EVIDENCE THAT LYMPHANGIOMYOMATOSIS IS CAUSED BY TSC2 MUTATIONS - CHROMOSOME 16P13 LOSS OF HETEROZYGOSITY IN ANGIOMYOLIPOMAS AND LYMPH-NODESFROM WOMEN WITH LYMPHANGIOMYOMATOSIS

Lymphangiomyomatosis (LAM) is a rare disease, of unknown etiology, aff ecting women almost exclusively. Lung transplantation is the only cons istently effective therapy for LAM. Microscopically, LAM consists of a diffuse proliferation of smooth muscle cells. LAM can occur without e vidence of other disease (referred to as ''sporadic LAM'') or in assoc iation with tuberous sclerosis complex (TSC). TSC is an autosomal domi nant tumor suppressor gene syndrome characterized by seizures, mental retardation, and tumors in the brain, heart, skin, and kidney. Renal a ngiomyolipomas occur in similar to 50% of sporadic LAM patients and in 70% of TSC patients. Loss of heterozygosity (LOH) in the chromosomal region for the TSC2 gene occurs in 60% of TSC-associated angiomyolipom as. Because of the similar pulmonary and renal manifestations of TSC a nd sporadic LAM, we hypothesized that LAM and TSC have a common geneti c basis. We analyzed renal angiomyolipomas, from 13 women with sporadi c LAM, for LOH in the regions of the TSC1 (chromosome 9q34) and TSC2 ( chromosome 16p13) genes. TSC2 LOH was detected in seven (54%) of the a ngiomyolipomas. We also found TSC2 LOH in four lymph nodes from a woma n with retroperitoneal LAM. No TSC1 LOH was found. Our findings indica te that the TSC2 gene may be involved in the pathogenesis of sporadic LAM. However, genetic transmission of LAM has not been reported. Women with LAM may have low-penetrance germ-line TSC2 mutations, or they ma y be mosaic, with TSC2 mutations in the lung and the kidney but not in other organs.