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Molecular Pathogenesis of Lymphangioleiomyomatosis

Lessons Learned from Orphans

Division of Respirology, Department of Medicine, University of Toronto; Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Gregory P. Downey, M.D., Executive Vice President Academic Affairs, K701b, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail: downeyg{at}njc.org

Lymphangioleiomyomatosis (LAM) is a rare progressive cystic lung disease affecting young women. The pivotal observation that LAM occurs both spontaneously and as part of the tuberous sclerosis complex (TSC) led to the hypothesis that these disorders share common genetic and pathogenetic mechanisms. In this review we describe the evolution of our understanding of the molecular and cellular basis of LAM and TSC, beginning with the discovery of the TSC1 and TSC2 genes and the demonstration of their involvement in sporadic (non-TSC) LAM. This was followed by rapid delineation of the signaling pathways in Drosophila melanogaster with confirmation in mice and humans. This knowledge served as the foundation for novel therapeutic approaches that are currently being used in human clinical trials.

Key Words: tuberous sclerosis • TSC1 • TSC2 • mTOR • signal transduction • estrogen

CLINICAL RELEVANCE This review will help clinicians understand the current concepts of the pathogenesis of LAM and apply this knowledge to currently available and experimental treatments for this devastating condition.

 

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