Mutation analysis of the TSC1 and TSC2 genes in Japanese patients with pulmonary lymphangioleiomyomatosis

Abstract

firmed the current concept of pathogenesis of LAM: TSC-LAM has a germline mutation but sporadic LAM does not; sporadic LAM is a TSC2 disease with two somatic mutations; and a variety of TSC mutations causes LAM. However, our study indicates that a fraction of sporadic LAM can be a TSC1 disease; therefore, both TSC genes should be examined, even for patients with sporadic LAM.

Molecular and genetic analysis of disseminated neoplastic cells in lymphangioleiomyomatosis

“…By using this approach, allelic loss of TSC2 was detected in 15 (75%) of the samples (Table 2). Allelic loss of TSC1 was not detected, consistent with previous reports that most genetic alterations in LAM were in the TSC2 gene (7,9,18).…”

“…It occurs as a sporadic disease or with tuberous sclerosis complex (TSC), which can be inherited as an autosomal dominant disorder involving multiorgan hamartomas, in which patients frequently develop lung and kidney lesions pathologically and genetically similar to those seen in LAM (4)(5)(6). LAM lesions are marked by proliferation of abnormal-appearing smooth muscle-like cells (LAM cells) that have loss of heterozygosity (LOH) (7) and inactivating mutations (8,9) in one of the two TSC genes. Most mutations have been described in TSC2 (16p13), with mutations in the TSC1 gene (9q34) being less frequent.…”

“…Most mutations have been described in TSC2 (16p13), with mutations in the TSC1 gene (9q34) being less frequent. In LAM lung lesions, LOH or other somatic mutations in either TSC gene have been reported (7)(8)(9). Renal AML contain abnormal blood vessels and adipose cells in addition to the smooth muscle-like LAM cells.…”

Rheb activates AMPK and reduces p27Kip1 levels in Tsc2-null cells via mTORC1-independent mechanisms: implications for cell proliferation and tumorigenesis

“…TSC and LAM result from the inactivation of either of the two tumor-suppressor genes, TSC1 that encodes hamartin (TSC1), and TSC2 that encodes tuberin (TSC2) (van Slegtenhorst et al, 1997;Carsillo et al, 2000;Sato et al, 2002). TSC1 and TSC2 form an active complex (TSC1/2) that negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling, which promotes cell growth (Huang and Manning, 2008).…”

Integration of mTOR and estrogen–ERK2 signaling in lymphangioleiomyomatosis pathogenesis

“…estrogen signaling | mTORC1 signaling | ERK signaling | EMT L ymphangioleiomyomatosis (LAM) is a destructive, progressive, multisystem disease in which smooth muscle-like "LAM cells" invade the lung (1)(2)(3)(4)(5)(6) and is associated with chylous pleural effusions, lymphatic obstruction, and renal angiomyolipomas (7). LAM occurs almost exclusively in women with onset often occurring in the childbearing years (5,6,8,9).…”