Published ahead of print on November 10, 2006, doi:10.1165/rcmb.2006-0372TR Am. J. Respir. Cell Mol. Biol., Volume 36, Number 4, April 2007, 398-408 A more recent version of this article appeared on April 1, 2007
Submitted on October 1, 2006 Molecular Pathogenesis of Lymphangioleiomyomatosis: Lessons Learned from OrphansStephen C Juvet1,1 Department of Medicine, Division of Respirology, University of Toronto, Toronto, ON, Canada, 2 Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA, 3 Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA, 4 Department of Medicine, Division of Respirology, University of Toronto, Toronto, ON, Canada; Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada * To whom correspondence should be addressed. E-mail: gregory.downey{at}utoronto.ca.
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.
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