GNAS

This locus has a highly complex imprinted expression pattern. It gives rise to maternally, paternally, and biallelically expressed transcripts that are derived from four alternative promoters and 5' exons. Some transcripts contain a differentially methylated region (DMR) at their 5' exons, and this DMR is commonly found in imprinted genes and correlates with transcript expression. An antisense transcript is produced from an overlapping locus on the opposite strand. One of the transcripts produced from this locus, and the antisense transcript, are paternally expressed noncoding RNAs, and may regulate imprinting in this region. In addition, one of the transcripts contains a second overlapping ORF, which encodes a structurally unrelated protein - Alex. Alternative splicing of downstream exons is also observed, which results in different forms of the stimulatory G-protein alpha subunit, a key element of the classical signal transduction pathway linking receptor-ligand interactions with the activation of adenylyl cyclase and a variety of cellular reponses. Multiple transcript variants encoding different isoforms have been found for this gene. Mutations in this gene result in pseudohypoparathyroidism type 1a, pseudohypoparathyroidism type 1b, Albright hereditary osteodystrophy, pseudopseudohypoparathyroidism, McCune-Albright syndrome, progressive osseus heteroplasia, polyostotic fibrous dysplasia of bone, and some pituitary tumors.

GNAS (guanine nucleotide binding protein, alpha stimulating) complex locus

Guanine nucleotide-binding proteins (G proteins) function as transducers in numerous signaling pathways controlled by G protein-coupled receptors (GPCRs) (PubMed:17110384).

Signaling involves the activation of adenylyl cyclases, resulting in increased levels of the signaling molecule cAMP (PubMed:26206488, PubMed:8702665).

GNAS functions downstream of several GPCRs, including beta-adrenergic receptors (PubMed:21488135).

Stimulates the Ras signaling pathway via RAPGEF2 (PubMed:12391161).

Activation of adenylate cyclase activity Source: UniProtKB
Adenylate cyclase-activating adrenergic receptor signaling pathway Source: UniProtKB
Adenylate cyclase-activating dopamine receptor signaling pathway Source: BHF-UCL
Adenylate cyclase-activating G protein-coupled receptor signaling pathway Source: UniProtKB
Bone development Source: UniProtKB
Cellular response to catecholamine stimulus Source: BHF-UCL
Cellular response to prostaglandin E stimulus Source: BHF-UCL
Cognition Source: UniProtKB
Developmental growth Source: UniProtKB
Hair follicle placode formation Source: UniProtKB
Intracellular transport Source: UniProtKB
Platelet aggregation Source: UniProtKB
Positive regulation of cAMP-mediated signaling Source: UniProtKB
Positive regulation of cold-induced thermogenesis Source: YuBioLab
Positive regulation of GTPase activity Source: UniProtKB
Sensory perception of smell Source: UniProtKB

Cell membrane

Albright hereditary osteodystrophy (AHO):
A disorder characterized by short stature, obesity, round facies, brachydactyly and subcutaneous calcification. It is often associated with pseudohypoparathyoidism, hypocalcemia and elevated PTH levels.
Pseudohypoparathyroidism 1A (PHP1A):
A disorder characterized by end-organ resistance to parathyroid hormone, hypocalcemia and hyperphosphatemia. It is commonly associated with Albright hereditary osteodystrophy whose features are short stature, obesity, round facies, short metacarpals and ectopic calcification.
McCune-Albright syndrome (MAS):
Characterized by polyostotic fibrous dysplasia, cafe-au-lait lesions, and a variety of endocrine disorders, including precocious puberty, hyperthyroidism, hypercortisolism, growth hormone excess, and hyperprolactinemia. The mutations producing MAS lead to constitutive activation of GS alpha.
Progressive osseous heteroplasia (POH):
Rare autosomal dominant disorder characterized by extensive dermal ossification during childhood, followed by disabling and widespread heterotopic ossification of skeletal muscle and deep connective tissue.
ACTH-independent macronodular adrenal hyperplasia 1 (AIMAH1):
A rare adrenal defect characterized by multiple, bilateral, non-pigmented, benign, adrenocortical nodules. It results in excessive production of cortisol leading to ACTH-independent Cushing syndrome. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes.
Pseudohypoparathyroidism 1B (PHP1B):
The disease is caused by variants affecting the gene represented in this entry. Most affected individuals have defects in methylation of the gene. In some cases microdeletions involving the STX16 appear to cause loss of methylation at exon A/B of GNAS, resulting in PHP1B. Paternal uniparental isodisomy have also been observed. A disorder characterized by end-organ resistance to parathyroid hormone, hypocalcemia and hyperphosphatemia. Patients affected with PHP1B lack developmental defects characteristic of Albright hereditary osteodystrophy, and typically show no other endocrine abnormalities besides resistance to PTH.
GNAS hyperfunction (GNASHYP):
This condition is characterized by increased trauma-related bleeding tendency, prolonged bleeding time, brachydactyly and mental retardation. Both the XLas isoforms and the ALEX protein are mutated which strongly reduces the interaction between them and this may allow unimpeded activation of the XLas isoforms.
Pseudohypoparathyroidism 1C (PHP1C):
A disorder characterized by end-organ resistance to parathyroid hormone, hypocalcemia and hyperphosphatemia. It is commonly associated with Albright hereditary osteodystrophy whose features are short stature, obesity, round facies, short metacarpals and ectopic calcification.