In 2 patients with McCune-Albright syndrome (174800), Weinstein et al. (1991) identified an arg201-to-his (R201H) mutation in exon 8 of the GNAS gene in endocrine organs affected in this disorder, such as gonads, adrenal glands, thyroid, and pituitary, as well as tissues not classically involved. In 2 endocrine organs, ovary and adrenal, the highest proportion of mutant alleles was found in regions of abnormal cell proliferation. Weinstein et al. (1991) concluded that somatic mutation of the GNAS gene early in embryogenesis resulted in the mosaic population of normal and mutant-bearing tissues that underlie the clinical manifestations of McCune-Albright syndrome. It remained an open question whether GNAS1 mutations were causally related to the nonendocrine abnormalities in 3 of the patients: chronic liver disease in 1, thymic hyperplasia in 2, gastrointestinal adenomatous polyps in 1, cardiopulmonary disease in 1, and sudden death in 2.
Schwindinger et al. (1992) found a G-to-A transition resulting in the R201H substitution in a patient with McCune-Albright syndrome who had severe bony involvement, characteristic skin lesions, and a history of hyperthyroidism. The mutation was found in a higher proportion of skin cells from affected areas than from unaffected areas. The findings confirmed the Happle (1986) hypothesis that this disorder is due to mosaicism for a postzygotic GNAS1 mutation. The authors noted that arg201 is also the site of ADP-ribosylation by the cholera toxin.
Collins et al. (2003) identified the R201H mutation in thyroid carcinoma from a patient with McCune-Albright syndrome.
In 2 growth hormone (GH; 139250)-secreting pituitary tumors (102200) surgically removed from patients with acromegaly, Landis et al. (1989) identified a somatic mutation in the GNAS1 gene, resulting in an R201H substitution. The mutation resulted in constitutive activation of Gs by inhibiting its GTPase activity and behaved like a dominantly acting oncogene.
Fragoso et al. (2003) identified a heterozygous R201H mutation in adrenal tissue from 2 unrelated patients with ACTH-independent macronodular adrenal hyperplasia (219080). Sato et al. (2014) identified a heterozygous somatic R201H mutation in adrenocortical tumors derived from 4 unrelated patients with ACTH-independent Cushing syndrome. GNAS-positive tumors were smaller (average diameter 31.9 mm) than tumors without GNAS mutations (average diameter 37.7 mm), but additional pathologic findings were not reported.
In 1 of 30 cases of juvenile ovarian granulosa cell tumor, the most common sex cord stromal tumor, Kalfa et al. (2006) detected the R201H mutation of the GNAS gene. Laser microdissection confirmed that the mutation was exclusively localized in the tumoral granulosa cells and was absent in the ovarian stroma.
