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

Authors

Marjorie J. Lindhurst, National Human Genome Research Institute (NHGRI)
Victoria E.R. Parker, University of Cambridge
Felicity Payne, Wellcome Trust
Julie C. Sapp, National Human Genome Research Institute (NHGRI)
Simon Rudge, The Babraham Institute
Julie Harris, University of Cambridge
Alison M. Witkowski, National Human Genome Research Institute (NHGRI)
Qifeng Zhang, The Babraham Institute
Matthijs P. Groeneveld, University of Cambridge
Carol E. Scott, Wellcome Trust
Allan Daly, Wellcome Trust
Susan M. Huson, Health Innovation Manchester
Laura L. Tosi, Childrens National Health System
Michael L. Cunningham, University of Washington School of Medicine
Thomas N. Darling, Uniformed Services University of the Health Sciences
Joseph Geer, Greenwood Genetics Center
Zoran Gucev, SS Cyril and Methodius University Faculty of Medicine
V. Reid Sutton, Baylor College of Medicine
Christos Tziotzios, University of Glasgow
Adrian K. Dixon, School of Clinical Medicine
Timothy Helliwell, University of Liverpool
Stephen O'Rahilly, University of Cambridge
David B. Savage, University of Cambridge
Michael J.O. Wakelam, The Babraham Institute
Inês Barroso, University of Cambridge
Leslie G. Biesecker, National Human Genome Research Institute (NHGRI)
Robert K. Semple, University of Cambridge

Document Type

Journal Article

Publication Date

8-1-2012

Journal

Nature Genetics

Volume

44

Issue

8

DOI

10.1038/ng.2332

Abstract

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 p110Î ± 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. © 2012 Nature America, Inc. All rights reserved.

APA Citation

Lindhurst, M., Parker, V., Payne, F., Sapp, J., Rudge, S., Harris, J., Witkowski, A., Zhang, Q., Groeneveld, M., Scott, C., Daly, A., Huson, S., Tosi, L., Cunningham, M., Darling, T., Geer, J., Gucev, Z., Sutton, V., Tziotzios, C., Dixon, A., Helliwell, T., O'Rahilly, S., Savage, D., Wakelam, M., Barroso, I., Biesecker, L., & Semple, R. (2012). Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Nature Genetics, 44 (8). http://dx.doi.org/10.1038/ng.2332