The expression of hamartin, the product of the TSC1 gene, in normal human tissues and in TSC1- and TSC2-linked angiomyolipomas

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characte rized by seizures, mental retardation, and hamartomatous tumors in multiple organs, including subependymal giant cell astrocytomas, cardiac rhabdomyom as, and renal angiomyolipomas. Mutations in two genes are associated with T SC: TSC1, which was cloned in 1997, and TSC2, which was cloned in 1993. We report here the expression of hamartin, the product of the TSC1 gene, in no rmal human tissues and in renal angiomyolipomas from TSC1- and TSC2-linked patients. By Western blot analysis, hamartin is strongly expressed in brain , kidney, and heart, all of which are frequently affected in TSC, By immuno histochemical analysis, the expression pattern of hamartin in normal human tissues was almost identical to that of tuberin, the product of the TSC2 ge ne. This is consistent with the recent finding that tuberin and hamartin in teract and with the clinical similarity between TSC1- and TSC2-linked disea se. Strong hamartin expression was seen in cortical neurons, renal tubular epithelial cells, pancreatic islet cells, bronchial epithelial cells, and p ulmonary macrophages. Hamartin was also expressed in endocrine tissues, inc luding islet cells of the pancreas, follicular cells of the thyroid, and th e zona reticularis of the adrenal cortex In eight angiomyolipomas from a TS C1-linked patient, no hamartin expression was detected, whereas tuberin, th e product of the TSC2 gene, was expressed. In 19 angiomyolipomas from a TSC 2-linked patient, in whose angiomyolipomas lass of tuberin expression had p reviously been shown, hamartin expression was present. These data suggest t hat tuberin and hamartin immunoreactivity can distinguish tumors with under lying TSC1 mutations from those with TSC2 mutations. This differentiation m ight have diagnostic implications.