Tuberous sclerosis pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: José Eduardo Riceto Loyola Junior, M.D.[2]
Overview
Hamartin and tuberin, which are encoded by TSC1 and TSC2 genes respectively, function as a complex which is involved in the control of cell growth and cell division. Thus, mutations at the TSC1 and TSC2 loci result in a loss of control of cell growth and cell division, and therefore a predisposition to forming tumors.
Pathophysiology
Genetics
- Patients with tuberous sclerosis have loss-of-function germline mutations in one of the alleles of the following tumor suppressor genes: TSC1 or TSC2.
- One third of the mutations is inherited, two thirds are de novo mutations. The mutations causes the loss of one allele, but as long as the second one remains intact, the cell won't present any metabolic change.
- When there is a second TSC1 or TSC2 mutation, which typically occurs in multiple cells over a person's lifetime, then the disease starts to manifest (fitting the "two-hit" tumor-suppressor gene model, with the germline mutation inactivating one gene and then a somatic event inactivating the remaining other one).
- TSC1 codes for a protein called hamartin, and TSC2 codes for a protein called tuberin.
- Tuberin and Hamartin belong to a protein complex that inhibits the mammalian target of rapamycin (mTOR) complex 1 via RAS homologue enriched in brain (RHEB) which regulates cell growth.
- In a normal patient, RHEB activates mTORC1 when bound to GTP, but in TSC there is a hyperactivation of RHEB and consequently of mTORC1. mTOR regulates cellular proliferation, autophagy, growth and protein and lipid synthesis and it enhances protein translation when activated, reprograming the cell metabolism, which increases cell proliferation but also may make it vulnerable to death in nutrient-restricted media.
- Besides the TSC-RHEB-mTORC1 pathway, there is evidence of alternate pathways also having a role in the disease that are mTORC1 independent, but they are currently under investigation.[1][2]
References
- ↑ "NIH - Tuberous Sclerosis". NIH. 07/20/2020. Check date values in:
|date=(help) - ↑ Henske EP, Jóźwiak S, Kingswood JC, Sampson JR, Thiele EA (2016). "Tuberous sclerosis complex". Nat Rev Dis Primers. 2: 16035. doi:10.1038/nrdp.2016.35. PMID 27226234.