsc1 and Tsc2 had critical functions in axon formation and growth in mouse. Overexpression of Tsc1/Tsc2 suppressed axon formation, whereas lack of Tsc1 or Tsc2 induced ectopic axons in vitro and in mouse brain. Tsc2 was phosphorylated and inhibited in axons, but not dendrites. Inactivation of Tsc1/Tsc2 promoted axonal growth, at least in part, via upregulation of neuronal polarity Sad kinase (see BRSK2; 609236), which was also elevated in cortical tubers of a TSC patient. Choi et al. (2008) concluded that TSC1 and TSC2 have critical roles in neuronal polarity, and that a common pathway regulates polarization and growth in neurons and cell size in other tissues.
Hartman et al. (2009) reported that hamartin (TSC1) localized to the basal body of the primary cilium, and that Tsc1-null and Tsc2-null mouse embryonic fibroblasts (MEFs) were significantly more likely to contain a primary cilium than wildtype controls. In addition, the cilia of Tsc1- and Tsc2-null MEFs were 17 to 27% longer than cilia from wildtype MEFs. Enhanced ciliary formation in the Tsc1- and Tsc2-null MEFs was not abrogated by rapamycin, which suggests an mTOR-independent mechanism. Polycystin-1 (PC1; see 601313) has been found to interact with TSC2, but Pkd1-null MEFs did not have enhanced ciliary formation. While activation of mTOR has been observed in renal cysts from ADPKD patients, Pkd1-null MEFs did not have evidence of constitutive mTOR activation, thereby underscoring the independent functions of the TSC proteins and PC1 in regulation of primary cilia and mTOR.
Auerbach et al. (2011) used electrophysiologic and biochemical assays of neuronal protein synthesis in the hippocampus of Tsc2 heterozygote and Fmr1 (309550)-null male mice to show that synaptic dysfunction caused by these mutations falls at opposite ends of a physiologic spectrum. Tsc2 heterozygous mice have a specific deficit in metabotropic glutamate receptor-mediated long-term synaptic depression. Synaptic, biochemical, and cognitive defects in these mutants were corrected by treatments that modulate metabotropic Grm5 (604102) in opposite directions, and deficits in the mutants disappeared in mice bred to carry both mutations. Auerbach et al. (2011) concluded that normal synaptic plasticity and cognition occur within an optimal range of metabotropic glutamate receptor-mediated protein synthesis, and deviations in either direction can lead to shared behavioral impairments.
Ha et al. (2014) found that 6-hydroxydopamine-induced oxidative stress induced expression of Tnfaip8l1 (615869), which they called Oxi-beta, in cultured mouse dopaminergic neurons, leading to increased autophagy and cell death. Increased Oxi-beta expression stabilized Tsc2, a negative regulator of Mtor, which suppresses autophagy and promotes cell survival. Oxi-beta stabilized Tsc2 by binding directly to Fbxw5, a component of the Cul4 E3 ligase complex that promotes proteasomal degradation of Tsc2. Oxi-beta competed with Tsc2 for binding to Fbxw5, and the Oxi-beta-Tsc2 interaction protected Tsc2 from proteasome-mediated degradation.
Zhang et al. (2014) showed that as well as increasing protein synthesis, mTORC1 (see 601231) activation in mouse and human cells also promotes an increased capacity for protein degradation. Cells with activated mTORC1 exhibited elevated levels of intact and active proteasomes through a global increase in the expression of genes encoding proteasome subunits. The increase in proteasome gene expression, cellular proteasome content, and rates of protein turnover downstream of mTORC1 were all dependent on induction of the transcription factor NRF1 (NFE2L1; 163260). Genetic activation of mTORC1 through loss of the tuberous sclerosis complex tumor suppressors TSC1 (605284) or TSC2, or physiologic activation of mTORC1 in response to growth factors or feeding, resulted in increased NRF1 expression in cells and tissues. Zhang et al. (2014) found that this NRF1-dependent elevation in proteasome levels serves to increase the intracellular pool of amino acids, which thereby influences rates of new protein synthesis. The authors therefore concluded that mTORC1 signaling increases the efficiency of proteasome-mediated protein degradation for both quality control and as a mechanism to supply substrate for sustained protein synthesis.
Ranek et al. (2019) showed that phosphorylation or gain- or loss-of-function mutations at either of 2 adjacent serine residues in TSC2 (S1365 and S1366 in mice; S1364 and S1365 in humans) could bidirectionally control mTORC1 activity stimulated by growth factors or hemodynamic stress, and consequently modulate cell growth and autophagy. However, basal mTORC1 activity remained unchanged. In the heart, or in isolated cardiomyocytes or fibroblasts, protein kinase G1 (PKG1; 176894) phosphorylates these TSC2 sites. PKG1 is a primary effector of nitric oxide and natriuretic peptide (see 108780) signaling, and protects against heart disease. Suppression of hypertrophy and stimulation of autophagy in cardiomyocytes by PKG1 requires TSC2 phosphorylation. Homozygous knockin mice that expressed a phosphorylation-silencing mutation in TSC2 (S1365A) developed worse heart disease and had higher mortality after sustained pressure overload of the heart, owing to mTORC1 hyperactivity that could not be rescued by PKG1 stimulation. However, cardiac disease was reduced, and survival of heterozygote Tsc2(S1365A) knockin mice subjected to the same stress was improved by PKG1 activation or expression of a phosphorylation-mimicking mutation (Tsc2(S1365E)). Resting mTORC1 activity was not altered in either knockin model. Ranek et al. (2019) concluded that TSC2 phosphorylation is both required and sufficient for PKG1-mediated cardiac protection against pressure overload. They suggested that the serine residues identified by them provided a genetic tool for bidirectional regulation of the amplitude of stress-stimulated mTORC1 activity.
Tuberous Sclerosis 2
Kandt et al. (1992) estimated that approximately 60% of tuberous sclerosis families have their disorder as a result of mutation on chromosome 16.
Using DNA markers, Green et al. (1994), found allele loss on 16p13.3 in 3 angiomyolipomas, 1 cardiac rhabdomyoma, 1 cortical tuber, and 1 giant cell astrocytoma. This led them to suggest that the TSC2 gene functions as a tumor suppressor gene, in accordance with the Knudson hypothesis. Similar evidence for a tumor suppressor function for the TSC1 gene (605284) had been adduced from studies of loss of heterozygosity (LOH).
Carbonara et al. (1996) studied LOH in both the TSC1 and TSC2 loci and 7 tumor suppressor gene-containing regions, p53 (191170), NF1 (613113), NF2 (607379), BRCA1 (113705), APC (611731), VHL (608537), and MLM (155600), in 20 hamartomas from 18 tuberous sclerosis patients. Overall, 8 angiomyolipomas, 8 giant cell astrocytomas, 1 cortical tuber, and 3 rhabdomyomas were analyzed. LOH at either TSC locus was found in a large fraction of the informative patients, both sporadic (7 of 14) and familial (1 of 4). A statistically significant preponderance of LOH of TSC2 was observed in the sporadic group (P less than 0.01). Carbonara et al. (1996) suspected that bias in the selection for TSC patients with the most severe organ impairment was responsible for the finding. According to this suggestion, a TSC2 defect may confer a greater risk for early kidney failure or, possibly, a more rapid growth of a giant cell astrocytoma. None of the 7 antioncogenes tested showed LOH, indicating that the loss of either TSC gene product may be sufficient to promote hamartomatous cell growth. The observation of LOH at different markers in an astrocytoma and in an angiomyolipoma from the same patients suggested to the authors the multifocal origin of a second-hit mutation.
