Analysis of the basic genetic defect in tuberous sclerosis would be greatly expedited by definitive determination of the chromosomal location of the TSC gene or genes.
The identification of the TSC1 gene on chromosome 9q, along with functional studies and mutational analyses of both TSC genes, will likely provide fascinating insights into the pathogenesis of TSC.
Analysis of TSC-associated hamartomas has shown loss of heterozygosity for the regions of chromosomes 9 and 16 known to harbour TSC genes, consistent with the occurrence of somatic 'second-hit' mutations.
These data support the hypothesis that both the TSC genes act as tumour suppressors and that the manifestations of TSC in patients with germline TSC mutations rise from "second hit" somatic mutations inactivating the remaining normal copy of the TSC gene.
The mechanism underlying the association of autism and TSC is as yet unclear but clinical features and neuroimaging investigations suggest that an abnormal TSC gene may directly influence the development of autism rather than it being a secondary effect of seizures or MR.
We examined mutations of both TSC genes in 6 Japanese patients with TSC-LAM and 22 patients with sporadic LAM and identified six unique and novel mutations.
We found that in addition to the differential expression of the TSC genes in some normal tissues compared with that in the TSC-affected fetus, the cellular localization and distribution of hamartin and tuberin were dramatically different in different tissues.
Recent data suggest that functional inactivation of TSC proteins might also be involved in the development of other diseases not associated with TSC, such as sporadic bladder cancer, breast cancer, ovarian carcinoma, gall bladder carcinoma, non-small-cell carcinoma of the lung, and Alzheimer's disease.
Our knowledge of TSC genetics and pathophysiology has expanded dramatically in recent years: two genetic loci were discovered in the 1990s and recent elucidation of TSC's interaction with the mTOR pathway has changed how we manage the disease.
Identifying functional polymorphic variants of interacting partners affecting TSC gene functions will delineate the mechanisms leading to TSC disease severity, ultimately resulting in treatment strategies.
Both diseases are caused by mutations of TSC1 or TSC2 (TSC is tuberous sclerosis complex) that impair GAP (GTPase-activating protein) activity of the TSC1-TSC2 complex for Rheb, leading to inappropriate activity of signalling downstream of mTORC1 (mTOR complex 1). mTOR inhibitors are already used in a variety of clinical settings including as immunosuppressants, anticancer agents and antiproliferative agents in drug-eluting coronary artery stents.
The tuberous sclerosis (TSC) genes, TSC1 and TSC2, encode hamartin and tuberin, respectively, and are putative tumor suppressor genes that were originally identified due to their involvement in the inherited autosomal dominant disorder tuberous sclerosis.
In tuberous sclerosis complex (TSC), a substantially increased risk of developing epilepsy is present as a result of a disruption of a TSC gene expression in the brain and secondary abnormal cellular differentiation, migration, and proliferation.
A purported mechanism of hamartomatous proliferation in TSC is constitutive activation of the mammalian target of rapamycin (mTOR) signaling pathway dysregulated by a functional loss of TSC genes.
Taken together, our studies raise the possibility of a gene × environment interaction between heterozygous TSC gene mutations and gestational immune activation in the pathogenesis of TSC-related ASD.
Recent studies suggest that clinical similarities between BHDS and TSC may be explained by FLCN and TSC proteins functioning on a common pathway, mammalian target of rapamycin.
From this analysis, mutations in TSC genes were identified in 5 samples from the AML-TSC patients (mutation detection rate=71%) and 3 samples from AML-non-TSC patients (mutation detection rate=21%).
Mutations in tuberous sclerosis (TSC) genes cause the genetic disorder TSC, as well as other neoplasms, including lymphangioleiomyomatosis (LAM) and angiomyolipomas (AMLs).