Loss of heterozygosity in tuberous sclerosis hamartomas.

Abstract

We have previously described in tuberous sclerosis (TSC) hamartomas the phenomenon of loss of heterozygosity (LOH) for DNA markers in the region of both the TSC2 gene on chromosome 16pl3.3 and the TSC1 gene on 9q34.We now describe the spectrum of LOH in 51 TSC hamartomas from 34 cases of TSC. DNA was extracted from leucocytes or normal paraffin embedded tissue, and from frozen paraffin embedded hamartoma tissue from the same patient. The samples were analysed for 11 markers spanning the TSC1 locus and nine markers spanning the TSC2 locus. Twenty-one of 51 hamartomas showed LOH (41%). There was significantly more LOH on 16pl3.3, with 16 hamartomas showing LOH around TSC2, and five in the vicinity of TSC1. No hamartoma showed LOH for markers around both loci. All the areas of LOH on chromosome 9 were large, but the smallest region of overlap lay between the markers D9S149 and D9S114, providing independent evidence for the localisation of the TSCl gene.These data show that LOH is a common finding in a wide range of hamartomas, affecting the same TSC locus in different lesions from the same patient but not affecting both loci. 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. (J Med Genet 1996;33:962-964) Key words: tuberous sclerosis; loss of heterozygosity; hamartoma.Tuberous sclerosis (TSC) is an autosomal dominant condition characterised by tumourlike malformations (hamartomas) of the skin, brain, heart, kidney, and other organs. The disease prevalence is estimated at 1 in 10 000, with two thirds of cases being sporadic and representing new dominant mutations. Common hamartomas occurring in tuberous sclerosis include cortical tubers, subependymal nodules, retinal astrocytomas, renal angiomyolipomas, benign giant cell astrocytomas, and cardiac rhabdomyomas.Two loci have been confirmed for TSC, with approximately 50% of familial cases linked to TSC1 at 9q34 and the remainder to TSC2 at 16pl3.3.' The TSC1 gene lies in a 2.7Mb region between markers D9S 149 and D9S1 14.2 The TSC2 gene has been cloned and about 5% of patients show large germline deletions of this gene.' The predicted protein sequence has a short area of homology to a RAP 1-GTPase activating protein (rap 1 GAP or GAP3), and the expressed TSC2 protein has raplGAP activity in vitro. 4 We and others have described the phenomenon of loss of heterozygosity (LOH) in the region of the TSC1 or TSC2 genes in hamartomas from cases of TSC.5-7 The presence of LOH on 16p 13.3 in TSC hamartomas, and the finding of large germline deletions in the TSC2 gene in cases ofTSC strongly suggest that the TSC2 gene acts as a tumour or growth suppressor, according to Knudson's hypothesis.8 The finding of LOH in TSC hamartomas for 9q34 suggests a similar role for the TSC 1 gene. We now present our findings in a large series of TSC hamartomas.We analysed 51 TSC ham...

Mutation analysis of the TSC1 and TSC2 genes in Japanese patients with pulmonary lymphangioleiomyomatosis

“…TSC is a hereditary disor-der with an autosomal dominant trait, characterized by seizures; mental retardation; and hamartomas of the brain, retina, skin, heart, lungs, and kidneys (Gomez 1999;Short et al 1995). TSC is a tumor-suppressor gene syndrome in which Knudson's two-hit theory (Knudson 1971) is applied for the development of TSC-associated hamartoma (Henske et al 1996;Sepp et al 1996) and patients with TSC have a germline mutation of either the TSC1 or the TSC2 gene (Jones et al , 1999Wilson et al 1996;Yamashita et al 2000). The TSC1 gene codes for a 130-kDa protein named hamartin, which is located on chromosome 9q34 (Van Slegtenhorst et al 1997), and the TSC2 gene codes for a 200-kDa protein named tuberin (Consortium 1993), located on chromosome 16p13.3.…”

Loss of function of the tuberous sclerosis 2 tumor suppressor gene results in embryonic lethality characterized by disrupted neuroepithelial growth and development

“…The tumor suppressor properties of the tuberous sclerosis 2 (TSC2) gene have been established in both human and rodent tumors (1)(2)(3)(4)(5)(6). In humans, tuberous sclerosis (TSC) is an autosomal dominant syndrome associated with the development of hamartomas in various tissues (7).…”

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].…”

“…The TSC phenotype in individuals with germline TSC mutations may be explained by the Bsecond hit theory^. Sporadic somatic mutation of the remaining copy of TSC leads to a loss of heterozygosity in a given cell, resulting in tumor formation [85].…”