Green et al. (1996) used nonrandom X chromosome inactivation studies to demonstrate the clonality of tuberous sclerosis hamartomas. Previously, LOH for DNA markers in the region of either the TSC1 gene on 9q34 or the TSC2 gene on 16p13.3 had supported the conclusion that these lesions are indeed clonal. In the studies of X-chromosome inactivation, Green et al. (1996) examined clonality in 13 TSC hamartomas from female cases by analyzing X-chromosome inactivation in DNA extracted from archival paraffin-embedded tumors compared with normal tissue from the same patient. Seven of the cases were sporadic; 2 were from families linked to 9q34, 1 was from a family linked to 16p13.3 and 3 were from families too small to assign by linkage. Only 4 of the 13 hamartomas had previously shown LOH, 1 in the region of the TSC1 gene and 3 in the region of the TSC2 gene. A PCR assay was used to analyze differential methylation of the HpaII restriction site adjacent to the androgen-receptor triplet-repeat polymorphism on Xq11-q12. In 12 of the lesions, there was a skewed inactivation pattern, one X-chromosome being fully methylated and the other unmethylated. Normal tissue showed a random pattern of inactivation. The finding was considered particularly intriguing by the authors since the lesions were composed of more than 1 cell type.
Henske et al. (1996) analyzed 87 lesions from 47 TSC patients for LOH in the TSC1 and TSC2 regions. Of the 28 patients with angiomyolipomas or rhabdomyomas LOH for 16p13 was detected in lesions from 12 (57%). LOH for 9q34 was detected only in 1 patient. The authors noted that LOH occurred only in 4% of TSC brain lesions and suggested that TSC brain lesions may result from a different pathogenetic mechanism than TSC kidney or rhabdomyoma lesions.
Niida et al. (2001) analyzed 24 hamartomas from 10 patients for second-hit mutations by multiple methods including LOH analysis, SSCP screening of TSC1 and TSC2, promoter methylation studies of TSC2, and clonality analysis. The results provided evidence that complete inactivation of the TSC genes is characteristic of renal angiomyolipomas but not of other TSC lesions.
Sepp et al. (1996) described the spectrum of LOH in 51 hamartomas from 34 cases of tuberous sclerosis. Of 51 hamartomas analyzed, 21 (41%) showed LOH; 16 hamartomas showed LOH around TSC2 and 5 showed LOH in the vicinity of TSC1. No hamartomas showed LOH for markers around both loci. Sepp et al. (1996) reported that there did not appear to be any major differences in the frequency of LOH between the different types of hamartoma.
Bjornsson et al. (1996) studied 6 TSC-associated renal cell carcinomas (RCCs). Their findings suggested that some TSC-associated RCCs have clinical, pathologic, and genetic features which distinguish them from sporadic RCC. Clinically, the TSC-associated RCC occurred at a younger age (36 years) than sporadic tumors and occurred primarily in women (5 out of 6 cases). LOH was observed on 9q34, 16p13.3, and in 2 cases on chromosome 3p.
To facilitate the search for mutations in tuberin, Wilson et al. (1996) designed an RT-PCR-based assay system to scan the expressed coding region of the TSC2 gene in lymphoblasts. Using 34 overlapping PCR assays, they performed SSCP analysis of DNA from 26 apparently sporadic TSC cases, 2 TSC families uninformative for linkage, and 2 confirmed chromosome 16-linked TSC families. Of the 60 chromosomes scanned, 14 showed abnormal SSCP mobility shifts. Using direct PCR sequencing, they identified 5 missense mutations, 1 3-bp in-frame deletion, and 1 2-bp frameshift deletion, 1 nonsense mutation, 1 29-bp tandem duplication, and 5 silent nucleotide changes thought to be polymorphisms. There was no apparent clustering of mutations within the TSC2 gene. The authors commented that the diversity of mutation types argued that TSC2 may not act in a classic tumor suppressor fashion. In addition, they saw no specific correlation between the different mutations and clinical severity or expression.
Au et al. (1997) tested 88 TSC probands with the TSC2 cDNA by Southern blot analysis, searching for gross deletions, rearrangements, or insertions. They detected 2 deletions and a rare intragenic polymorphic variant.
Van Bakel et al. (1997) stated that mutations in the TSC2 gene on 16p13.3 are responsible for approximately 50% of familial tuberous sclerosis. Large germline deletions of TSC2 occur in less than 5% of cases, and a number of small intragenic mutations have been described. Using the protein truncation test (PTT), van Bakel et al. (1997) analyzed mRNA from 18 unrelated cases of tuberous sclerosis for TSC2 mutations. Three cases were predicted to be TSC2 mutations on the basis of linkage analysis or because a hamartoma from the patient showed LOH for 16p13.3 markers. Confirmed mutations were identified in 5 (28%) of the families studied.
Sampson et al. (1997) studied 27 unrelated patients with tuberous sclerosis and renal cystic disease. They found that 22 patients had contiguous deletions of TSC2 and PKD1. In 17 patients with constitutional deletions, cystic disease was severe, with early renal insufficiency. One patient with deletion of TSC2 and of only the 3-prime untranslated region (UTR) of PKD1 had few cysts. Four patients were somatic mosaics; the severity of their cystic disease varied considerably. Mosaicism and mild cystic disease also were demonstrated in the parents of 3 of the constitutionally deleted patients. Five patients without contiguous deletions had relatively mild cystic disease, 3 of whom had gross rearrangements of TSC2, while 2 had no identified mutation. Thus, Sampson et al. (1997) concluded that significant renal cystic disease in tuberous sclerosis usually reflects mutational involvement of the PKD1 gene, and mosaicism for large deletions of TSC2 and PKD1 occurs frequently.
Maheshwar et al. (1997) used SSCP analysis of exons 34-38 of the TSC2 gene in 173 unrelated patients with tuberous sclerosis, and direct sequencing of variant conformers together with study of additional family members enabled characterization of mutations in 14 cases. Missense mutations occurred in exons 36, 37, and 38 in 8 cases, 4 of whom shared the same recurrent change, pro1675 to leu (191092.0009). Each of the 5 different missense mutations identified was shown to occur de novo in at least 1 sporadic case of tuberous sclerosis. The high proportion of missense mutations detected in the region of the TSC2 gene that encodes the GAP-related domain supports its key role in the regulation of cellular growth.
Au et al. (1998) tested 90 patients with tuberous sclerosis complex for mutations in the TSC2 gene by means of single-strand conformation analysis (SSCA) of genomic DNA. Patients included 56 sporadic cases and 34 familial probands. All 41 exons of the TSC2 gene were studied. They identified 32 SSCA changes: 22 disease-causing mutations, and 10 polymorphic variants. Mutations were detected at a much higher frequency in the sporadic cases (32%) than in the multiplex families (9%). Among the 8 families for which linkage to the TSC2 region of chromosome 16 had been determined, only 1 mutation was found. Mutations were distributed uniformly across the gene; they included 5 deletions, 3 insertions, 10 missense mutations, 2 nonsense mutations, and 2 tandem duplications. No mutations were detected in exons 25 and 31, which are spliced out in the isoforms. No correspondence between variability of phenotype and type of mutation (missense vs early termination) was found. They commented that diagnostic testing is difficult because of the genetic heterogeneity of TSC, with at least 2 causative genes, the large size of the TSC2 gene, and the variety of mutations.
