title: Mosaic Disorders of the PI3K/PTEN/AKT/TSC/mTORC1 Signaling Pathway.
abstract: Somatic mutations in genes of the PI3K/PTEN/AKT/TSC/mTORC1 signaling pathway cause segmental overgrowth, hamartomas, and malignant tumors. Mosaicism for activating mutations in AKT1 or PIK3CA cause Proteus syndrome and PIK3CA-Related Overgrowth Spectrum, respectively. Postzygotic mutations in PTEN or TSC1/TSC2 cause mosaic forms of PTEN hamartoma tumor syndrome or tuberous sclerosis complex, respectively. Distinct features observed in these mosaic conditions in part reflect differences in embryological timing or tissue type harboring the mutant cells. Deep sequencing of affected tissue is useful for diagnosis. Drugs targeting mTORC1 or other points along this signaling pathway are in clinical trials to treat these disorders.
authors.affiliation: Department of Dermatology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
authors.forename: Neera
authors.initials: N
authors.lastname: Nathan
authors.affiliation: Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, Building 49, Room 4A56, 49 Convent Drive, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kim M
authors.initials: KM
authors.lastname: Keppler-Noreuil
authors.affiliation: Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, Building 49, Room 4A56, 49 Convent Drive, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Biesecker
authors.affiliation: Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, Building 10, Room 6D05, 10 Center Drive, National Institutes of Health, Bethesda, MD 20892-1590, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Moss
authors.affiliation: Department of Dermatology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA. Electronic address: thomas.darling@usuhs.edu.
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Darling
mesh_terms: D006223:Hamartoma Syndrome, Multiple / Q000150:complications / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D009030:Mosaicism; D046912:Multiprotein Complexes / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics; D010641:Phenotype; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics; D016715:Proteus Syndrome / Q000150:complications / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics; D012871:Skin Diseases / Q000209:etiology / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D014402:Tuberous Sclerosis / Q000150:complications / Q000235:genetics*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D046912:Multiprotein Complexes; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D058539:Phosphatidylinositol 3-Kinase; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase
keywords: Mosaicism; Next-generation sequencing; PIK3CA-related overgrowth spectrum; PTEN hamartoma tumor syndrome; Proteus syndrome; Sirolimus; Tuberous sclerosis complex; mTORC1