Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a progressive and often fatal interstitia l lung disease characterized by a diffuse proliferation of abnormal smooth muscle cells in the lungs. LAM is of unusual interest biologically because it affects almost exclusively young women. LAM can occur as an isolated dis order (sporadic LAM) or in association with tuberous sclerosis complex. Ren al angiomyolipomas, which are found in most tuberous sclerosis patients, al so occur in 60% of sporadic LAM patients. We previously found TSC2 loss of heterozygosity in 7 of 13 (54%) of angiomyolipomas from sporadic LAM patien ts, suggesting that LAM and TSC could have a common genetic basis. In this study, we report the identification of somatic TSC2 mutations in five of se ven angiomyolipomas from sporadic LAM patients. In all four patients from w hom lung tissue was available, the same mutation found in the angiomyolipom a was present in the abnormal pulmonary smooth muscle cells. In no case was the mutation present in normal kidney, morphologically normal lung, or lym phoblastoid cells, Our data demonstrate that somatic mutations in the TSC2 gene occur in the angiomyolipomas and pulmonary LAM cells of women with spo radic LAM, strongly supporting a direct role of TSC2 in the pathogenesis of this disease.