While the TSC1 gene on 9q34.3 and the TSC2 gene on 16p appeared to account for all familial cases of tuberous sclerosis, with each representing approximately 50% of the mutations, the proportion of sporadic cases with mutations in TSC1 and TSC2 was unknown. Beauchamp et al. (1998) examined the entire coding sequence of the TSC2 gene in 20 familial and 20 sporadic cases and identified a total of 21 mutations representing 50% and 55% of familial and sporadic cases, respectively. Of the 21 mutations, 20 were novel and included 6 missense, 6 nonsense, 5 frameshifts, 2 splice alterations, a 34-bp deletion resulting in abnormal splicing, and an 18-bp deletion which maintained the reading frame. The mutations were distributed throughout the coding sequence with no specific hotspots. There was no apparent correlation between mutation type and clinical severity of the disease. The results documented that at least 50% of sporadic cases arise from mutations in the TSC2 gene.
Verhoef et al. (1999) described a 12-year-old boy with tuberous sclerosis complex who presented with a large retroperitoneal tumor. Exploratory surgery revealed an infiltrative tumor originating from the pancreas, with local metastases to the lymph nodes. The histologic diagnosis was malignant islet cell tumor. Pancreatic hormone levels were normal. A connection between the malignancy and TSC was demonstrated by LOH of the TSC2 gene in the tumor. The primary mutation in this patient, gln478 to ter (191092.0008), was located in exon 13 of the TSC2 gene. Pancreatic islet cell tumors have mainly been associated with type I multiple endocrine neoplasia (MEN1; 131100).
The findings of Verhoef et al. (1999) supported a tumor suppressor function for the TSC2 gene in accordance with the Knudson 2-hit hypothesis. In this case, the first hit was the gln478-to-ter germline mutation; the second hit involved deletion of the haplotype allele, leaving the nonfunctional germline mutated copy. A similar conclusion was reached by Au et al. (1999), who studied hamartomas from patients in whom the germline TSC2 mutation had been identified (Au et al., 1998). In angiomyolipomas from 2 independent patients and in facial angiofibromas from 1 patient, the authors could identify the second somatic hit in the TSC2 gene. All were diagnosed with tuberous sclerosis according to standard criteria by Roach et al. (1998). These 3 patients had serious renal disease resulting primarily from angiomyolipomas with only minor cysts present. The findings in these patients demonstrated that intragenic TSC2 mutations, without involvement of the neighboring PKD1 gene, can result in a life-threatening renal phenotype in patients with tuberous sclerosis.
Cheadle et al. (2000) reviewed the molecular genetic advances in tuberous sclerosis. They found reports of 154 cases with mutations in the TSC1 gene and 292 cases with mutations in the TSC2 gene. Fifty percent (145/292) of TSC2 mutations were point mutations. In contrast to TSC1, nonsense mutations in TSC2 made up only 38% (55 of 145) in the point mutation class.
Khare et al. (2001) reported a missense mutation in the TSC2 gene (191092.0011) in 2 families with mild physical features of TSC. One family also had significant clustering of neuropsychiatric disorders in the affected individuals.
Le Caignec et al. (2009) reported a French kindred with tuberous sclerosis in which they identified 3 independent heterozygous mutations: the R905W mutation in a female patient (191092.0014), a splice site mutation in her first cousin once removed (191092.0016), and a missense mutation (W441X; 191092.0017) in 3 patients from a more distantly related branch of the family, including a woman, her son, and her niece. None of the 3 apparently de novo mutations was found in any of 16 unaffected family members tested. Le Caignec et al. (2009) suggested that perhaps the TSC2 mutation rate had been underestimated, or that a heritable defect in a DNA repair gene segregating in the family, unlinked to the TSC2 gene, might predispose to the occurrence of multiple TSC2 mutations in this family.
Pulmonary Lymphangioleiomyomatosis
Pulmonary lymphangioleiomyomatosis (LAM; 606690), also known as pulmonary lymphangiomyomatosis, is a rare disease that occurs almost exclusively in women. Although most cases of LAM are pulmonary, cases with retroperitoneal, pelvic, or perirenal involvement in lymph nodes and extranodal sites have been reported. LAM can occur as an isolated disorder or in association with tuberous sclerosis. Among patients with tuberous sclerosis it is said to be the third most frequent cause of TSC-related death, after renal disease and brain tumors (Castro et al., 1995). Renal angiomyolipomas occur in approximately 50% of sporadic LAM patients and in 70% of TSC patients. Loss of heterozygosity (LOH) in the chromosomal region for the TSC2 gene occurs in 60% of TSC-associated angiomyolipomas. Because of the similar pulmonary and renal manifestations of TSC and sporadic LAM, Smolarek et al. (1998) hypothesized that LAM and TSC have a common genetic basis. They analyzed renal angiomyolipomas from 13 women with sporadic LAM for LOH in the region of the TSC1 (9q34) and TSC2 (16p13) genes. TSC2 LOH was detected in 7 (54%) of the angiomyolipomas. They also found TSC2 LOH in 4 lymph nodes from a woman with retroperitoneal LAM. No TSC1 LOH was found. The findings indicated that the TSC2 gene may be involved in the pathogenesis of sporadic LAM. They noted, however, that genetic transmission of LAM had not been reported. Women with LAM may have low penetrance germline TSC2 mutations, or they may be mosaic, with TSC2 mutations in the lung and the kidney but not in other organs. Examination of DNA from peripheral blood lymphocytes or lymphoblastoid cells of 12 LAM patients and culture of lung cells taken at the time of transplantation for LAM in 8 patients did not reveal any TSC2 mutations (Astrinidis et al., 2000). In 69 patients with pulmonary lymphangioleiomyomatosis, all women, Urban et al. (1999) found no familial instance.
Carsillo et al. (2000) described mutations in the TSC2 gene as a cause of sporadic pulmonary lymphangioleiomyomatosis. They identified somatic TSC2 mutations in 5 of 7 angiomyolipomas from sporadic LAM patients. In all 4 patients from whom lung tissue was available, the same mutation found in the angiomyolipoma was present in the abnormal pulmonary smooth muscle cells. In no case was the mutation present in normal kidney, morphologically normal lung, or lymphoblastoid cells. TSC2 LOH was present in 4 of the 5 angiomyolipomas in which the authors identified TSC2 mutations. Therefore, these 4 angiomyolipomas had inactivation of both alleles of TSC2, consistent with the Knudson 2-hit hypothesis and the role of TSC2 as a tumor suppressor gene. No mutations in the TSC1 gene were found. Carsillo et al. (2000) recognized that a model to account for the presence of TSC2 mutations in the renal angiomyolipoma and pulmonary LAM cells but not in other tissues is necessary. They proposed 2 potential mechanisms, either of which would represent a novel mechanism for a disease associated with tumor suppressor gene mutations. One model suggests that sporadic LAM results from somatic mosaicism for TSC2 mutations. Sporadic LAM patients could have TSC2 mutations only in selected kidney and lung cells, and not in surrounding cells within the normal kidney or lung. According to this model, one would expect multiple independent tumor foci, whereas most sporadic LAM patients have a single angiomyolipoma. The second model entertained by Carsillo et al. (2000) involves the migration or spread of smooth muscle cells from the angiomyolipoma to the lung. Angiomyolipomas are histologically benign neoplasms; however, in patients with sporadic, solitary renal angiomyolipomas, it is not unusual to find angiomyolipoma cells in perirenal lymph nodes, suggesting that these cells are capable of spreading beyond the primary tumor.
