TSC1 and TSC2: genes that are mutated in the human genetic disorder tuberous sclerosis

Sampson, Julian R.

doi:10.1042/bst0310592

Cited by 34 publications

(12 citation statements)

References 35 publications

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“…One of us (DJK) has also recently confirmed that mosaicism is relatively common among patients with large genomic changes in TSC1 and TSC2 , being seen in 8 of 54 (15%) index patients. However, it appears to be much less common than this for the common small mutations in TSC1 and TSC2 , though the true incidence is uncertain due to mosaicism detection limitations (Verhoef et al, 1995; Kwiatkowska et al, 1999; Dabora et al, 2001; Sampson. 2003; Roberts et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Distinct clinical characteristics of Tuberous Sclerosis Complex patients with no mutation identified

Camposano

Greenberg

Kwiatkowski

et al. 2009

Annals of Human Genetics

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SummaryTuberous Sclerosis Complex (TSC) is a multi-system disorder that is highly variable in its clinical presentation. Current molecular diagnostic methods permit identification of mutations in either TSC1 or TSC2 in 75-85% of TSC patients. Here we examine the clinical characteristics of those TSC patients who have no mutation identified (NMI). A retrospective review of our patient population that had comprehensive testing for mutations in TSC1/TSC2 identified 23/157 (15%) that were NMI. NMI patients had a lower incidence of brain findings on imaging studies, neurological features, and renal findings than those with TSC2 mutations. In contrast, NMI patients had a lower incidence of seizures than TSC patients with TSC1 mutations, but had a higher incidence of both renal angiomyolipomas and pulmonary lymphangioleiomyomatosis. This distinct constellation of findings suggest that NMI patients may have a unique molecular pathogenesis, different from that seen in TSC patients with the usual mutations in TSC1 and TSC2. We suggest that the mechanisms of disease in these patients include both mosaicism for a TSC2 mutation, and unusual non-coding region mutations in TSC2.

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Section: Discussionmentioning

confidence: 99%

Distinct clinical characteristics of Tuberous Sclerosis Complex patients with no mutation identified

Camposano

Greenberg

Kwiatkowski

et al. 2009

Annals of Human Genetics

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“…As a nutrient sensor, mTORC1 activity fluctuates in vivo in direct response to nutrients, energy status, and growth factor stimulation, which collectively balance cell growth. Complex pathway responses integrate signaling through mTORC1, and disruptions in circuitry signaling can lead to cellular overgrowth and oncogenesis (Inoki et al, 2003;Benvenuto et al, 2000;Sampson, 2003).…”

Section: Introductionmentioning

confidence: 99%

Integrated actions of mTOR complexes 1 and 2 for growth and development of Dictyostelium

Jaiswal¹,

Majithia²,

Rösel³

et al. 2019

Int. J. Dev. Biol.

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Multi-protein complexes mTORC1 and mTORC2 are required for growth and development of eukaryotes. mTORC1 is a nutrient sensor that integrates metabolic signals and energy state to regulate cell growth/proliferation, whereas, mTORC2 primarily regulates developmental processes. Dictyostelium proliferate in rich growth media, but initiate development upon nutrient depletion. Both mTOR complexes play essential roles in Dictyostelium, where growth and developmental cycles independently require, respectively, mTORC1 or mTORC2. Many protein associations and regulatory pathways for mTORC1 and mTORC2 in Dictyostelium have context similarity to mammalian cells and specificity to inhibition by the immunosuppressive drug rapamycin. In Dictyostelium, mTORC1 function is inactivated upon starvation-induced development, but development is directly induced through rapamycin-mediated inhibition of mTORC1 activity, even in the absence of nutrient withdrawal. Pharmacologic inhibition of mTORC1, in the absence of nutrient loss, has allowed the identification of a class of essential up-regulated, developmentally-associated signaling genes and down-regulated, growth genes. We also review functional pathway regulations that integrate mTORC1/mTORC2 activities and emphasize complexity of small GTPase regulation of mTORC2 activity. Finally, epistases experiments have suggested novel upstream pathway cross-talk in Dictyostelium that requires mTORC1 and mTORC2, but for separate and independent downstream functions.

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“…2 The ocular, skeletal, gastrointestinal, hepatic, and splenic systems are also frequently affected. 4 Genetic mutations associated with tuberous sclerosis have been mapped to two separate loci containing the genes encoding TSC1/Hamartin and TSC2/Tuberin, 5,6 which collaborate to restrict the activity of the cell growth machinery. Approximately one-third of tuberous sclerosis cases are familial in which one parent is affected.…”

Section: Genetics and Clinical Features Of Tuberous Sclerosismentioning

confidence: 99%

Tuberous Sclerosis and Insulin Resistance: Unlikely Bedfellows Reveal A TORrid Affair

Shah

Hunter²

2004

Cell Cycle

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TSC1 and TSC2: genes that are mutated in the human genetic disorder tuberous sclerosis

Cited by 34 publications

References 35 publications

Distinct clinical characteristics of Tuberous Sclerosis Complex patients with no mutation identified

Distinct clinical characteristics of Tuberous Sclerosis Complex patients with no mutation identified

Integrated actions of mTOR complexes 1 and 2 for growth and development of Dictyostelium

Tuberous Sclerosis and Insulin Resistance: Unlikely Bedfellows Reveal A TORrid Affair

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