McCune-Albright Syndrome (MAS) is a disorder characterized by involvement of multiple tissues, including skin, bone and endocrine glands. MAS is caused by post-zygotic mosaicism for GNAS gene mutations, which lead to a constitutively active form of the Gαs protein and increased cAMP levels. In the somatotropes of the pituitary, this increased cAMP leads to excessive growth hormone (GH) secretion. Somatostatin analogues (SSA), such as octreotide, that binds to somatostatin receptor SSTR2 are used in MAS patients to reduce GH secretion. However, MAS patients generally do not respond well to SSA, and GH control can rarely be achieved with SSA alone. In an in vitro model of MAS, five of the most common activating GNAS mutations lead to an increased level of cAMP, and a resistance to the treatment with SSA due to hyperactivated phosphokinase A. To further determine the underlying molecular causes of the SSA resistance, we studied the phosphorylation status of Filamin A (FLNA), a protein that couples somatostatin receptors to their cytoplasmic partners and to the cytoskeleton. Preliminary results suggest that three mutations of the GNAS gene may increase the phosphorylation status of FLNA.
