Our laboratory studies two related disorders: tuberous sclerosis complex (TSC) and pulmonary lymphangiomyomatosis (LAM). Tuberous sclerosis is an autosomal dominantly inherited disease with an incidence of approximately one in 10,000 births. TSC is characterized by seizures, mental retardation, autism, and benign tumors or "hamartomas." These tumors can occur in virtually any organ system, particularly brain, kidney, heart, and skin. Malignant tumors can also occur in tuberous sclerosis, particularly in the kidney, although they are less frequent than benign tumors.
Mutations in two tumor suppressor genes cause TSC: the TSC1 gene, on chromosome 9q34, which encodes a 140 kDa protein called hamartin, and the TSC2 gene, on chromosome 16p13, which encodes a 200 kDa protein, tuberin. The cellular functions of these proteins are an area of active investigation in our laboratory.
Pulmonary LAM is of unusual interest biologically because it affects almost exclusively young women. LAM shares two features with TSC: a distinctive smooth muscle cell pulmonary infiltrate and benign renal angiomyolipomas. However, LAM is not genetically transmitted. LAM can occur without other disease or in association with TSC. Lung transplantation is the only effective therapy for patients with end-stage LAM. We have found that somatic mutations in the TSC2 gene cause LAM. The same TSC2 mutations were identified in both the renal angiomyolipomas and the LAM smooth muscle cells in the lung, but not in normal kidney, normal lung, or blood cells. This suggests the possibility of an unusual disease mechanism in LAM: metastasis of histologically benign smooth muscle cells from the renal angiomyolipoma to the lungs.