Sato et al. (2002) studied the TSC1 and TSC2 genes in 6 Japanese patients with pulmonary LAM in association with the tuberous sclerosis complex (TSC-LAM) and 22 patients with sporadic LAM and identified 6 novel mutations. TSC2 germline mutations were detected in 2 (33.3%) of the 6 patients with TSC-LAM, and a TSC1 germline mutation was detected in 1 (4.5%) of the 22 sporadic LAM patients. In accordance with the tumor suppressor model, LOH was detected in LAM cells from 3 of 4 patients with TSC-LAM and from 4 of 8 patients with sporadic LAM. Furthermore, an identical LOH or 2 identical somatic mutations were demonstrated in LAM cells microdissected from several tissues, suggesting that LAM cells can spread from one lesion to another. These results confirmed the prevailing concept of pathogenesis of LAM: TSC-LAM has a germline mutation, but sporadic LAM does not; sporadic LAM is a TSC2 disease with 2 somatic mutations; and a variety of TSC mutations can cause LAM. However, this study indicated that a fraction of sporadic LAM can be a TSC1 disease; therefore, both TSC genes should be examined, even in patients with sporadic LAM.
Women with a sporadic form of lymphangiomyomatosis do not have germline TSC1 or TSC2 mutations (Carsillo et al., 2000). Sixty percent of such patients have renal angiomyolipomas. In patients with both sporadic lymphangiomyomatosis and angiomyolipoma, identical sporadic TSC2 mutations have been identified in the abnormal lung and kidney cells but not in normal cells (Karbowniczek et al., 2003), suggesting that lymphangiomyomatosis and angiomyolipoma cells are genetically related and most likely arise from a common progenitor cell. These data led to the 'benign metastasis' hypothesis for the pathogenesis of lymphangiomyomatosis, which proposes that histologically benign cells with mutations in TSC1 or TSC2 may have the ability to travel to the lungs from angiomyolipomas in the kidney. The fact that pulmonary lymphangiomyomatosis occurs only in women has led to the hypothesis that estrogen regulates TSC signaling and, perhaps, also the migration of TSC2-deficient cells (Crino et al., 2006).
Focal Cortical Dysplasia, Type II, Somatic
In brain tissue resected from a 10-year-old girl with seizures due to focal cortical dysplasia type II (FCORD2; 607341), Lim et al. (2017) identified a de novo somatic missense mutation in the TSC2 (V1547I; 191092.0018). The mutation was found by targeted sequencing of genes in the MTOR pathway in 40 patients with the disorder; the mutant allele frequency in this patient's brain tissue was very low, about 1 to 1.5%. Patient dystrophic brain cells and V1547I-transfected cells showed increased S6K phosphorylation (RPS6KB1; 608938) compared to wildtype, consistent with hyperactivation of the mTOR pathway. Mutant TSC2 showed impaired GAP activity, but normal binding to TSC1. Abnormal S6K phosphorylation in transfected cells was inhibited by treatment with rapamycin.
Jones et al. (1997) comprehensively defined the TSC1 mutation spectrum in 171 sequentially ascertained, unrelated TSC patients by SSCP and heteroduplex analysis of all 21 coding exons, and by assaying a restriction fragment spanning the whole locus. Mutations were identified in 9 of 24 familial cases, but in only 13 of 147 sporadic cases. In contrast, a limited screen revealed TSC2 mutations in 2 of the 24 familial cases and in 45 of the 147 sporadic cases. Thus, TSC1 mutations were significantly underrepresented among sporadic cases. Both large deletions and missense mutations were common at the TSC2 locus, whereas most TSC1 mutations were small truncated lesions. Mental retardation was significantly less frequent among carriers of TSC1 mutations than TSC2 mutations (odds ratio, 5.54 for sporadic cases only; 6.78 +/- 1.54 when a single randomly selected patient per multigeneration family was also included). No correlation between mental retardation and the type of mutation was found. Jones et al. (1997) concluded that there is a reduced risk of mental retardation in TSC1 as opposed to TSC2 disease and that consequent ascertainment bias, at least in part, explains the relative paucity of TSC1 mutations in sporadic TSC.
Jones et al. (1999) performed a comprehensive mutation analysis of the TSC1 and TSC2 genes in a cohort of 150 unrelated TSC patients and their families, using heteroduplex and SSCP analysis of all coding exons, and pulsed field gel electrophoresis, Southern blot analysis, and long PCR to screen for large rearrangements. Mutations were characterized in 120 (80%) of the 150 cases, affecting the TSC1 gene in 22 cases and the TSC2 gene in 98 cases. Twenty-two patients had TSC2 missense mutations that were located predominantly in the GAP-related domain (8 cases) and in a small region encoded in exons 16 and 17, between nucleotides 1849 and 1859 (8 cases), consistent with the presence of residues performing key functions at these sites. In contrast, all TSC1 mutations were predicted to be truncating, consistent with a structural or adaptor role for the encoded protein. Intellectual disability was significantly more frequent in TSC2 sporadic cases than in TSC1 sporadic cases.
Niida et al. (1999) reported mutation analysis of the entire coding region of both TSC1 and TSC2 genes in 126 unrelated TSC patients, including 40 familial and 86 sporadic cases, by SSCP followed by direct sequencing. Mutations were identified in a total of 74 (59%) cases, including 16 TSC1 mutations (5 sporadic and 11 familial) and 58 TSC2 mutations (42 sporadic and 16 familial). Overall, significantly more TSC2 mutations were found in this population, with a relatively equal distribution of mutations between TSC1 and TSC2 among the familial cases, but a marked underrepresentation of TSC1 mutations among the sporadic cases (P = 0.0035, Fisher exact test). All TSC1 mutations were predicted to be protein truncating; however, in TSC2, 13 missense mutations were found, 5 clustering in the GAP-related domain and 3 others occurring in exon 16. Upon comparison of clinical manifestations, including the incidence of intellectual disability, they could not find any observable differences between TSC1 and TSC2 patients.
Yamashita et al. (2000) examined 27 unrelated Japanese patients with tuberous sclerosis (23 sporadic and 4 familial) for mutations in the TSC1 and TSC2 genes, using SSCP analysis of genomic DNA. They identified 6 possible pathogenic mutations in TSC2 in the sporadic cases only, including 2 frameshifts, 1 in-frame deletion, and 3 missense mutations. Two of the TSC2 mutations were expected to result in a truncated tuberin gene product. The authors did not find a difference in severity of clinical manifestations between their patients with TSC1 and TSC2.
