What causes McCune-Albright syndrome (MAS)?

Updated: Jan 17, 2019
  • Author: Gabriel I Uwaifo, MD; Chief Editor: George T Griffing, MD  more...
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Answer

MAS is caused by a sporadic, early postzygotic somatic mutation in the GNAS1 gene at locus 20q13.1-13.2, coding for the G protein subunit Gs alpha. [22] This genetic finding has been noted and confirmed in various tissue specimens from patients with MAS. [23] Researchers have isolated activating mutations of GNAS1 in pituitary adenomas, thyroid adenomas, ovarian cysts, monostotic bone dysplasia, and the adrenal glands. [24] GNAS1 gene abnormality in pseudohypoparathyroidism I-a has also been noted. [25]

G proteins couple cell surface receptors to intracellular proteins to activate or inactivate signaling cascades. The stimulatory G protein is normally activated when a hormone or other ligand binds to the cell surface receptor (see the image below). The activated Gs alpha disassociates from the receptor, binds to adenylyl cyclase, and stimulates an increase in intracellular cyclic adenosine monophosphate (cAMP) levels. Gs alpha then is inactivated, reassociates with the receptor, and is again available for hormone-mediated reactivation.

The G protein cycle begins with ligand binding to The G protein cycle begins with ligand binding to a 7-transmembrane domain G protein-coupled receptor (GPCR). Binding of the cognate ligand forms a ligand-receptor complex, which then stimulates an exchange of guanosine triphosphate (GTP) for guanosine diphosphate (GDP) on the alpha subunit of the stimulatory G protein (Gs alpha). This activates the alpha subunit, which subsequently stimulates adenylyl cyclase (AC) to increase production of cyclic adenosine monophosphate (cAMP). The alpha subunit contains intrinsic guanosine triphosphatase (GTPase) activity, which cleaves a phosphate group from GTP, converting it to GDP, and thus inactivates the alpha subunit. The inactivated alpha subunit is now ready to be reactivated by ligand-receptor binding, so that the next cycle of signal transduction can occur.

The mutations that cause MAS occur at a site in the protein that mediates inactivation of Gs alpha (see the image below). Once activated, the mutated Gs alpha subunit remains activated for a prolonged period despite the absence of hormone (GPCR ligand) stimulation. This results in constitutive activation of Gs alpha, constant stimulation of adenylyl cyclase, and persistently high levels of intracellular cAMP. Increased cAMP levels can mediate mitogenesis and increased cell function. The specific phenotype depends on the cell type containing the mutation.

Mutations in McCune-Albright syndrome inactivate i Mutations in McCune-Albright syndrome inactivate intrinsic guanosine triphosphatase (GTPase) activity, thus preventing inactivation of the "turned-on" Gs alpha subunit. Once activated, the mutated Gs alpha subunit is able to continuously stimulate adenylyl cyclase, even in absence of ligand binding to its cognate GPCR receptor. The result is elevation of intracellular cyclic adenosine monophosphate (cAMP) and continual stimulation of downstream cAMP signaling cascades.

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