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GNAS

Function

Guanine nucleotide-binding proteins (G proteins) function as transducers in numerous signaling pathways controlled by G protein-coupled receptors (GPCRs) (PubMed:12391161, PubMed:17110384, PubMed:21488135, PubMed:26206488, PubMed:8702665, PubMed:10200251). The alpha chain contains the guanine nucleotide binding site and alternates between an active, GTP-bound state and an inactive, GDP-bound state (PubMed:12391161, PubMed:17110384, PubMed:10200251). Signaling by an activated GPCR promotes GDP release and GTP binding (PubMed:12391161, PubMed:17110384, PubMed:10200251). The alpha subunit has a low GTPase activity that converts bound GTP to GDP, thereby terminating the signal (PubMed:12391161, PubMed:17110384, PubMed:10200251). Both GDP release and GTP hydrolysis are modulated by numerous regulatory proteins (PubMed:12391161, PubMed:17110384, PubMed:10200251). Signaling involves the activation of adenylyl cyclases, resulting in increased levels of the signaling molecule cAMP (PubMed:17110384, PubMed:26206488, PubMed:26206488, PubMed:8702665). Functions downstream of beta-adrenergic receptors (PubMed:21488135). Stimulates the Ras signaling pathway via RAPGEF2 (PubMed:12391161).

Involvement in disease

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.

None

The disease is caused by variants affecting the gene represented in this entry.

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.

None

The disease is caused by variants affecting the gene represented in this entry.

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.

None

The disease is caused by variants affecting the gene represented in this entry.

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.

None

The disease is caused by variants affecting the gene represented in this entry.

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.

None

The disease is caused by variants affecting the gene represented in this entry.

Pseudohypoparathyroidism 1B

PHP1B

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.

None

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.

GNAS hyperfunction

GNASHYP

This condition is characterized by increased trauma-related bleeding tendency, prolonged bleeding time, brachydactyly and intellectual disability. 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.

None

The disease is caused by variants affecting the gene represented in this entry.

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.

None

The disease is caused by variants affecting the gene represented in this entry.

Sequence Similarities

Belongs to the G-alpha family. G(s) subfamily.

Cellular localization

Alternative names

GNAS1, GSP, GNAS, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Adenylate cyclase-stimulating G alpha protein

swissprot:P63092 swissprot:Q5JWF2 omim:139320 entrezGene:2778