Journal
NATURE GENETICS
Volume 44, Issue 8, Pages 928-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2332
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Funding
- Proteus Syndrome Foundations of the United States and United Kingdom
- Wellcome Trust [097721/Z/11/Z, 80952/Z/06/Z, 078986/Z/06/Z, 098051/Z/05/Z, 091551/Z/10/Z]
- UK Medical Research Council Centre for Obesity and Related Disorders
- UK National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre
- Intramural Research Program of the National Human Genome Research Institute
- Biotechnology and Biological Sciences Research Council (BBSRC)
- Manchester NIHR Biomedical Research Centre
- BBSRC [BBS/E/B/0000C227, BBS/E/B/000C0415] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BBS/E/B/0000C227, BBS/E/B/000C0415] Funding Source: researchfish
- Medical Research Council [G0600717B] Funding Source: researchfish
- Wellcome Trust [091551/Z/10/Z, 097721/Z/11/Z] Funding Source: Wellcome Trust
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The phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is critical for cellular growth and metabolism. Correspondingly, loss of function of PTEN, a negative regulator of PI3K, or activating mutations in AKT1, AKT2 or AKT3 have been found in distinct disorders featuring overgrowth or hypoglycemia. We performed exome sequencing of DNA from unaffected and affected cells from an individual with an unclassified syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified the cancer-associated mutation encoding p.His1047Leu in PIK3CA, the gene that encodes the p110 alpha catalytic subunit of PI3K, only in affected cells. Sequencing of PIK3CA in ten additional individuals with overlapping syndromes identified either the p.His1047Leu alteration or a second cancer-associated alteration, p.His1047Arg, in nine cases. Affected dermal fibroblasts showed enhanced basal and epidermal growth factor (EGF)-stimulated phosphatidylinositol 3,4,5-trisphosphate(PIP3) generation and concomitant activation of downstream signaling relative to their unaffected counterparts. Our findings characterize a distinct overgrowth syndrome, biochemically demonstrate activation of PI3K signaling and thereby identify a rational therapeutic target.
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