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

Nat Genet 2012 Jun 24;44(8):928-33. Epub 2012 Jun 24.

The National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.2332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3461408PMC
June 2012
39 Reads

Publication Analysis

Top Keywords

activating mutations
8
cases dermal
4
cells individual
4
unaffected cells
4
dermal fibroblasts
4
dna unaffected
4
phis1047arg cases
4
individual unclassified
4
second cancer-associated
4
congenital progressive
4
syndrome congenital
4
cancer-associated alteration
4
alteration phis1047arg
4
unclassified syndrome
4
fibroblasts enhanced
4
sequencing dna
4
factor egf-stimulated
4
overgrowth hypoglycemia
4
featuring overgrowth
4
disorders featuring
4

References

(Supplied by CrossRef)

TL Yuan et al.
Oncogene 2008

R Happle et al.
J. Am. Acad. Dermatol. 2010

MJ Lindhurst et al.
N. Engl. J. Med. 2011

JD Carpten et al.
Nature 2007

R Happle et al.
Br. J. Dermatol. 2007

L Biesecker et al.
Eur. J. Hum. Genet. 2006

CE Oduber et al.
Ann. Plast. Surg. 2008

Y Samuels et al.
Science 2004

J Clark et al.
Nat. Methods 2011

D Mandelker et al.
Proc. Natl. Acad. Sci. USA 2009

Similar Publications