GNAS haploinsufficiency leads to subcutaneous tumor formation with collagen and elastin deposition and calcification.
BACKGROUND
The heterotrimeric G protein alpha-subunit G(s)alpha links receptors to stimulation of cAMP/protein kinase A signaling, which inhibits skin fibroblast proliferation and collagen synthesis. We now describe the development of fibrous tumors in mice with heterozygous disruption of the Gnas gene, which encodes G(s)alpha and other gene products.


RESULTS
Disruption of Gnas exon 2 on either the maternal or paternal allele (Gnas(E2-/+)) results in fibromas or angiofibromas on the ears, paws and tail beginning at 4 months of age. The tumors were composed of fibroblastic cell proliferation with collagen and elastin deposition and calcification, and seemed to be associated with mechanical skin damage. The presence of calcification was associated with greater amounts of matrix metalloproteinase-2, suggesting an association between calcium deposition and extracellular matrix degradation. Osteoblast-specific markers were absent, consistent with the calcification not being secondary to ossification. Molecular studies showed that the tumors were not associated with deletion of the wild-type allele, making it unlikely that these tumors resulted from homozygous loss of G(s)alpha.


CONCLUSIONS
These findings provide in vivo evidence that G(s)alpha pathways inhibit fibroblast and endothelial proliferation and matrix deposition.
Sakamoto
Akio
A
Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA. akio@med.kyushu-u.ac.jp
Weinstein
Lee S
LS
Plagge
Antonius
A
Eckhaus
Michael
M
Kelsey
Gavin
G
D018322:Angiofibroma / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D002114:Calcinosis / Q000209:etiology; D002864:Chromogranins; D003094:Collagen / Q000378:metabolism*; D004549:Elastin / Q000378:metabolism*; D005350:Fibroma / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics* / Q000502:physiology; D051379:Mice; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology
D002864:Chromogranins; D003094:Collagen; D004549:Elastin; C498642:Gnas protein, mouse; D019205:GTP-Binding Protein alpha Subunits, Gs