Abstract

Patients with McCune-Albright syndrome (MAS), characterized primarily by hyperpigmented skin lesions, precocious puberty, and fibrous dyslasia of bone, carry postzygotic heterozygous mutations of GNAS causing constitutive cAMP signaling. GNAS encodes the a-subunit of the stimulatory G protein (Gsa), as well as a large variant (XLas) derived from the paternal allele. The mutations causing MAS affect both GNAS products, but whether XLas, like Gsa, can be involved in the pathogenesis remains unknown. Here, we investigated biopsy samples from four previously reported and eight new patients with MAS. Activating mutations of GNAS (Arg201 with respect to the amino acid sequence of Gsa) were present in all the previously reported and five of the new cases. The mutation was detected within the paternally expressed XLas transcript in five and the maternally expressed NESP55 transcript in four cases. Tissues carrying paternal mutations appeared to have higher XLas mRNA levels than maternal mutations. The human XLas mutant analogous to Gsa-R201H (XLas-R543H) showed markedly higher basal cAMP accumulation than wild-type XLas in transfected cells. Wild-type XLas demonstrated higher basal and isoproterenol-induced cAMP signaling than Gsa and co-purified with Gß1?2 in transduced cells. XLas mRNA was measurable in mouse calvarial cells, with its level being significantly higher in undifferentiated cells than those expressing preosteoblastic markers osterix and alkaline phosphatase. XLas mRNA was also expressed in murine bone marrow stromal cells and preosteoblastic MC3T3-E1 cells. Our findings are consistent with the possibility that constitutive XLas activity adds to the molecular pathogenesis of MAS and fibrous dysplasia of bone.

View details for DOI 10.1016/j.bone.2010.09.032

View details for Web of Science ID 000286543700019

View details for PubMedID 20887824