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Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA.

Authors: Lindhurst, Marjorie J  Parker, Victoria E R  Payne, Felicity  Sapp, Julie C  Rudge, Simon  Harris, Julie  Witkowski, Alison M  Zhang, Qifeng  Groeneveld, Matthijs P  Scott, Carol E  Daly, Allan  Huson, Susan M  Tosi, Laura L  Cunningham, Michael L  Darling, Thomas N  Geer, Joseph  Gucev, Zoran  Sutton, V Reid  Tziotzios, Christos  Dixon, Adrian K  Helliwell, Timothy  O'Rahilly, Stephen  Savage, David B  Wakelam, Michael J O  Barroso, InĂªs  Biesecker, Leslie G  Semple, Robert K 
Citation: Lindhurst MJ, etal., Nat Genet. 2012 Jun 24;44(8):928-33. doi: 10.1038/ng.2332.
Pubmed: (View Article at PubMed) PMID:22729222
DOI: Full-text: DOI:10.1038/ng.2332

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 p110α 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 (PIP(3)) 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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RGD Object Information
RGD ID: 13207409
Created: 2017-07-27
Species: All species
Last Modified: 2017-07-27
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.