GNAS – McCune-Albright syndrome

McCune-Albright syndrome (MAS) is a sporadic, mosaic disorder characterized by polyostotic fibrous dysplasia, café-au-lait skin macules, precocious puberty and multiple endocrinopathies. It is caused by postzygotic, activating missense mutations in the stimulatory G-protein α-subunit encoded by GNAS, resulting in constitutive cAMP overproduction.

Extensive case series and reports document over 200 unrelated patients with mosaic missense mutations at codon Arg201 of GNAS (e.g., p.Arg201His), identified only in affected tissues and absent from peripheral blood by standard methods (PMID:7907339; PMID:8410501). Radiologic and histologic analyses confirm recurrent unilateral or patchy bone lesions, café-au-lait pigmentation, thyroid nodules, pituitary adenomas, adrenal hyperplasia, and other tissue-specific manifestations (PMID:10048608).

Genetic evidence is Strong: dozens of independent probands across multiple cohorts carry gain-of-function GNAS variants, predominantly at Arg201, without familial segregation due to the postzygotic mosaicism. These case counts exceed the ClinGen genetic cap for strong evidence in AD conditions.

Functional studies are Strong: patient-derived cells and heterologous models show that Arg201 mutations abolish GTPase activity of Gsα, leading to persistent adenylate cyclase activation and elevated intracellular cAMP levels (PMID:18349068). A Gpa33-driven R201C knock-in mouse exhibits increased cAMP signaling and cooperates with APC loss to drive neoplasia, mirroring human phenotypes (PMID:20531296).

No credible conflicting evidence disputes the activating role of GNAS variants in MAS.

Definitive integration of genetic, segregation (mosaic), and functional data supports a Definitive association between GNAS and McCune-Albright syndrome. Key Take-home: somatic activating variants in GNAS are the unequivocal molecular cause of MAS, guiding diagnosis, mosaicism assessment, and potential targeted interventions.

References

• The Journal of clinical endocrinology and metabolism • 1994 • A family pedigree exhibiting features of both multiple endocrine neoplasia type 1 and McCune-Albright syndromes. PMID:7907339
• The Journal of pediatrics • 1993 • Severe endocrine and nonendocrine manifestations of the McCune-Albright syndrome associated with activating mutations of stimulatory G protein GS. PMID:8410501
• European journal of pediatrics • 1999 • Imaging of McCune-Albright syndrome using bone single photon emission computed tomography. PMID:10048608
• Journal of clinical endocrinology and metabolism • 2008 • The role of type 1 and type 2 5'-deiodinase in the pathophysiology of the 3,5,3'-triiodothyronine toxicosis of McCune-Albright syndrome. PMID:18349068
• Oncogene • 2010 • The activating mutation R201C in GNAS promotes intestinal tumourigenesis in Apc(Min/+) mice through activation of Wnt and ERK1/2 MAPK pathways. PMID:20531296

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