Tuberous sclerosis complex is multisystem disorder characterized by the widespread development of growths known as hamartomas in many tissues and organs, particularly within the brain, eyes, skin, kidneys, heart, lungs and skeleton. The most severely affected system is the central nervous system with the occurrence in affected individuals of seizures (80-90 percent), mental retardation (50-60 percent), and autism (up to 50 percent). TSC is inherited as an autosomal dominant disorder, but approximately two-thirds of affected patients are sporadic due to new germline mutations. Genetic linkage studies have shown locus heterogeneity for the disease, with at least two TSC determining genes on chromosomes 9 and 16 which have been termed TSC1 and TSC2 respectively. The TSC1 gene encodes a novel protein, hamartin that contains a single transmembrane domain and a large cytoplasmic tail with a coiled-coil domain. The TSC2 gene encodes a novel protein tuberin that contains a region of homology to the GTPase activating protein rap1GAP. We have performed a comprehensive mutational analysis of the TSC1 and TSC2 genes and noted that TSC1 mutations are significantly underrepresented in sporadic patients. However, the occurrence of the second somatic mutation in TSC lesions, particularly brain lesions is not clear. In order to understand whether this is due to cellular pleomorphism, or if haploinsufficiency of tuberin/hamartin is enough to promote tumor genesis, we will perform genetic analysis on laser capture microdissected lesions. We have identified a novel protein associated with Myc named Pam as an interacting protein for tuberin. Mutations in both the Drosophila (hiw) and C. elegans (rpm-1) homologs of Pam show synaptic overgrowth. Our hypothesis that Pam is an essential component of the tuberin-hamartin complex, particularly in the CNS where these proteins may have a critical role in cortical neuron function will be examined. The domain of Pam that interacts with tuberin reveals 90 percent similarity with the fly homolog HIW. The possible physical and genetic interaction between the Drosophila TSC2 product Gigas and HIW will be examined. Thus the studies aimed at defining the role of tuberin-hamartin in the mammalian CNS will be further strengthened by the Drosophila model system where genetic manipulations are possible. The information obtained here will elucidate the physiological functions of these tumor suppressors, which will aid in designing better therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041917-04
Application #
6790531
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Finkelstein, Robert
Project Start
2001-09-30
Project End
2006-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
4
Fiscal Year
2004
Total Cost
$173,000
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
James, Marianne F; Lelke, Johanna M; Maccollin, Mia et al. (2008) Modeling NF2 with human arachnoidal and meningioma cell culture systems: NF2 silencing reflects the benign character of tumor growth. Neurobiol Dis 29:278-92
Santos, Tulio M; Han, Sangyeul; Bowser, Mark et al. (2006) Alternative splicing in protein associated with Myc (Pam) influences its binding to c-Myc. J Neurosci Res 83:222-32
Han, Sangyeul; Santos, Tulio M; Puga, Ana et al. (2004) Phosphorylation of tuberin as a novel mechanism for somatic inactivation of the tuberous sclerosis complex proteins in brain lesions. Cancer Res 64:812-6
Lee-Jones, Lisa; Aligianis, Irene; Davies, Peter A et al. (2004) Sacrococcygeal chordomas in patients with tuberous sclerosis complex show somatic loss of TSC1 or TSC2. Genes Chromosomes Cancer 41:80-5
Murthy, Vanishree; Han, Sangyeul; Beauchamp, Roberta L et al. (2004) Pam and its ortholog highwire interact with and may negatively regulate the TSC1.TSC2 complex. J Biol Chem 279:1351-8
Ramesh, V (2003) Aspects of tuberous sclerosis complex (TSC) protein function in the brain. Biochem Soc Trans 31:579-83
Haddad, Luciana A; Smith, Nicole; Bowser, Mark et al. (2002) The TSC1 tumor suppressor hamartin interacts with neurofilament-L and possibly functions as a novel integrator of the neuronal cytoskeleton. J Biol Chem 277:44180-6