Abstract
The McCune Albright syndrome (MAS) is a sporadic disorder with pleiotropic manifestations including autonomous endocrine hyperfunction, polyostotic fibrous dysplasia, and cafe-au-lait skin pigmentation. Since the endocrine abnormalities in MAS (e.g. gonadotropin-independent precocious puberty, growth hormone hypersecretion, hyperthyroidism, hypercortisolism) are all consistent with constitutive activation of the cAMP 2nd messenger system, we screened tissues from patients with MAS for mutations in the G protein a subunit (Gs-α) that regulates cAMP formation. We found missense mutations that lead to constitutive activation of Gs-α (either Arg 201-> His or Arg 201-> Cys) in affected endocrine tissues from all subjects with MAS studied. The mutations were found in a mosaic distribution consistent with a somatic mutation occurring early in embryogenesis. Gs-α mutations were also found in dysplastic bone samples, and in various nonendocrine tissues such as liver and heart. Mutations in the latter may be responsible for previously underappreciated manifestations of MAS such as hepatobiliary disease and early death. Identification of constitutively activating mutations of Gs-α as the cause of most if not all of the manifestations of MAS has important implications for our understanding of cAMP regulation of cell function, and ultimately, for treatment of MAS.
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Spiegel, A., Shenker, A. & Weinstein, L. THE MCCUNE ALBRIGHT SYNDROME: A GENETICALLY DETERMINED SIGNAL TRANSDUCTION DISORDER. Pediatr Res 33 (Suppl 5), S6–S7 (1993). https://doi.org/10.1203/00006450-199305001-00026
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DOI: https://doi.org/10.1203/00006450-199305001-00026
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