Project: Research project

Project Details


McCune-Albright syndrome (MAS) is an non-genetic disorder in which
affected subjects show a variety of seemingly unrelated abnormalities
including polyostotic fibrous dysplasia, pigmented skin lesions (cafe-au-
lait spots), and autonomous hyperfunction of various endocrine organs
including gonads, anterior pituitary, thyroid, and adrenal cortex. The
endocrine abnormalities lead to precocious puberty, gigantism/acromegaly,
hyperthyroidism, and hypercortisolism. The cause of this sporadic
disorder has been enigmatic, but speculations have centered on a defect
in signal transduction leading to endocrine hyperfunction. The
distribution of skin lesions has also suggested the possibility of a
somatic mutation acquired early in embryogenesis and affecting only a
subset of cells (mosaicism). Since a G protein mutation could plausibly
explain the endocrine manifestations, we searched for and found mutations
of the Gs-alpha gene that lead to constitutive activation of the Gs
protein. These mutations were found in a mosaic distribution; notably,
mutant gene was undetectable in normal-appearing portions of endocrine
glands, but as present at heterozygous levels in neoplastic portions of
endocrine tissue. Mutant Gs-alpha was also detected in dysplastic bone
lesions, both in the polyostotic, "classical" form of MAS and in a "form
fruste" of the disease, monostotic fibrous dysplasia. Occurrence of
mutant Gs-alpha in organs such as heart and liver suggest a possible role
in "non-classical" manifestations, including sudden death. Our studies
suggest that MAS is caused by a somatic mutation in the Gs-alpha gene
occurring early in development and found in a mosaic distribution. More
focal manifestations of the disease such as monostotic fibrous dysplasia
may be caused by somatic mutation of the Gs-alpha gene occurring later
in development.
StatusNot started


  • Genetics(clinical)