title: Mutation analysis of the TSC1 and TSC2 genes in Japanese patients with pulmonary lymphangioleiomyomatosis.
abstract: Pulmonary lymphangioleiomyomatosis (LAM) is a destructive lung disease characterized by a diffuse hamartomatous proliferation of smooth muscle cells (LAM cells) in the lungs. Pulmonary LAM can occur as an isolated form (sporadic LAM) or in association with tuberous sclerosis complex (TSC) (TSC-LAM), a genetic disorder with autosomal dominant inheritance with various expressivity resulting from mutations of either the TSC1 or TSC2 gene. We examined mutations of both TSC genes in 6 Japanese patients with TSC-LAM and 22 patients with sporadic LAM and identified six unique and novel mutations. TSC2 germline mutations were detected in 2 (33.3%) of 6 patients with TSC-LAM and TSC1 germline mutation in 1 (4.5%) of 22 sporadic LAM patients. In accordance with the tumor-suppressor model, loss of heterozygosity (LOH) was detected in LAM cells from 3 of 4 patients with TSC-LAM and from 4 of 8 patients with sporadic LAM. Furthermore, an identical LOH or two identical somatic mutations were demonstrated in LAM cells microdissected from several tissues, suggesting LAM cells can spread from one lesion to another. Our results from Japanese patients with LAM confirmed 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.
authors.affiliation: Department of Respiratory Medicine Juntendo University, School of Medicine, Tokyo, Japan.
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Sato
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Seyama
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Fujii
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maruyama
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Setoguchi
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Iwakami
authors.forename: Yoshinosuke
authors.initials: Y
authors.lastname: Fukuchi
authors.forename: Okio
authors.initials: O
authors.lastname: Hino
mesh_terms: D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007564:Japan / Q000453:epidemiology; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics*; D018192:Lymphangioleiomyomatosis / Q000235:genetics*; D009130:Muscle, Smooth / Q000737:chemistry; D011110:Polymorphism, Genetic; D011506:Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D014402:Tuberous Sclerosis / Q000235:genetics; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins
chemical_list: D017931:DNA Primers; D004273:DNA, Neoplasm; D011506:Proteins; D012097:Repressor Proteins; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins