National Cancer Institute®
Last Modified: February 1, 2002
UI - 11741832
AU - Nellist M; Verhaaf B; Goedbloed MA; Reuser AJ; van den Ouweland AM;
TI - Halley DJ TSC2 missense mutations inhibit tuberin phosphorylation and prevent formation of the tuberin-hamartin complex.
SO - Hum Mol Genet 2001 Dec 1;10(25):2889-98
AD - Department of Clinical Genetics, Erasmus University, 3015 GE Rotterdam, The Netherlands. firstname.lastname@example.org
Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by a broad phenotypic spectrum that includes seizures, mental retardation, renal dysfunction and dermatological abnormalities. Inactivating mutations to either of the TSC1 and TSC2 tumour suppressor genes are responsible for the disease. TSC1 and TSC2 encode two large novel proteins called hamartin and tuberin, respectively. Hamartin and tuberin interact directly with each other and it has been reported that tuberin may act as a chaperone, preventing hamartin self-aggregation and maintaining the tuberin-hamartin complex in a soluble form. In this study, the ability of tuberin to act as a chaperone for hamartin was used to investigate the tuberin-hamartin interaction in more detail. A domain within tuberin necessary for the chaperone function was identified, and the effects of TSC2 missense mutations on the tuberin-hamartin interaction were investigated to allow specific residues within the central domain of tuberin that are important for the interaction with hamartin to be pin-pointed. In addition, the results confirm that phosphorylation may play an important role in the formation of the tuberin-hamartin complex. Although mutations that prevent tuberin tyrosine phosphorylation also inhibit tuberin-hamartin binding and the chaperone function, our results indicate that only hamartin is phosphorylated in the tuberin-hamartin complex.
UI - 11741833
AU - Hodges AK; Li S; Maynard J; Parry L; Braverman R; Cheadle JP; DeClue JE;
TI - Sampson JR Pathological mutations in TSC1 and TSC2 disrupt the interaction between hamartin and tuberin.
SO - Hum Mol Genet 2001 Dec 1;10(25):2899-905
AD - Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK. email@example.com
Critical functions of hamartin and tuberin, encoded by the TSC1 and TSC2 genes, are likely to be closely linked. The proteins interact directly with one another and mutations affecting either gene result in the tuberous sclerosis phenotype. However, the regions of hamartin and tuberin that interact have not been well defined, and the relationship between their interaction and the pathogenesis of tuberous sclerosis has not been explored. To address these issues a series of hamartin and tuberin constructs were used to assay for interaction in the yeast two-hybrid system. Hamartin (amino acids 302-430) and tuberin (amino acids 1-418) interacted strongly with one another. A region of tuberin encoding a putative coiled-coil (amino acids 346-371) was necessary but not sufficient to mediate the interaction with hamartin, as more N-terminal residues were also required. A region of hamartin (amino acids 719-998) predicted to encode coiled-coils was capable of oligermerization but was not important for the interaction with tuberin. Subtle, non-truncating mutations identified in patients with tuberous sclerosis and located within the putative binding regions of hamartin (N198_F199delinsI;593-595delACT) or tuberin (G294E and I365del), abolished or dramatically reduced interaction of the proteins as assessed by yeast two-hybrid assays and by co-immunoprecipitation of the full-length proteins from Cos7 cells. In contrast, three non-pathogenic missense polymorphisms of tuberin (R261W, M286V, R367Q) in the same region as the disease-causing TSC2 mutations did not. These results indicate a requirement for interaction in critical growth suppressing functions of hamartin and tuberin.
UI - 11774213
AU - Fang L; Wu Z; Wang N; Lin M; Murong S
TI - [Mutation and polymorphism in exon 4 of tuberous sclerosis complex gene]
SO - Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2001 Dec;18(6):448-51
AD - Department of Neurology, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian,350005 P.R. China. firstname.lastname@example.org
OBJECTIVE: To study the characteristic of mutation and polymorphism in exon 4 of tuberous sclerosis complex gene(TSC1) in Chinese. METHODS: Twenty-five TSC patients and 23 parents from 21 families were enrolled. The mutation of exon 4 in these subjects was identified by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and further confirmed by direct sequencing. RESULTS: The normal controls had the same SSCP bands. In 25 TSC patients, a sporadic case was found to display variant banding pattern and be heterozygous for 352 insA mutation by sequencing. In 23 parents who were normal on clinical examination, another bandshift was found on a mother who had two affected children, which was confirmed as 347A-->C(Val42Val) single nucleotide polymorphism(SNP) by sequencing. CONCLUSION: The 352 insA mutation is a new causative mutation and the 347A-->C is a rare single nucleotide polymorphism.
