This report describes tuberous sclerosis 1 (TSC1); TSC1 exhibits autosomal dominant inheritance. The human gene implicated in this disease is TSC1 (also called hamartin), which acts in a complex with TSC2. The tuberous sclerosis complex (TSC) regulates the activity of mTOR complex 1 and thus has a key role in the regulation of cell growth and proliferation. TSC1 is also associated with lymphangioleiomyomatosis (MIM:606690) and has been tentatively identified as a susceptibility locus for autism (FBhh0000520). There is a single fly ortholog, Tsc1, for which classical loss-of-function alleles, RNAi-targeting constructs and an allele caused by insertional mutagenesis have been generated.
The human TSC1 gene has not been introduced into flies.
Animals homozygous for loss-of-function alleles of Dmel\Tsc1 die before the end of larval stage. Effects upon cell growth have been assayed using somatic clones. Extensive genetic and physical interactions for Dmel\Tsc1 have been described; see below and in the gene report for Tsc1.
For transgenic human constructs, fly transgenic constructs and classical alleles, detailed phenotypic descriptions can be found in the allele reports; allele reports can be accessed from the gene report or by clicking on the allele symbols in the Disease Ontology and Reagent tables below.
Using Drosophila cell lines that are wild-type, deficient for TSC1 (Dmel\Tsc1) or deficient for TSC2 (Dmel\gig), synthetic lethal/semi-lethal interaction screens have been conducted to identify gene targets that preferentially reduce growth in TSC deficient cells. Using high-throughput RNAi screens, Drosophila orthologs of putative targets of FDA-approved drugs were among the genes targeted. Introduction of a variable dose analysis paradigm has allowed more sensitive screens. Based on analyses of the resulting networks of interactions, several candidate drugs have been identified and have been tested further in Drosophila and mammalian cells deficient for either TSC1 or TSC2.
See also the human disease model reports for tuberous sclerosis 2 (FBhh0000225) and tuberous sclerosis complex (FBhh0000198).
[updated Feb. 2018 by FlyBase; FBrf0222196]
Tuberous sclerosis complex (TSC) is a rare, multi-system genetic disease that causes benign tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. It usually affects the central nervous system and results in a combination of symptoms including seizures, developmental delay, behavioral problems, skin abnormalities, and kidney disease. Many TSC patients show evidence of the disorder in the first year of life. However, clinical features can be subtle initially, and many signs and symptoms take years to develop. [from NINDS, NINDS Tuberous Sclerosis Information Page, 2016.3.22].
Tuberous sclerosis is a rare genetic multisystem disorder that is typically apparent shortly after birth. The disorder may be characterized by seizures; mental retardation; distinctive skin lesions; and hamartomas (benign, tumor-like nodules) of the brain, retina, heart, kidneys, lungs, or other tissues or organs. In addition, many affected individuals may have cyst-like areas within certain skeletal regions, particularly the phalanges. Characteristic skin lesions include sharply defined areas of hypopigmentation that may develop during infancy and relatively small reddish nodules that may appear on the cheeks and nose beginning at approximately age four. These reddish lesions eventually enlarge, coalesce, and develop a wart-like appearance (sebaceous adenomas). Additional skin lesions may also develop, including cafe-au-lait spots; fibromas (benign, fibrous nodules) arising around or beneath the nails; or shagreen patches (rough, elevated, "knobby" lesions) on the lower back. [from NORD, Tuberous Sclerosis, 2016.3.17]
[TUBEROUS SCLEROSIS 1; TSC1](https://omim.org/entry/191100)
[TSC COMPLEX SUBUNIT 1; TSC1](https://omim.org/entry/605284)
Tuberous sclerosis complex (TSC) is a multisystem disorder characterized by hamartomas in multiple organ systems, including the brain, skin, heart, kidneys, and lung. Central nervous system manifestations include epilepsy, learning difficulties, behavioral problems, and autism. Renal lesions, usually angiomyolipomas, can cause clinical problems secondary to hemorrhage or by compression and replacement of healthy renal tissue, which can cause renal failure. Patients can also develop renal cysts and renal-cell carcinomas. Pulmonary lymphangioleiomyomatosis can develop in the lungs. Skin lesions include melanotic macules, facial angiofibromas, and patches of connective tissue nevi. There is a wide clinical spectrum, and some patients may have minimal symptoms with no neurologic disability. Patients with tuberous sclerosis 2 generally have more severe disease than patients with tuberous sclerosis 1.
See the description for tuberous sclerosis complex.
[from MIM:191100, 2016.3.17]
Tuberous sclerosis complex has an autosomal dominant pattern of inheritance. [from MIM:613254, 2016.3.18]
The TSC1 and TSC2 genes encode hamartin and tuberin, respectively. They physically interact and function as tumor suppressors.
In complex with TSC2, TSC1 inhibits the nutrient-mediated or growth factor-stimulated phosphorylation of S6K1 and EIF4EBP1 by negatively regulating mTORC1 signaling. It seems not to be required for TSC2 GAP activity towards RHEB. TSC1 is mplicated as a tumor suppressor. It is involved in microtubule-mediated protein transport, but this seems to be due to unregulated mTOR signaling. [UniProt, Q92574 (TSC1_HUMAN), 2016.3.17]
TSC1 encodes a growth inhibitory protein thought to play a role in the stabilization of tuberin [from Gene Cards, TSC1, 2016.3.17]
One to one: 1 human to 1 Drosophila.
Ortholog of human TSC1 (1 Drosophila to 1 human). Dmel\Tsc1 shares 23% identity and 40% similarity with human TSC1.
