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

Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by seizures, mental retardation, and hamartomatous tumors in multiple organs, including subependymal giant cell astrocytomas, cardiac rhabdomyomas, and renal angiomyolipomas. Mutations in two genes are associated with TSC: 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 normal 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 immunohistochemical analysis, the expression pattern of hamartin in normal human tissues was almost identical to that of tuberin, the product of the TSC2 gene. This is consistent with the recent finding that tuberin and hamartin interact and with the clinical similarity between TSC1- and TSC2-linked disease. Strong hamartin expression was seen in cortical neurons, renal tubular epithelial cells, pancreatic islet cells, bronchial epithelial cells, and pulmonary macrophages. Hamartin was also expressed in endocrine tissues, including islet cells of the pancreas, follicular cells of the thyroid, and the zona reticularis of the adrenal cortex. In eight angiomyolipomas from a TSC1-linked patient, no hamartin expression was detected, whereas tuberin, the product of the TSC2 gene, was expressed. In 19 angiomyolipomas from a TSC2-linked patient, in whose angiomyolipomas loss of tuberin expression had previously been shown, hamartin expression was present. These data suggest that tuberin and hamartin immunoreactivity can distinguish tumors with underlying TSC1 mutations from those with TSC2 mutations. This differentiation might have diagnostic implications.