UI - 11811958
AU - Noonan DJ; Lou D; Griffith N; Vanaman TC
TI - A calmodulin binding site in the tuberous sclerosis 2 gene product is essential for regulation of transcription events and is altered by mutations linked to tuberous sclerosis and lymphangioleiomyomatosis.
SO - Arch Biochem Biophys 2002 Feb 1;398(1):132-40
AD - Department of Biochemistry, University of Kentucky, 800 Rose Street, Lexington, Kentucky 40536, USA. email@example.com
Mutations in the tuberous sclerosis 2 (TSC2) gene product have been genetically linked to the pathology of both tuberous sclerosis (TSC) and the gender-specific lung disease, lymphangioleiomyomatosis (LAM). Both diseases are classified as disorders of cellular migration, proliferation, and differentiation. Earlier studies from our laboratory (1) linked TSC2 with steroid/nuclear receptor signaling. Studies presented here provide evidence for calmodulin (CaM) signaling in the propagation of this TSC2 activity. Far Western screening of a lambda phage human brain cDNA library to identify interacting proteins for the TSC2 gene product (tuberin) yielded multiple clones encoding human CaM. Direct binding with 32P-labeled tuberin demonstrated Ca2+-dependent binding to CaM-Sepharose which was lost upon deletion of the C-terminal 72 residues. The sequence (1740)WIARLRHIKRLRQRIC(1755) was identified as one capable of forming a basic amphipathic helix indicative of CaM binding domains in known calmodulin binding proteins. Studies with a synthetic peptide of this sequence demonstrated very tight Ca2+-dependent binding to CaM as judged by tryptophan fluorescence perturbation studies and phosphodiesterase activation by CaM. Deletion mutagenesis studies further suggested that this CaM binding domain is required for tuberin modulation of steroid receptor function and that mutations in this region may be involved in the pathology of TSC and LAM.
UI - 11812941
AU - Martignoni G; Bonetti F; Pea M; Tardanico R; Brunelli M; Eble JN
TI - Renal disease in adults with TSC2/PKD1 contiguous gene syndrome.
SO - Am J Surg Pathol 2002 Feb;26(2):198-205
AD - Dipartimento di Patologia-Sezione Anatomia Patologica, Policlinico G.B. Rossi, Universita' di Verona, Via delle Menegone, 10 Verona, 37134 Italy.
The most common renal lesions of tuberous sclerosis complex, an autosomal-dominant syndrome resulting from losses of TSC1 (9q34) or TSC2 (16p13.3), are renal cysts and angiomyolipomas. Epithelial neoplasms are less common. The TSC2 gene lies adjacent to PKD1, the major gene responsible for autosomal-dominant polycystic kidney disease. Recently, a deletion mutation disrupting both TSC2 and PKD1 has been described in young children with tuberous sclerosis complex with severe renal cystic disease. This disease has been termed the TSC2/PKD1 contiguous gene syndrome. We describe the lesions in the resected kidneys of two adults with TSC2/PDK1 contiguous gene syndrome, at the time of the nephrectomies: a 31-year-old man and his 44-year-old mother. The four kidneys were enlarged reniform masses composed of cysts lined by flattened, cuboidal, or, infrequently, large deeply eosinophilic epithelial cells. The kidneys also contained numerous classic angiomyolipomas and rare intraglomerular microlesions. In the son the largest tumor was a monotypic epithelioid angiomyolipoma. In the wall of his left renal pelvis there was a plaque-shaped, HMB-45-positive localized lesion of lymphangioleiomyomatosis. This is the first description of the renal lesions in adults with genetically confirmed TSC2/PDK1 contiguous gene syndrome. The pathologic findings highlight the importance of thorough sampling for histology in polycystic kidney diseases and indicate that the observation of an angiomyolipoma in biopsy material from patients with enlarged cystic kidneys should suggest the diagnosis of TSC2/PKD1 contiguous gene syndrome, even in cases without ultrasonographic and macroscopic evidence of angiomyolipoma.
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