Dabora et al. (2001) reported a comprehensive mutation analysis in 224 index patients with tuberous sclerosis and correlated mutation findings with clinical features. Mutations were identified in 186 (83%) of the 224 cases, comprising 138 small TSC2 mutations, 20 large TSC2 mutations, and 28 small TSC1 mutations. Using a standardized clinical assessment instrument covering 16 TSC manifestations, they found that sporadic patients with TSC1 mutations had, on average, milder disease in comparison with patients with TSC2 mutations, despite being of similar age. They had a lower frequency of seizures and moderate to severe mental retardation, fewer subependymal nodules and cortical tubers, less severe kidney involvement, no retinal hamartomas, and less severe facial angiofibroma. Patients in whom no mutation was found also had disease that was milder, on average, than that in patients with TSC2 mutations and were somewhat distinct from patients with TSC1 mutations. Although there was overlap in the spectrum of many clinical features of patients with TSC1 versus TSC2 mutations, some features (grade 2-4 kidney cysts or angiomyolipomas, forehead plaques, retinal hamartomas, and liver angiomyolipomas) were very rare or not seen at all in TSC1 patients. Thus, both germline and somatic mutations appear to be less common in TSC1 than in TSC2. The reduced severity of disease in patients without defined mutations suggests that many of these patients are mosaic for a TSC2 mutation and/or have TSC because of mutations in an as yet undefined locus with a relatively mild clinical phenotype.
Langkau et al. (2002) genotyped 68 unrelated and nonselected patients (59 sporadic and 9 familial) with clinically confirmed TSC and identified 29 mutations in the TSC2 gene and 2 mutations in the TSC1 gene. Thy noted that the TSC1-TSC2 mutation ratio in this group of patients differed significantly from the 1:1 ratio previously predicted on the basis of linkage studies. They suggested that milder phenotypes are more often associated with TSC1 mutations and are likely to escape ascertainment.
In 6 families with a mild form of tuberous sclerosis, Jansen et al. (2006) identified a heterozygous mutation in the TSC2 gene (R905Q; 191092.0013). The clinical phenotype was relatively mild in all affected individuals. There was complete absence of disfiguring skin lesions, radiographic apparent cortical tubers, intractable epilepsy, mental retardation, and severe organ involvement. The authors identified mutations in the same codon, R905W (191092.0014) and R905G (191092.0015), in other families with a more severe phenotype, including cortical tubers, seizures, cognitive impairment, and severe skin lesions. Functional expression studies showed that the codon 905 substitutions did not prevent the formation of the tuberin-hamartin complex, but all reduced the ability of tuberin to inhibit phosphorylation of the S6K linker domain. However, R905Q retained more inhibition ability compared to R905W or R905G. Jansen et al. (2006) noted that the R905W and R905G substitutions resulted in the incorporation of nonpolar amino acids into the sequence, whereas the R905Q substitution introduced a polar amino acid with an amido functional group. The findings established a genotype-phenotype correlation of mutations in the same codon that was supported by functional studies.
Au et al. (2007) performed mutation analyses on 325 individuals with definite tuberous sclerosis complex diagnostic status. The authors identified mutations in 72% (199 of 257) of de novo and 77% (53 of 68) of familial cases, with 17% of mutations in the TSC1 gene and 50% in the TSC2 gene. There were 4% unclassified variants and 29% with no mutation identified. Genotype/phenotype analyses of all observed tuberous sclerosis complex findings in probands were performed, including several clinical features not analyzed in 2 previous large studies. Au et al. (2007) showed that patients with TSC2 mutations have significantly more hypomelanotic macules and learning disability in contrast to those with TSC1 mutations, findings not noted in previous studies. The authors also observed results consistent with 2 similar studies suggesting that individuals with mutations in TSC2 have more severe symptoms.
Hereditary renal carcinoma was described in the rat by Eker (1954). These tumors share morphologic similarities with human renal cancer. Yeung et al. (1994) localized the inherited mutation to rat chromosome 10q12 by linkage analysis. This region is known to be syntenic with human 16p13.3, the site of the TSC2 gene. Yeung et al. (1994) found a specific rearrangement of the rat homolog of TSC2 which cosegregated with carriers of the predisposing mutation. Tumors with or without LOH expressed only the mutant allele, consistent with the 2-hit hypothesis of Knudson and the role of TSC2 as a tumor suppressor gene. The mutation in the rat gave rise to an aberrant transcript that deleted the 3-prime end, which normally contains a region of homology with the catalytic domain of rap1GAP. Kobayashi et al. (1995) likewise identified a germline mutation in the TSC2 gene in the Eker rat. In a separate publication, Kobayashi et al. (1995) reported the complete cDNA and genomic structure of the rat TSC2 gene. The deduced amino acid sequence (1,743 amino acids) showed 92% identity to the human counterpart. Surprisingly, there were 41 or more coding exons with small introns spanning a total of only approximately 35 kb of genomic DNA. Two alternative splicing events were recognized.
Rennebeck et al. (1998) demonstrated that in the Eker rat homozygosity for the Eker mutation in the Tsc2 gene was lethal in midgestation (the equivalent of mouse E9.5-E13.5), the time when the Tsc2 mRNA is highly expressed in embryonic neuroepithelium. During this period homozygous mutant Eker embryos lacking the functional Tsc2 gene product, tuberin, displayed dysraphia and papillary overgrowth of the neuroepithelium, indicating that loss of tuberin disrupted the normal development of this tissue. There was significant intraspecies variability in the penetrance of cranial abnormalities in mutant embryos: the Long-Evans strain with homozygous Eker mutants displayed these defects, whereas the Fisher 344 homozygous mutations had normal-appearing neuroepithelium. Taken together, the data indicated that the Tsc2 gene participates in normal brain development and suggested that inactivation of this gene may have similar functional consequences in both mature and embryonic brain.
Pilz et al. (1995) demonstrated that the mouse homolog of TSC2 maps to chromosome 17. They showed that although it maps to the same general region as t(w18) and t(h20) (2 previously described deletions associated with the T complex), Tsc2 actually did not fall within either of these deletions. Xu et al. (1995) described alternatively spliced isoforms of TSC2, one of which lacked the 43 amino acids encoded by exon 25. A third isoform exhibited a deletion of 44 amino acids spanning codons 946-989; amino acid 989 is a serine residue encoded by the first codon of exon 26. The 2 isoforms exist in newborn and adult mouse tissues, reinforcing the potential functional importance of these alternatively spliced products. Xu et al. (1995) speculated that the distinct polypeptides encoded by the TSC2 gene may have different targets as well as functions involved in the regulation of cell growth.
Ito and Rubin (1999) cloned the Drosophila gene gigas, which encodes a homolog of TSC2. Gigas displays 26% identity and 46% similarity with TSC2; the highest level of identity (53%) is found in the 164 amino acids of the putative Rap1GAP domain. Clones of gigas mutant cells in Drosophila induced in imaginal discs differentiate normally to produce adult structures. However, the cells in these clones are enlarged and repeat S phase without entering M phase. These results suggested that tuberous sclerosis may result from an underlying defect in cell cycle control.
The 400-Mb genome of the Japanese pufferfish, Fugu rubripes, is relatively free of repetitive DNA and contains genes with small introns at high density. Sandford et al. (1996) demonstrated that the genes that are mutant in polycystic kidney disease-1 (PKD1; 601313) and tuberous sclerosis-2 are conserved in the Fugu genome where they are tightly linked. In addition, sequences homologous to the SSTR5 gene (182455) were identified 5-prime to PKD1, defining a larger syntenic region. As in genomes of mouse and human, the Fugu TSC2 and PKD1 genes are adjacent in a tail-to-tail orientation.
Tapon et al. (2001) characterized mutations in the Drosophila Tsc1 and Tsc2 (gigas) genes. Inactivating mutations in either gene caused an identical phenotype characterized by enhanced growth and increased cell size with no change in ploidy. Overall, mutant cells spent less time in G1. Coexpression of both Tsc1 and Tsc2 restricted tissue growth and reduced cell size and cell proliferation. This phenotype was modulated by manipulations in cyclin levels. In postmitotic mutant cells, levels of cyclin E (123837) and cyclin A (123835) were elevated. This correlated with a tendency for these cells to reenter the cell cycle inappropriately, as is observed in the human lesions.
