Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting 1 in 6,000 births, that is characterized by benign tumors (hamartomas and hamartias) in multiple organ systems. Its major clinical manifestations are due to brain involvement -- seizures, mental retardation and autism and related disorders, each of which occur in about half of TSC patients. The existence of two genes (TSC1 and TSC2) causing this disorder was established by familiar genetic linkage studies. TSC2 was identified 4 years ago, and has weak GTPase activating protein (GAP) activity for two members of the Ras family of GTPases, rap1 and rab5. In the previous application, the PI proposed to identify the TSC1 gene by positional cloning. This is now accomplished by a collaborative effort by several laboratories. There are three specific aims in the competitive renewal application: 1) A detailed mutational analysis will be performed for both the TSC1 and TSC2 loci; 2) Development of murine models of TSC; and 3)Analysis of the function of TSC1 and TSC2 proteins, hamartin and tuberin.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS031535-05
Application #
2637887
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Spinella, Giovanna M
Project Start
1994-01-20
Project End
2002-01-31
Budget Start
1998-04-15
Budget End
1999-01-31
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

Qin, Wei; Chan, Jennifer A; Vinters, Harry V et al. (2010) Analysis of TSC cortical tubers by deep sequencing of TSC1, TSC2 and KRAS demonstrates that small second-hit mutations in these genes are rare events. Brain Pathol 20:1096-105
Qin, Wei; Kozlowski, Piotr; Taillon, Bruce E et al. (2010) Ultra deep sequencing detects a low rate of mosaic mutations in tuberous sclerosis complex. Hum Genet 127:573-82
Mozaffari, Melika; Hoogeveen-Westerveld, Marianne; Kwiatkowski, David et al. (2009) Identification of a region required for TSC1 stability by functional analysis of TSC1 missense mutations found in individuals with tuberous sclerosis complex. BMC Med Genet 10:88
Camposano, S E; Greenberg, E; Kwiatkowski, D J et al. (2009) Distinct clinical characteristics of tuberous sclerosis complex patients with no mutation identified. Ann Hum Genet 73:141-6
Kozlowski, Piotr; Bissler, John; Pei, York et al. (2008) Analysis of PKD1 for genomic deletion by multiplex ligation-dependent probe assay: absence of hot spots. Genomics 91:203-8
Choi, Yong-Jin; Di Nardo, Alessia; Kramvis, Ioannis et al. (2008) Tuberous sclerosis complex proteins control axon formation. Genes Dev 22:2485-95
Kozlowski, Piotr; Lin, Mei; Meikle, Lynsey et al. (2007) Robust method for distinguishing heterozygous from homozygous transgenic alleles by multiplex ligation-dependent probe assay. Biotechniques 42:584, 586, 588
Finlay, Geraldine A; Malhowski, Amy J; Liu, Yingling et al. (2007) Selective inhibition of growth of tuberous sclerosis complex 2 null cells by atorvastatin is associated with impaired Rheb and Rho GTPase function and reduced mTOR/S6 kinase activity. Cancer Res 67:9878-86
Kozlowski, Piotr; Roberts, Penelope; Dabora, Sandra et al. (2007) Identification of 54 large deletions/duplications in TSC1 and TSC2 using MLPA, and genotype-phenotype correlations. Hum Genet 121:389-400
Juvet, Stephen C; McCormack, Francis X; Kwiatkowski, David J et al. (2007) Molecular pathogenesis of lymphangioleiomyomatosis: lessons learned from orphans. Am J Respir Cell Mol Biol 36:398-408

Showing the most recent 10 out of 46 publications