GNAS is a complex imprinted gene that uses multiple promoters to generate several gene products, including the
G protein alpha-subunit (
G(s)alpha) that couples seven-transmembrane receptors to the cAMP-generating
enzyme adenylyl cyclase. Somatic activating
G(s)alpha mutations, which alter key residues required for the
GTPase turn-off reaction, are present in various endocrine
tumors and
fibrous dysplasia of bone, and in a more widespread distribution in patients with
McCune- Albright syndrome. Heterozygous inactivating
G(s)alpha mutations lead to
Albright hereditary osteodystrophy.
G(s)alpha is imprinted in a tissue-specific manner, being primarily expressed from the maternal allele in renal proximal tubules, thyroid, pituitary, and ovary. Maternally inherited mutations lead to
Albright hereditary osteodystrophy (AHO) plus PTH, TSH, and
gonadotropin resistance (
pseudohypoparathyroidism type 1A), whereas paternally inherited mutations lead to AHO alone.
Pseudohypoparathyroidism type 1B, in which patients develop PTH resistance without AHO, is almost always associated with a GNAS imprinting defect in which both alleles have a paternal-specific imprinting pattern on both parental alleles. Familial forms of the disease are associated with a mutation within a closely linked gene that deletes a region that is presumably required for establishing the maternal imprint, and therefore maternal inheritance of the mutation results in the GNAS imprinting defect. Imprinting of one differentially methylated region within GNAS is virtually always lost in
pseudohypoparathyroidism type 1B, and this region is probably responsible for tissue-specific
G(s)alpha imprinting. Mouse knockout models show that
G(s)alpha and the alternative
G(s)alpha isoform XLalphas that is expressed from the paternal GNAS allele may have opposite effects on energy metabolism in mice.