Potter et al. (2001) isolated a mutation in the Drosophila Tsc1 gene. Cells mutant for Tsc1 were dramatically increased in size yet differentiated normally. Organ size was also increased in tissues that contained a majority of mutant cells. Clones of Tsc1 mutant cells in the imaginal discs underwent additional divisions but retained normal ploidy. Potter et al. (2001) also showed that the Tsc1 protein binds to Drosophila Tsc2 in vitro. Overexpression of Tsc1 or Tsc2 alone in the wing and eye had no effect, but co-overexpression led to a decrease in cell size, cell number, and organ size. Genetic epistasis data were consistent with a model in which Tsc1 and Tsc2 function together in the insulin (INS; 176730) signaling pathway.
Kleymenova et al. (2001) found that rats with a germline inactivation of 1 allele of the Tsc2 tumor suppressor gene developed early-onset severe bilateral polycystic kidney disease, with similarities to the human contiguous gene syndrome caused by germline codeletion of the PKD1 and TSC2 genes. Polycystic rat renal cells retained 2 normal Pkd1 alleles but were null for Tsc2 and exhibited loss of lateral membrane-localized polycystin-1. In tuberin-deficient cells, intracellular trafficking of polycystin-1 was disrupted, resulting in sequestration of polycystin-1 within the Golgi, and reexpression of Tsc2 restored correct polycystin-1 membrane localization. These data identified tuberin as a determinant of polycystin-1 functional localization and, potentially, autosomal dominant polycystic kidney disease severity.
Hereditary renal carcinomas in the Eker rat are caused by germline retrotransposon insertion in the TSC2 gene. To elucidate the functional domains of TSC2 in vivo, Momose et al. (2002) generated transgenic Eker rats carrying deletions of the TSC2 gene. A transgene coding for the C-terminal region (amino acids 1425-1755) suppressed renal carcinogenesis, and the degree of suppression correlated with the level of expression of the transgene. The product of the transgene lacked the ability to bind to the TSC1 product (hamartin). Although a different transgene lacking the C-terminus of tuberin (amino acids 1-1755) completely suppressed renal carcinogenesis, it partially rescued homozygous mutants from embryonic lethality.
Ehninger et al. (2008) found that Tsc2 +/- mice developed cognitive deficits in the absence of neuropathology or seizures. Hyperactive Mtor signaling led to abnormal long-term potentiation in the CA1 region of the hippocampus and consequently to deficits in hippocampal-dependent learning. Brief treatment of adult mice with the Mtor inhibitor rapamycin rescued synaptic plasticity and the behavioral deficits.
Way et al. (2009) created a mouse model that selectively deleted the Tsc2 gene from radial glial progenitor cells in the developing cerebral cortex and hippocampus. These Tsc2-mutant mice were severely runted, developed postnatal megalencephaly and died at 3 to 4 weeks of age. Analysis of brain pathology demonstrated cortical and hippocampal lamination defects, hippocampal heterotopias, enlarged dysplastic neurons and glia, abnormal myelination and an astrocytosis. These histologic abnormalities were accompanied by activation of the Torc1 (CRTC1; 607536) pathway as assessed by increased phosphorylated S6 (180460) in brain lysates and tissue sections. Developmental analysis demonstrated that loss of Tsc2 increased the subventricular Tbr2-positive basal cell progenitor pool at the expense of early born Tbr1-positive postmitotic neurons. Way et al. (2009) concluded that loss of function of Tsc2 in radial glial progenitors is 1 initiating event in the development of TSC brain lesions, and that Tsc2 is important in the regulation of neural progenitor pools.
Patients with tuberous sclerosis often develop renal cysts and those with inherited codeletions of PKD1 gene (601313) develop severe, early-onset polycystic kidneys. Using mouse models, Bonnet et al. (2009) showed that many of the earliest lesions from Tsc1 +/-, Tsc2 +/-, and Pkd1 +/- mice did not exhibit activation of mTOR, confirming an mTOR-independent pathway of renal cystogenesis. Using Tsc1/Pkd1 and Tsc2/Pkd1 heterozygous double-mutants, the authors showed functional cooperation and an effect on renal primary cilium length between hamartin and tuberin with polycystin-1. The Tsc1, Tsc2, and Pkd1 gene products helped regulate primary cilia length in renal tubules, renal epithelial cells, and precystic hepatic cholangiocytes. Consistent with the function of cilia in modulating cell polarity, Bonnet et al. (2009) found that many dividing precystic renal tubule and hepatic bile duct cells from Tsc1, Tsc2, and Pkd1 heterozygous mice were highly misoriented. Bonnet et al. (2009) proposed that defects in cell polarity may underlie cystic disease associated with TSC1, TSC2, and PKD1, and that targeting of this pathway may be of key therapeutic benefit.
Pollizzi et al. (2009) generated mice carrying a hypomorphic allele of Tsc2-del3, involving deletion of exon 3 and loss of 37 amino acids near the N terminus of tuberin. Tsc2 del3/del3 mouse embryos survived until embryonic day 13.5, 2 days longer than Tsc2-null embryos. Tsc2 del3/del3 embryos died from underdevelopment of the liver, deficient hematopoiesis, aberrant vascular development, and hemorrhage. Tsc2 del3/+ mice had a markedly reduced kidney tumor burden in comparison with conventional Tsc2 +/- mice. Murine embryo fibroblast (MEF) cultures that were homozygous for the del3 allele expressed mutant tuberin at low levels and showed enhanced activation of Torc1, similar to Tsc2-null MEFs. The Tsc2 del3/del3 MEFs showed prominent reduction in the activation of AKT (AKT1; 164730), and similar findings were made in the analysis of homozygous del3 embryo lysates. Pollizzi et al. (2009) concluded that the Tsc2-del3 allele is hypomorphic with partial function due to reduced expression, and highlighted the consistency of AKT downregulation when Tsc1/Tsc2 function is reduced.
Cao et al. (2010) explanted smooth muscle cells (SMCs) from Tsc2 +/- mice to investigate the pathogenesis of aortic aneurysms caused by TSC2 mutations. Tsc2 +/- SMCs demonstrated increased phosphorylation of mTOR, S6 (180460), and p70S6K (608938) and increased proliferation rates compared to wildtype SMCs. Tsc2 +/- SMCs also had reduced expression of contractile proteins compared to wildtype SMCs. Exposure to alpha-elastin (ELN; 130160) fragments also decreased proliferation of Tsc2 +/- SMCs and increased levels of p27kip1 (CDKN1B; 600778), but failed to increase expression of contractile proteins. In response to artery injury, Tsc2 +/- mice significantly increased neointima formation compared with control mice; the increased neointima formation was inhibited by treatment with rapamycin. Cao et al. (2010) concluded that Tsc2 haploinsufficiency in SMCs increases proliferation and decreases contractile protein expression, suggesting that increased proliferative potential of the mutant cells may be suppressed in vivo by interaction with elastin.
