Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA.
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.
The National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.
Marjorie J
MJ
Lindhurst
Victoria E R
VE
Parker
Felicity
F
Payne
Julie C
JC
Sapp
Simon
S
Rudge
Julie
J
Harris
Alison M
AM
Witkowski
Qifeng
Q
Zhang
Matthijs P
MP
Groeneveld
Carol E
CE
Scott
Allan
A
Daly
Susan M
SM
Huson
Laura L
LL
Tosi
Michael L
ML
Cunningham
Thomas N
TN
Darling
Joseph
J
Geer
Zoran
Z
Gucev
V Reid
VR
Sutton
Christos
C
Tziotzios
Adrian K
AK
Dixon
Timothy
T
Helliwell
Stephen
S
O'Rahilly
David B
DB
Savage
Michael J O
MJ
Wakelam
Inês
I
Barroso
Leslie G
LG
Biesecker
Robert K
RK
Semple
D000273:Adipose Tissue / Q000201:enzymology* / Q000473:pathology*; D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D001842:Bone and Bones / Q000201:enzymology / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D058534:Class I Phosphatidylinositol 3-Kinases; D003238:Connective Tissue / Q000201:enzymology* / Q000473:pathology*; D004252:DNA Mutational Analysis; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D006801:Humans; D006965:Hyperplasia; D007223:Infant; D008297:Male; D008875:Middle Aged; D009030:Mosaicism; D009154:Mutation; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013577:Syndrome
D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051057:Proto-Oncogene Proteins c-akt