ACTIVATING MUTATIONS OF GS PROTEIN IN MONOSTOTIC FIBROUS LESIONS OF BONE

Activating mutations of the alpha chain of the heterotrimeric signal t ransducer Gs disrupt the inherent guanosine triphosphatase activity of the alpha chain, stimulate adenylyl cyclase, and can result in indepe ndent cell proliferation. Such mutations are identified in a number of endocrine disorders, including McCune-Albright syndrome, which is a t riad of endocrinopathy, cafe au lait spots, and polyostotic fibrous dy splasia. The mutation in this syndrome is a missense point mutation in exon 8 that results in the substitution of either histidine or cystei ne for arginine at position 201. Monostotic fibrous dysplasia is a non hereditary isolated bone lesion. Other isolated bone lesions that shar e some cytologic and clinical similarities to fibrous dysplasia are os teofibrous dysplasia and aggressive fibromatosis involving bone. Four cases of monostotic fibrous dysplasia, four cases of aggressive fibrom atosis involving bone, and one case of osteofibrous dysplasia were stu died to determine if a mutation was present in exon 8 of the alpha cha in of Gs. A missense mutation was present in all of the fibrous dyspla sias. The other fibrous lesions and uninvolved tissue did not contain a mutation. Somatic activating mutations of Gs differentiate fibrous d ysplasia from the other lesions and may be responsible for the loss of control of local proliferation and growth factor expression.