Tuberous sclerosis complex: genetics to pathogenesis.

Desiree-Magloire Bourneville first reported tuberous sclerosis complex as "tuberous sclerosis of the cerebral convolutions" in 1880. This disorder is characterized by multiple hamartomas in several organs, particularly the brain. Commonly recognized clinical features include hypomelanotic skin macules, facial angiofibromas, periungual fibromas, delayed development, and seizures. Abnormalities on brain imaging include subependymal nodules, cortical tubers, and radial white matter lines. The kidney, heart, and retina are among other commonly affected organs. Although the majority of cases (65%) are sporadic, genetic linkage studies of familial cases led to the discovery of two separate genes linked to tuberous sclerosis complex: TSC1, located at chromosome 9q34, encoding a protein called hamartin; and TSC2, located at chromosome 16p13.3, encoding a protein called tuberin. Tuberin has a region of homology to rap1GAP, a guanosine triphosphatase-activating protein. This observation is consistent with the idea of tuberin functioning in a cellular signaling pathway. Hamartin contains a single potential transmembrane domain; orthologues in yeast, drosophila, and rat have been cloned. Hamartin also binds to ezrin and other ezrin-radixin-moesin proteins, which link the cell membrane to the cytoskeleton. Tuberin and hamartin interact directly with each other, and the complex may function together to regulate specific cellular processes. This study reviews current ideas regarding the function of tuberin and hamartin, and the pathogenesis of tuberous sclerosis complex.