Identification of the Tuberous Sclerosis Gene TSC1 on Chromosome 9q34

Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the widespread development of distinctive tumors termed hamartomas. TSC-determining loci have been mapped to chromosomes 9q34 (TSC1) and 16p13 (TSC2). The TSC1 gene was identified from a 900-kilobase region containing at least 30 genes. The 8.6-kilobase TSC1 transcript is widely expressed and encodes a protein of 130 kilodaltons (hamartin) that has homology to a putative yeast protein of unknown function. Thirty-two distinct mutations were identified in TSC1, 30 of which were truncating, and a single mutation (2105delAAAG) was seen in six apparently unrelated patients. In one of these six, a somatic mutation in the wild-type allele was found in a TSC-associated renal carcinoma, which suggests that hamartin acts as a tumor suppressor.

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

“…TSC1 and TSC2 are widely expressed in human tissues, such as heart, brain, lung, liver, kidney, pancreas and skeletal muscle (Consortium, 1993;van Slegtenhorst et al, 1997;Huang and Manning, 2008). The two proteins interact through coiled-coil domains to form a stable, functional heterodimer (van Slegtenhorst et al, 1998).…”

“…Loss of chromosome 16p (locus for TSC2) or promoter hypermethylation of the TSC genes has been detected in a substantial proportion of ovarian, gall bladder and breast cancer (Knowles et al, 2003;Jiang et al, 2005). Germ-line mutations in TSC1 and TSC2 predispose to TSC (Consortium, 1993;van Slegtenhorst et al, 1997), which is characterized by the development of widespread hamartomas in several organs including brain (cortical tubers and subependymal glial nodules), kidneys (angiomyolipomas, AML), skin ((angio) fibromas), heart (rhabdomyomas) and lungs (lymphangioleiomyomatosis (LAM)) ( Table 1). In addition, these patients develop early onset brain cancer (subependymal giant cell astrocytomas (SEGAs)) and different types of renal cancer (Table 1) (Schwartz et al, 2007;Curatolo et al, 2008;Ess, 2010).…”

Rheb activates AMPK and reduces p27Kip1 levels in Tsc2-null cells via mTORC1-independent mechanisms: implications for cell proliferation and tumorigenesis

“…TSC and LAM result from the inactivation of either of the two tumor-suppressor genes, TSC1 that encodes hamartin (TSC1), and TSC2 that encodes tuberin (TSC2) (van Slegtenhorst et al, 1997;Carsillo et al, 2000;Sato et al, 2002). TSC1 and TSC2 form an active complex (TSC1/2) that negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling, which promotes cell growth (Huang and Manning, 2008).…”

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

“…The term CHARGE is an acronym for the syndrome's six core features: C, coloboma of the iris/retina; H, heart defects; A, atresia of the choanae; R, retardation of growth/development; G, genital abnormalities; and E, ear abnormalities. Occurring once in every 8500-10,000 live births [42,43], CHARGE syndrome also involves a range of secondary features, including deafness, laryngomalacia, vestibulocochlear defects, facial [80][81][82][83][84][85][86][87] CHARGE = C, coloboma of the iris/retina; H, heart defects; A, atresia of the choanae; R, retardation of growth/development; G, genital abnormalities; and E, ear abnormalities; PI3K = phosphoinositide 3-kinase; AKT = protein kinase B; MAPK = mitogen-activated protein kinase; mTOR = mammalian target of rapamycin nerve palsy, and oral clefts [44][45][46][47]. Many individuals with CHARGE syndrome are reported to exhibit autistic-like behaviors, with an estimated 27.5% meeting classification for autism [45].…”

“…These tumors, known as hamartomas, have an unpredictable distribution, but are often found within the brain, the skin, the heart, the kidneys, and the lungs [80,81]. TSC is associated with a variety of cognitive and developmental deficits, including ID, ADHD, and epilepsy.…”