This is a mechanism module, not a disease; do not create an "mTORopathy" Disease entry. Disorder entries reference nodes via conforms_to, for example "mtorc1_hyperactivation#Constitutive mTORC1 Hyperactivation". The trigger node is written as one node with three regulator branches because every branch converges on the same rate-limiting step; a conforming node names only the regulator its disease loses. The second-hit node is optional for conformers: it is the established mechanism in tuberous sclerosis complex, sporadic lymphangioleiomyomatosis and DEPDC5-related focal cortical dysplasia, but SZT2-related disease is biallelic germline and some PTEN hamartomas form on haploinsufficiency alone, so those entries conform to the trigger and central-effector nodes without it. conforms_to takes a single value (dismech#13923), so a node that already conforms elsewhere keeps that binding: the PTEN germline-loss trigger nodes in PTEN_Hamartoma_Tumor_Syndrome, Cowden_Syndrome and Bannayan-Riley-Ruvalcaba_Syndrome stay on germline_two_hit_tumor_predisposition and conform to this module only at their hamartoma node; do not repoint them. Autophagy suppression is deliberately left as a terminal effector with no edge into lesion formation: in TSC the residual autophagy that persists is itself required for tumour growth (PMID:21746920), so the module does not assert that low autophagy causes the lesion. Disorders whose mTORC1 signalling is reduced rather than released (POLR-related leukodystrophy, Roberts syndrome, several immunodeficiencies) are a different mechanism and do not conform here. Xogenesis anchor: the terminal output is a hamartoma (MPATH:74), an OGMS:0000078 pathological anatomical structure produced by an OGMS:0000081 pathological derivation; process genus OGMS:0000061. The site is disorder-specific (UBERON term on the conforming node) because the same lesion forms in brain, kidney, skin, lung and gut. The anchor is prose only: no descriptor slot admits an MPATH or OGMS term.
Loss of an Upstream mTORC1 Negative Regulator
trigger
The conserved initiating lesion is loss of function of one of the proteins that hold mTORC1 in check. Three branches converge: the TSC1/TSC2 complex, whose GAP activity toward Rheb is lost in tuberous sclerosis complex and lymphangioleiomyomatosis; the GATOR1 complex (DEPDC5, NPRL2, NPRL3), the GAP toward the Rag GTPases on the amino-acid sensing arm, together with KICSTOR/SZT2, which anchors GATOR1 to the lysosome; PTEN, whose lipid phosphatase restrains the PI3K-AKT input to the TSC complex; and STK11/LKB1, the kinase that activates AMPK, which in turn phosphorylates TSC2 and Raptor to repress mTORC1 under energy stress, so STK11 loss removes that restraint in Peutz-Jeghers syndrome. Each is a tumour-suppressor-type brake, so loss rather than gain of the gene product releases the pathway.
Downstream
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Somatic Second-Hit Biallelic Inactivation in the Lesion
A heterozygous germline loss is completed by a somatic second hit in the cells that form the lesion.
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Constitutive mTORC1 Hyperactivation
Loss of the regulator, whether haploinsufficient or biallelic, releases mTORC1 from nutrient and growth-factor control.
Show evidence (6 references)
"TSC1 and TSC2 encode the core components of the TSC1/2 complex (TSC1/2), a negative regulator of the mechanistic target of rapamycin (MTOR) complex 1 (TORC1)."
Establishes the TSC complex as an mTORC1 negative regulator, the branch lost in tuberous sclerosis complex and lymphangioleiomyomatosis.
"DEP domain-containing 5 protein (DEPDC5) is a repressor of the recently recognized amino acid-sensing branch of the mTORC1 pathway"
Places DEPDC5, and so the GATOR1 complex, on the amino-acid sensing arm as a second, independent brake on mTORC1.
"is required for amino acid or glucose deprivation to inhibit mTORC1 in cultured human cells"
Shows that the KICSTOR complex, of which SZT2 is a component, is needed for nutrient deprivation to inhibit mTORC1, so SZT2 loss removes the same brake GATOR1 loss does.
+ 3 more references
Somatic Second-Hit Biallelic Inactivation in the Lesion
amplifier
In the germline syndromes the heterozygous first hit is typically completed in the lesion by a somatic second hit at the same locus (loss of heterozygosity, a second point variant, or a brain-restricted mosaic variant), so that the hamartoma or dysplastic focus is biallelically null while the surrounding tissue is not. In sporadic disease both hits are somatic. This two-hit step is why lesions are focal and multifocal rather than diffuse.
Downstream
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Constitutive mTORC1 Hyperactivation
Biallelic loss in the lesion removes the brake entirely in those cells.
Show evidence (3 references)
"Twenty of 32 (62%) samples showed copy neutral LOH (CN-LOH) in TSC2 or TSC1 with at least 8 different LOH regions, and 30 of 32 (94%) had biallelic loss of either TSC2 or TSC1."
Direct human evidence that TSC lesions are biallelically null at the TSC locus, the second-hit mechanism in its canonical disease.
"a biallelic 2-hit - brain somatic and germline - mutational mechanism in DEPDC5 causes focal epilepsy with FCD"
The same two-hit architecture on the GATOR1 branch, with the second hit restricted to the dysplastic brain tissue.
