GNAS complex locus

GNAS
Identifiers
Aliases	GNAS, AHO, C20orf45, GNAS1, GPSA, GSA, GSP, NESP, POH, SCG6, SgVI, GNAS complex locus, PITA3
External IDs	OMIM: 139320 MGI: 95777 HomoloGene: 55534 GeneCards: GNAS
Gene location (Human) Chr. Chromosome 20 (human)[1] Band 20q13.32 Start 58,839,718 bp[1] End 58,911,192 bp[1]
Gene location (Mouse) Chr. Chromosome 2 (mouse)[2] Band 2 H4|2 97.89 cM Start 174,126,113 bp[2] End 174,188,537 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in postcentral gyrus Brodmann area 46 pituitary gland anterior pituitary Brodmann area 10 entorhinal cortex superior frontal gyrus frontal pole parotid gland left lobe of thyroid gland Top expressed in superior cervical ganglion entorhinal cortex dorsomedial hypothalamic nucleus pituitary gland median eminence dermis superior colliculus left lung lobe paraventricular nucleus of hypothalamus arcuate nucleus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function molecular function nucleotide binding G-protein beta/gamma-subunit complex binding GTP binding signal transducer activity metal ion binding protein binding GTPase activity guanyl nucleotide binding adenylate cyclase activator activity insulin-like growth factor receptor binding mu-type opioid receptor binding corticotropin-releasing hormone receptor 1 binding beta-2 adrenergic receptor binding ionotropic glutamate receptor binding D1 dopamine receptor binding G protein-coupled receptor binding Cellular component cytoplasm perinuclear region of cytoplasm extracellular region transport vesicle cytoplasmic vesicle nucleus cytosol trans-Golgi network membrane membrane plasma membrane heterotrimeric G-protein complex intrinsic component of membrane extracellular exosome ruffle cell projection dendrite apical plasma membrane Biological process female pregnancy negative regulation of multicellular organism growth response to parathyroid hormone protein secretion positive regulation of cold-induced thermogenesis hair follicle placode formation cellular response to catecholamine stimulus adenylate cyclase-activating dopamine receptor signaling pathway adenylate cyclase-activating G protein-coupled receptor signaling pathway cognition regulation of insulin secretion cellular response to glucagon stimulus intracellular transport positive regulation of cAMP-mediated signaling activation of adenylate cyclase activity cellular response to prostaglandin E stimulus adenylate cyclase-activating adrenergic receptor signaling pathway sensory perception of smell positive regulation of GTPase activity developmental growth renal water homeostasis bone development platelet aggregation signal transduction G protein-coupled receptor signaling pathway regulation of signal transduction skeletal system development genetic imprinting multicellular organism growth positive regulation of osteoclast differentiation endochondral ossification regulation of parathyroid hormone secretion post-embryonic development post-embryonic body morphogenesis DNA methylation cartilage development positive regulation of osteoblast differentiation tissue homeostasis sensory perception of chemical stimulus embryonic cranial skeleton morphogenesis energy reserve metabolic process skin development embryonic hindlimb morphogenesis adenylate cyclase-modulating G protein-coupled receptor signaling pathway positive regulation of catalytic activity Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2778 14683 Ensembl ENSG00000087460 ENSMUSG00000027523 UniProt O95467 P63092 P84996 Q5JWF2 P63094 Q6R0H7 Q9Z0F1 Q6R0H6 RefSeq (mRNA) NM_000516 NM_001077488 NM_001077489 NM_001077490 NM_001309840 NM_001309842 NM_001309861 NM_001309883 NM_016592 NM_080425 NM_080426 NM_001077507 NM_001077510 NM_010309 NM_010310 NM_019690 NM_022000 NM_201616 NM_201617 NM_201618 NM_001310083 NM_001310085 NM_001364030 RefSeq (protein) NP_000507 NP_001070956 NP_001070957 NP_001070958 NP_001296769 NP_001296771 NP_001296790 NP_001296812 NP_057676 NP_536350 NP_536351 NP_000507.1 NP_001070956.1 NP_001070957.1 NP_001070958.1 NP_001296769.1 NP_536350.2 NP_536351.1 NP_001070958.1 NP_001296812.1 NP_001296812.1 NP_536350.2 NP_001070975 NP_001070978 NP_001297012 NP_001297014 NP_034439 NP_062664 NP_068840 NP_963910 NP_963911 NP_963912 NP_001350959 NP_001070975.1 NP_001297014.1 NP_034439.2 NP_963911.1 NP_062664.2 NP_068840.2 NP_001070975.1 NP_001297014.1 NP_963911.1 NP_963912.1 Location (UCSC) Chr 20: 58.84 – 58.91 Mb Chr 2: 174.13 – 174.19 Mb PubMed search [3] [4]
Wikidata
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GNAS complex locus is a gene locus in humans. Its main product is the heterotrimeric G-protein alpha subunit G_s-α, a key component of G protein-coupled receptor-regulated adenylyl cyclase signal transduction pathways. GNAS stands for Guanine Nucleotide binding protein, Alpha Stimulating activity polypeptide.^[5]