Lim et al. (2017) demonstrated that knockdown of the Tsc2 gene in developing mouse neurons, using the CRISPR/CASP9 somatic genome editing method in utero, resulted in abnormal neuronal phenotypes resembling focal cortical dysplasia type II in humans, hyperactivation of the mTOR pathway, and epileptic seizures in mice. There was also evidence of abnormal radial migration of cortical neurons in CRISPR-treated neurons. Seizures were almost completely rescued by rapamycin treatment.
Ercan et al. (2017) found that loss of Tsc1/Tsc2 in mouse neurons resulted in a block in oligodendrocyte development in vitro and in oligodendrocyte hypomyelination in vivo. These processes were mediated by neuronal Ctgf (121009), which was highly expressed and secreted from Tsc-deficient neurons and blocked development of oligodendrocytes. Expression of Srf (600589), the transcriptional regulator of Ctgf, was also decreased in Tsc-deficient neurons. Myelination could be improved by genetic ablation of Ctgf in neurons lacking Tsc1. Electron microscopy analysis suggested that this rescue of myelination was caused by the rescue of myelinated axon numbers, rather than changes in myelin thickness.
Du et al. (2018) found that mice with specific deletion of Tsc2 in pericytes had growth inhibition, seizures, focal weakness, and early mortality, with a median survival of 115 days. Whole-mouse necropsy showed that mutant mice developed multifocal hemangiopericytoma (HPC) in different organs. Immunohistochemical analysis suggested that HPC resulted from activation of mTorc induced by recombination and loss of Tsc2 in pericytes. Recombination was also observed in cell types and organs of mutant mice, but HPC developed only in selected sites, and not in lung or kidney.
Kumar et al. (1995) described a de novo 1-bp deletion (which they called del5110A) in exon 39 of the TSC2 gene, found in a patient with tuberous sclerosis (613254). The patient, a 2-year-old Caucasian female, showed at birth a patch on her left ankle and multiple hypopigmented patches on her back and trunk. She later developed facial plaques on her forehead but no facial angiofibromas or ungual fibromata. Onset of generalized seizures occurred at 7 months of age. CT scan of the brain demonstrated cerebral cortical tubers and subependymal nodules. Renal ultrasound showed multiple cysts in both kidneys. The parents were clinically normal and did not have the mutation.
Studying an African American tuberous sclerosis-2 (613254) family that showed a high likelihood for linkage to chromosome 16, Kumar et al. (1995) identified a 4590/4591 delC mutation in exon 34. The 1-bp deletion in codon 1525 caused a frameshift resulting in the creation of a premature stop codon 28 residues downstream. In addition, they detected in the family a 4525 del4 polymorphism in the 2 partially overlapping polyadenylation signals segregating in exon 40. The polymorphism was detected in 6 of 72 African American control chromosomes examined and was not detected in 80 Caucasian control chromosomes tested. Almost all previously detected mutations had been in sporadic cases.
Vrtel et al. (1996) described a nonsense mutation at the 5-prime end of the TSC2 gene in a father and his son. The authors stated that the case illustrated the usefulness of mutation analysis in the diagnosis of families with an incomplete phenotype of tuberous sclerosis (613254). The family was ascertained through a discovery of fetal bradycardia and arrhythmia in the proband at 20 weeks' gestation. At 24 weeks' gestation, an intracardiac mass suspected of being a rhabdomyosarcoma was detected by fetal ultrasound and the diagnosis of tuberous sclerosis was suggested. A boy, weighing 2,500 g, was delivered at 39 weeks. Postnatal ECG showed intermittent second and third degree atrioventricular block. Echography of the brain, liver, and kidneys showed no abnormalities and the studies of the retina were also normal. At 3 months of age a hypomelanotic macule, 25 x 15 mm, was noted on the buttock using Woods light. The 30-year-old father showed no abnormalities on study of the brain, heart, skin, and retina, and the most questionable changes in the kidneys. All tooth surfaces showed pit-shaped enamel defects, corresponding to the dental pits described in patients with tuberous sclerosis. In addition, 2 gingival fibromas were found. The father and son showed an A-to-T transversion at nucleotide 52, resulting in a change of lysine (AAG) to a stop codon (TAG) at amino acid position 12 (K12X). Allele-specific oligonucleotide hybridization (ASO) was performed on DNA from all family members. The mutation was not present in the twin sisters of the father or in either of his 2 parents. Flanking markers suggested that the mutated chromosome was of grandmaternal origin. The authors noted that it is possible that the mildly affected father was mosaic (although this was not detected), with the new mutation occurring by chance on the chromosome 16 he received from his mother.
Yates et al. (1997) investigated the family in which 3 sibs with tuberous sclerosis (613254) had unaffected parents. Polymorphic markers showed that different maternal and paternal haplotypes in affected children excluded TSC1 as the cause of the disease; on the other hand, for the TSC2 markers, all the affected children had the same maternal and paternal haplotypes, as did 3 of their unaffected sibs. Mutation screening by RT-PCR and direct sequencing of the TSC2 gene identified a 4-bp insertion (TACT) following nucleotide 2077 in exon 18 in the 3 affected children but not in 5 unaffected sibs or the parents. This mutation would cause a frameshift and premature termination at codon 703. Absence of the mutation in lymphocyte DNA from the parents was consistent with germline mosaicism and this was confirmed by finding identical chromosome 16 haplotypes in affected and unaffected sibs, providing unequivocal evidence for 2 different cell lines in the gametes. Molecular analysis of the TSC2 alleles present in affected subjects showed that the mutation had been inherited from the mother. This was the first case of germline mosaicism in tuberous sclerosis proven by molecular genetic analysis and also the first example of female germline mosaicism for a characterized autosomal dominant gene mutation apparently not associated with somatic mosaicism. The sibship from northern Ireland had 9 children; 3 of the 6 unaffected sibs had the identical chromosome 16 haplotype as the affected sibs, derived from the mother. Yates et al. (1997) stated that nonpenetrance in 1 of the parents and the 3 unaffected children with the high risk haplotype is highly improbable; there was only 1 reported family where this was a possibility (Webb and Osborne, 1991). Yates et al. (1997) suggested that germline mosaicism was first postulated by Bowen (1974) to explain the occurrence of the fully penetrant condition achondroplasia in 2 sisters born to normal parents. Since that time, germline mosaicism had been established by molecular means in several disorders. In tuberous sclerosis, 1 case of proven somatic mosaicism had been reported (Verhoef et al., 1995).
In a patient with tuberous sclerosis (613254), Wilson et al. (1996) and Au et al. (1998) found a 1513C-T transition in the TSC2 gene predicted to cause an arg505-to-ter (R505X) nonsense change in the protein, with early termination.
In 2 unrelated patients with tuberous sclerosis (613254), Au et al. (1998) found a 1832G-A transition in exon 16 of the TSC2 gene, predicted to cause an arg611-to-gln (R611Q) amino acid substitution in the protein. A change in the same codon had been reported in a patient with tuberous sclerosis by Wilson et al. (1996).
In tissues from 2 unrelated patients with pulmonary lymphangioleiomyomatosis (606690), Carsillo et al. (2000) identified an 1832G-A transition in exon 16 of the TSC2 gene, resulting in an arg611-to-gln mutation. In 1 patient the tissue studied was kidney angiomyolipoma; in the other, both kidney and pulmonary tumors were studied.
