Mosaic Disorders of the PI3K/PTEN/AKT/TSC/mTORC1 Signaling Pathway

Neera Nathan; Kim M Keppler-Noreuil; Leslie G Biesecker; Joel Moss; Thomas N Darling

doi:10.1016/j.det.2016.07.001

Mosaic Disorders of the PI3K/PTEN/AKT/TSC/mTORC1 Signaling Pathway

Dermatol Clin. 2017 Jan;35(1):51-60. doi: 10.1016/j.det.2016.07.001.

Authors

Neera Nathan¹, Kim M Keppler-Noreuil², Leslie G Biesecker², Joel Moss³, Thomas N Darling⁴

Affiliations

¹ Department of Dermatology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
² 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.
³ 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.
⁴ Department of Dermatology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA. Electronic address: thomas.darling@usuhs.edu.

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.

Keywords: Mosaicism; Next-generation sequencing; PIK3CA-related overgrowth spectrum; PTEN hamartoma tumor syndrome; Proteus syndrome; Sirolimus; Tuberous sclerosis complex; mTORC1.

Published by Elsevier Inc.

Publication types

Review

MeSH terms

Hamartoma Syndrome, Multiple / complications
Hamartoma Syndrome, Multiple / genetics*
High-Throughput Nucleotide Sequencing
Humans
Mechanistic Target of Rapamycin Complex 1
Mosaicism*
Multiprotein Complexes / genetics
PTEN Phosphohydrolase / genetics
Phenotype
Phosphatidylinositol 3-Kinase / genetics
Proteus Syndrome / complications
Proteus Syndrome / genetics*
Proto-Oncogene Proteins c-akt / genetics
Sequence Analysis, DNA
Signal Transduction / genetics
Skin Diseases / etiology
Skin Diseases / genetics*
TOR Serine-Threonine Kinases / genetics
Tuberous Sclerosis / complications
Tuberous Sclerosis / genetics*
Tuberous Sclerosis Complex 1 Protein
Tuberous Sclerosis Complex 2 Protein
Tumor Suppressor Proteins / genetics

Substances

Multiprotein Complexes
TSC1 protein, human
TSC2 protein, human
Tuberous Sclerosis Complex 1 Protein
Tuberous Sclerosis Complex 2 Protein
Tumor Suppressor Proteins
Phosphatidylinositol 3-Kinase
Mechanistic Target of Rapamycin Complex 1
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
PTEN Phosphohydrolase

Abstract

Publication types

MeSH terms

Substances

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