Gene[edit]

This gene 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 with distinct 5' exons. Some transcripts contain a differentially methylated region (DMR) within their 5' exons; such DMRs are commonly found in imprinted genes and correlate with transcript expression. An antisense transcript also exists, and this antisense transcript and one of the sense transcripts are paternally expressed, produce non-coding RNAs and may regulate imprinting in this region. In addition, one of the transcripts contains a second frame-shifted open reading frame, which encodes a structurally unrelated protein named ALEX.^[6][7]

Products and functions[edit]

The GNAS locus is imprinted and encodes 5 main transcripts:

• G_s-α (G_s-α long, P63092-1), biallelic
• A/B transcript (G_s-α short, P63092-2), biallelic: contains an alternate 5' terminal exon (A/B or Exon 1A) and uses a downstream start codon to have a shortened amino terminal region.
  • STX16 deletion causes loss of methylation at the A/B exon, leading to PHP1B.
• XLαs (Extra long alpha-s, Q5JWF2), paternal
  • ALEX (Alternative gene product encoded by XL-exon, P84996), may inhibit XLαs
• NESP55 (Neuroendocrine secretory protein 55, O95467), maternal
• antisense GNAS transcript (Nespas: neuroendocrine secretory protein antisense)
  • Binds to the PRC2 complex.^[8] Abolition of expression causes abnormal methylation and imprinting loss.^[9]

Alternative splicing of downstream exons is also observed, which results in different forms of the G_s-α, a key element of the classical signal transduction pathway linking receptor-ligand interactions with the activation of adenylyl cyclase and a variety of cellular responses. Multiple transcript variants have been found for this gene, but the full-length nature and/or biological validity of some variants have not been determined.

Three of the GNAS gene products, G_sα-long, G_sα-short, and XLαs, are different forms of G_sα, and differ mainly in the N-terminal region. Traditional G protein-coupled receptor signaling proceeds primarily through G_sα-long and G_sα-short, the most abundant, ubiquitously-expressed protein products of this gene. XLαs is the "extra large" isoform, and has a very long N-terminal region with some internal repeats not well-conserved across species. The XL exon also encodes in another reading frame the protein product ALEX, an inhibitory cofactor binding to the unique domain.^[10][7] The structure for GNAS is solved for the canonical P63092-1 isoform only, and little is known about what the special region of XLas or ALEX looks like.

NESP55 is a protein product completely unrelated to the GNAS protein. It undergoes extensive posttranslation processing, and is sometimes grouped as a granin.^[11] Nearly nothing is known about its structure; protein structure prediction predicts a mostly disordered protein with an N-terminal globular domain made up of alpha-helices.^[12][13]

Clinical significance[edit]

Mutations in GNAS products are associated with:

• Albright hereditary osteodystrophy
• pseudohypoparathyroidism type Ia and Ib
• pseudopseudohypoparathyroidism
• McCune–Albright syndrome
• Myxoma^[14]

Mutations in this gene also result in progressive osseous heteroplasia, polyostotic fibrous dysplasia of bone, and some pituitary tumors.^[15] Mutations in the repeat region of the XL exon leads to a hyperactive form of XLas due to lowered interaction with ALEX. As XLas is expressed in platelets, the risk of bleeding is elevated.^[16][10]

Many alleles in mice have been constructed for analyzing disease associations. Mice with this gene half knocked-out and half-mutated (tm1Jop/Oedsml) display increased heart weight, increased startle reflex, and abnormalities in bone structure and mineralization;^[17] some other alternations can be lethal.^[18] Metabolic problems resembling pseudohypoparathyroidism are seen in heterozygous mutated (wt/Oedsml) mice.^[19] Knocking out the antisense transcript is known to, at minimum, cause methylation defects.^[20]

Interactions[edit]

G protein-coupled receptor-activated G_sα binds to the enzyme adenylyl cyclase, increasing its rate of conversion of ATP to cyclic AMP.^[21]

G_sα has been shown to interact with RIC8A.^[22]

References[edit]

Further reading[edit]

External links[edit]

• GNAS+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• WikiGene index for literature mentioning this gene:
  • GNAS: human, mouse, rat
  • Nespas: human, mouse