In a Japanese patient with tuberous sclerosis (613254) who manifested with multiple lung cysts and pneumothorax, Zhang et al. (1999) identified a T-to-G transversion at nucleotide 2168 in exon 19 of the TSC2 gene that caused a leu-to-arg substitution at codon 717. This mutation was not found in any other family member or in 100 normal Japanese. Quantitative analysis of normal and mutated SSCP bands revealed no loss of heterozygosity in the lung cyst tissue.
In a 12-year-old boy with tuberous sclerosis complex (613254), Verhoef et al. (1999) found that a large retroperitoneal tumor represented an infiltrative tumor originating from the pancreas, with local metastases of the lymph nodes. The histologic finding was malignant islet cell tumor. The connection between the malignancy and TSC was demonstrated by loss of heterozygosity of the TSC2 gene in the tumor. The primary germline mutation was a C-to-T transition of nucleotide 1450 in exon 13 of the TSC2 gene, resulting in a gln478-to-ter substitution. The mutation was absent in DNA isolated from peripheral leukocytes of the unaffected parents and therefore represented a de novo mutation.
In 4 unrelated patients with tuberous sclerosis-2 (613254), Maheshwar et al. (1997) identified a C-to-T transition at nucleotide 5042 of the TSC2 gene, which resulted in a proline-to-leucine substitution at codon 1675 (P1675L).
In pulmonary lymphangioleiomyomatosis (606690) tissue and in a renal angiomyolipoma from the same patient, Carsillo et al. (2000) demonstrated a 1096G-T transversion in exon 10 of the TSC2 gene, resulting in a glu366-to-ter mutation.
In affected members of a family with mild physical features of tuberous sclerosis (613254) in association with neuropsychiatric disorders, Khare et al. (2001) reported an A-to-C transversion at nucleotide 4508 in exon 34 of the TSC2 gene. This mutation resulted in the substitution of a proline residue for a glutamine at codon 1503 (Q2503P), which Khare et al. (2001) pointed out is within a region with homology to Rap1 GTPase-activating protein (600278). Khare et al. (2001) also found this mutation in an unrelated family from the same geographic area.
In a pair of twin boys in whom marker studies supported a probability of monozygosity greater than 99.9%, Martin et al. (2003) found highly discordant clinical manifestations of tuberous sclerosis (613254) despite an identical 18-bp in-frame deletion (nucleotides 5256-5273) in exon 40 of the TSC2 gene. The twins had similar CNS features, as both were severely mentally retarded with motor delay. Obvious differences were seen in the skin, heart, and kidneys. Whereas twin T. had a shagreen patch of the skin and a heart rhabdomyoma, twin M. had none. Twin M. was diagnosed early (at the age of 3 years) to have renal lesions, namely, angiomyolipomas and cystic alterations. At 6 years of age, twin T. also started to have the same types of renal lesions as twin M. Martin et al. (2003) suggested that the Knudson hypothesis (Knudson, 1971) explained the difference, assuming that many of the features such as the skin, cardiac, and renal alterations present a 2-hit phenomenon, the second hit depending on a random somatic event.
In affected members of a large French Canadian family with tuberous sclerosis (613254), Jansen et al. (2006) identified a heterozygous 2714G-A transition in exon 23 of the TSC2 gene, resulting in an arg905-to-gln (R905Q) substitution. The clinical phenotype was relatively mild in all affected individuals. There was complete absence of disfiguring skin lesions, radiographic apparent cortical tubers, intractable epilepsy, mental retardation, and severe organ involvement. Of 25 mutation carriers, 12 had a complete workup: 5 had definite TSC, 4 had probable TSC, 1 had possible TSC, and 2 fulfilled no diagnostic criteria for the disorder. Hypomelanotic macules were present in 92%, epilepsy in 60%, learning difficulties in 52%, imaging abnormalities in 24%, renal lesions in 8%, and retinal abnormalities in 4%. Additional studies identified 15 individuals from 5 families with the R905Q mutation. The phenotype was again relatively mild, similar to the first family. Of note, the mutation was not present in 1 family member with epilepsy and cognitive impairment nor in 5 family members with depigmented skin lesions. Jansen et al. (2006) referred to these cases as phenocopies.
Jansen et al. (2006) identified additional mutations in the same codon, R905W (191092.0014) and R905G (191092.0015), in patients with a more severe phenotype.
In 12 patients with tuberous sclerosis (613254), Jansen et al. (2006) identified a 2713C-T transition in the TSC gene, resulting in an arg905-to-trp (R905W) substitution. The phenotype was more severe compared to that observed in patients with the R905Q (191092.0013) mutation.
In a female patient from a French kindred segregating autosomal dominant tuberous sclerosis, Le Caignec et al. (2009) identified heterozygosity for the R905W mutation in the TSC2 gene. The mutation, which was not found in 16 unaffected family members, was most likely de novo, since neither parent had features of TSC and the mutation was absent in her mother; however, DNA was unavailable from her father. Le Caignec et al. (2009) also identified heterozygosity for 2 additional independent mutations in other affected members of this kindred, including her first cousin once removed (191092.0016) and 3 other, more distant, relatives (191092.0017).
In a patient with tuberous sclerosis (613254), Jansen et al. (2006) identified a 2713C-G transversion in the TSC gene, resulting in an arg905-to-gly (R905G) substitution. The phenotype was more severe compared to that observed in patients with the R905Q (191092.0013) mutation.
In a female patient from a French kindred segregating autosomal dominant tuberous sclerosis (613254), Le Caignec et al. (2009) identified heterozygosity for a 4-bp deletion in intron 20 (+1delGTAG) of the TSC2 gene. The de novo mutation was not found in 16 unaffected family members, including her parents, or in 100 controls. Le Caignec et al. (2009) also identified heterozygosity for 2 additional independent mutations in other affected members of this kindred, including her first cousin once removed (191092.0014) and 3 other, more distant, relatives (191092.0017).
In an affected mother and her affected son and niece in a French kindred segregating autosomal dominant tuberous sclerosis (613254), Le Caignec et al. (2009) identified heterozygosity for a 1322G-A substitution in exon 12 of the TSC2 gene, resulting in a trp441-to-ter (W441X) substitution. The mother had 1 affected brother, father of her affected niece, who was deceased. The mutation was not detected in 16 unaffected family members, including her 8 other brothers and sisters; however, 2 sisters carried the same haplotype as the 3 affected individuals, indicating gonadal mosaicism in 1 of the parents. Le Caignec et al. (2009) also identified heterozygosity for 2 additional independent mutations in other, more distant, relatives in this kindred (see 191092.0014 and 191092.0016).
In brain tissue resected from a 10-year-old girl (FCD94) with seizures due to focal cortical dysplasia type II (FCORD2; 607341), Lim et al. (2017) identified a de novo somatic c.4639G-A transition (c.4639G-A, NM_000548.4) in the TSC2 gene, resulting in a val1547-to-ile (V1547I) substitution at a highly conserved residue in the GAP domain. The mutation, which was found by targeted sequencing of genes in the MTOR pathway, was not found in the 1000 Genomes Project database, but was present at a very low frequency (3.34 x 10(-5)) in the ExAC database. The mutant allele frequency in brain tissue was very low, about 1 to 1.5%. Patient dystrophic brain cells and V1547I-transfected cells showed increased S6K phosphorylation (RPS6KB1; 608938) compared to wildtype, consistent with hyperactivation of the mTOR pathway. Mutant TSC2 showed impaired GAP activity, but normal binding to TSC1. Abnormal S6K phosphorylation in transfected cells was inhibited by treatment with rapamycin.
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