Tuberous sclerosis complex (TSC)1 and TSC2 are tumor suppressors that inhibit cell growth and mutation of either gene causes benign tumors in multiple tissues. The TSC1 and TSC2 gene products form a functional complex that has GTPase-activating protein (GAP) activity toward Ras homolog enriched in brain (Rheb) to inhibit mammalian target of rapamycin complex 1 (mTORC1), which is constitutively activated in TSC mutant tumors.
Germline TSC1 and/or TSC2 mutations are the cause of tuberous sclerosis complex (TSC). Mutations are inactivating TSC1 by protein truncation. In TSC2, large genomic deletions are observed in <10% of cases; point mutations have been reported; they are widely dispersed, with no cluster; truncating effect is seen in 2/3 of cases. TSC is an autosomal dominant multi-system disorder that affects especially the brain, kidneys, heart, and skin. The molecular basis of TSC is a functional impairment of the hamartin-tuberin complex. TSC is characterized by hamartomas (benign overgrowths predominantly of a cell or tissue type that occurs normally in the organ) and hamartias (developmental abnormalities of tissue combination). Clinical symptoms can range from benign hypopigmented macules of the skin to profound mental retardation with intractable seizures to premature death from a variety of disease-associated causes. Renal cell carcinoma develops occasionally in TSC patients.
Defects in TSC1 may be a cause of focal cortical dysplasia of Taylor balloon cell type (FCDBC). FCDBC is a subtype of cortical dysplasias linked to chronic intractable epilepsy. Cortical dysplasias display a broad spectrum of structural changes, which appear to result from changes in proliferation, migration, differentiation, and apoptosis of neuronal precursors and neurons during cortical development.
Defects in TSC2 are a cause of lymphangioleiomyomatosis (LAM). LAM is a progressive and often fatal lung disease characterized by a diffuse proliferation of abnormal smooth muscle cells in the lungs. It affects almost exclusively young women and can occur as an isolated disorder or in association with tuberous sclerosis complex.
Somatic TSC1 mutations have been observed in urinary tract and bone cancers. No mutation hotspot has been described. Somatic TSC2 mutations have been observed angiomyolipomas and pulmonary LAM cells from women with sporadic LAM
References (open access):
The tuberous sclerosis complex. Orlova KA, Crino PB. Ann N Y Acad Sci. 2010 Jan;1184:87-105.