"Our data demonstrate that somatic mutations in the TSC2 gene occur in the angiomyolipomas and pulmonary LAM cells of women with sporadic LAM, strongly supporting a direct role of TSC2 in the pathogenesis of this disease."
In sporadic lymphangioleiomyomatosis both hits are somatic, showing the lesion-restricted biallelic loss does not need a germline first hit.
Constitutive mTORC1 Hyperactivation
central effector
The rate-limiting, disorder-agnostic step and the key conformance target. With the regulator gone, mTORC1 stays active at the lysosomal surface regardless of amino-acid, glucose or growth-factor supply, read out as persistently phosphorylated S6K and ribosomal protein S6 even under starvation. Every branch of the trigger node converges here, and the rapalogs act here.
Downstream
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Translation and Anabolic Cell Growth Upregulation
Unrestrained mTORC1 phosphorylates S6K and 4E-BP, driving protein and lipid synthesis and cell growth.
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Autophagy Suppression
Persistent mTORC1 activity holds the autophagy-initiating kinase ULK1 in its inhibited state.
Show evidence (6 references)
"Pathogenic variants in TSC1 and TSC2 lead to mTORC1 hyperactivation, producing benign tumours in multiple organs, including the brain and kidneys, and drug-resistant epilepsy, a typical sign of TSC."
States the central effector for the TSC branch and ties it to the module's terminal lesions.
"The pathogenic molecular mechanism linked to GATOR1 haploinsufficiency is a hyperactivation of mTORC1 pathway"
The GATOR1 branch converges on the same effector.
"Increased phosphorylation of S6 kinase and S6 was identified in patient-derived cell lines under amino acid-starved condition, suggestive of constitutive hyperactivation of mTORC1 signaling."
Demonstrates the defining property of the node, signalling that persists under nutrient starvation, on the SZT2 branch.
+ 3 more references
Translation and Anabolic Cell Growth Upregulation
effector
Constitutive mTORC1 output is anabolic: phosphorylation of S6 kinase and the 4E-BP translational repressors raises cap-dependent translation and ribosome biogenesis, and the lipid-synthetic program is engaged, so cells enlarge and proliferate. In the brain this produces the cytomegalic, dysmorphic neurons and balloon cells of focal cortical dysplasia; in other organs the enlarged, proliferating cells of the hamartoma.
Downstream
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Hamartomatous Overgrowth and Dysplastic Lesion Formation
Enlarged, proliferating, biallelically null cells accumulate into a focal lesion.
Show evidence (3 references)
"we detected increased phosphorylation levels of the ribosomal protein S6, a well-known readout of mTORC1 activity"
The translational readout of the effector measured in human lesion tissue.
"the mechanistic target of rapamycin (mTOR) signalling pathway, which in turn plays a pivotal part in regulating cell growth, proliferation, autophagy and protein and lipid synthesis"
Names the anabolic outputs of mTOR signalling that this node and the autophagy node divide between them.
"Loss of PTEN activates this pathway and leads to increased cellular growth, migration, proliferation, and survival."
The same growth and proliferation output on the PTEN branch.
Autophagy Suppression
effector
mTORC1 is a direct inhibitor of autophagy: under nutrient sufficiency it phosphorylates ULK1 and blocks its activation by AMPK, and when mTORC1 is constitutively active that block persists regardless of nutrient state. In TSC lesions the autophagy substrate p62/SQSTM1 accumulates as a consequence. The residual autophagy that remains is nonetheless required for tumour growth, so this node is an effector of the hyperactive state and is not drawn as a cause of the lesion.
Show evidence (3 references)
"Under nutrient sufficiency, high mTOR activity prevents Ulk1 activation by phosphorylating Ulk1 Ser 757 and disrupting the interaction between Ulk1 and AMPK."
The molecular mechanism by which active mTORC1 suppresses autophagy initiation.
"TSC-associated tumors exhibit hyperactivation of mammalian target of rapamycin complex 1 (mTORC1), a direct inhibitor of autophagy."
States, as the paper's framing of the human disease, that the lesions of the canonical mTORopathy carry hyperactive mTORC1 and that mTORC1 directly inhibits autophagy.
"the autophagy substrate that accumulates in TSC tumors as a consequence of low autophagy levels"
p62/SQSTM1 accumulation in Tsc2-null tumours is the in vivo readout of suppressed autophagy in the lesion.
Allosteric mTORC1 Inhibition (Rapalogs: Sirolimus, Everolimus)
Platform:
Small molecule
Sirolimus (rapamycin) and everolimus bind FKBP12 and allosterically inhibit mTORC1, partially restoring the brake the disease has lost. This is the drug-target pattern for conforming disorders: everolimus is approved for TSC-associated subependymal giant cell astrocytoma, renal angiomyolipoma and seizures, sirolimus for lymphangioleiomyomatosis, and both are under evaluation for the GATOR1 focal epilepsies and the PTEN hamartoma syndromes. The inhibition is cytostatic, so lesions regrow on withdrawal; conforming entries record the indication and evidence specific to their disease.
Evidence: 3