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FLASH GENE
Symbol GNAS contributors: mct/npt - updated : 09-07-2019
HGNC name GNAS complex locus
HGNC id 4392
Corresponding disease
DEL20Q13 chromosome 20q interstitial deletion of paternal origin, including the GNAS complex locus
MCAS McCune-Albright syndrome
PAD growth hormone secreting pituitary adenoma
PHP1A pseudohypoparathyroism 1A
PHP1B pseudohypoparathyroidism, type 1B
PHP1C pseudohypoparathyroidism type IC
POH progressive osseous heteroplasia
PPHP pseudopseudohypoparathyroidism, Albright osteodystrophy phenotype
Location 20q13.32      Physical location : 57.414.794 - 57.486.249
Synonym name
  • guanine nucleotide binding protein (G protein), alpha stimulating activity polypeptide 1
  • adenylate cyclase-stimulating G alpha protein
  • Gsalpha
  • secretogranin VI
  • extra large alphas protein
  • neuroendocrine secretory protein
  • alternative gene product encoded by XL-exon
  • Synonym symbol(s) GSA, GPSA, GNAS1, NESP55, GSP, XL2, NESP, GNASXL, XLalphas, C20orf45, SCG6, MGC33735, Galphas
    DNA
    TYPE functioning gene
    STRUCTURE 71.45 kb     13 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence alternative promoter
    cytosine-phosphate-guanine/HTF
    text structure three CpG islands, one specific exon and exons 2-13 common with GNAS1, yet sharing no coding sequence stop codon 5' to exon 2
  • an imprinting control element in the differentially methylated region at exon 1A required for the tissue-specific imprinting
  • three differentially methylated regions (DMRs) upstream of the promoter (from upstream to downstream): the paternally methylated NESP55 promoter region, the maternally methylated NESP antisense (NESPAS)/XLalphas promoter region and the maternally methylated exon 1A region just upstream of the promoter
  • MAPPING cloned Y linked Y status confirmed
    Map cen - GNAS - TH1L - CTSZ - qter
    Authors Bonthron (00)
    RNA
    TRANSCRIPTS type messenger
    text encoding multiple products by use of 4 alternative first exons that splice onto a common set of downstream exons
  • maternally, paternally, and biallelically expressed proteins derived from alternatively spliced transcripts with alternate 5' exons
  • identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    13 - 1926 45.7 394 biallelically expressed, ubiquitous Mattera, Levine (1991)
  • also known as alpha-s-2
  • P3 downstream P2
  • required for coupling ligand-activated forms of hormone receptors to intracellular generation of cAMP
  • using a different promoter and exon, termed "exon 1-prime" (or "exon 1A"), located 2.5 kb upstream of GNAS exon 1
  • 13 splicing initiation site 2581 28 245 localized to large secretory vesicles of endocrine cells and neurons, maternally expressed (paternally imprinted) Hayward, Weiss, Levine (1991)
  • also known as NESP55, chromogranin-like protein
  • upstream P1
  • containing a cis-acting element for imprinting of the maternal GNAS allele
  • using an alternate 5' exon, generated from the most centromeric of the first exons (splicing onto common exons 2-13)
  • does not overlap the coding regions used by variants alpha-s-2, alpha-s-1, XL-alphaS
  • 12 initiation site 1884 - 380 paternally expressed (maternally imprinted) Kehlenbach, Plagge, Levine (1991)
  • also known GNASS, XL-alpha-S
  • P2-14kb further 3' from P1
  • antagonizing GSA-dependent signaling pathway and controling suckling, blood glucose and energy homeostasis
  • 13 splicing 3784 - 626 biallelically expressed, imprinted only in certain hormone-responsive tissues (renal proximal tubule) Mattera, Robertson, Levine (1991)
  • also known GNASXL, alpha-s-1
  • required for coupling ligand-activated forms of hormone receptors to intracellular generation of cAMP
  • lacking an internal exon but maintains the reading frame compared to alpha-s-2
  • 12 - 1881 - 379 - Levine (1991)
    also known as variant 7, isoform g
    13 - 1586 - 395 - Levine (1991)
    also known as variant 6, isoform f
    13 - 3784 - 1037 - Levine (1991)
    also called alpha s XXL, alex, alexX
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestivemouthtongue  predominantly
     pancreas exocrine   highly
     stomach   moderately
    Nervousbrain   moderately
    Reproductivefemale systemuteruscervix moderately
     female systembreastmammary gland moderately
    Respiratoryrespiratory tractlarynx  highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Nervousperipherous   
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    IMPRINTING maternally, paternally
    text
  • maternally, paternally, and biallelically expressed proteins produced by different patterns of promoter use
  • imprinting defects may affect Gs expression in imprinted tissues (renal proximal tubule and thyroid)
  • expression in renal proximal tubules occurs predominantly from the maternal allele (important determinant of hormone resistance in kindreds with pseudohypoparathyroidism)
  • PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • ras-like GTPase domain with three regions named switches 1, 2 and 3 and including the sites for guanine nucleotide binding and effector interaction
  • secondary structure
  • an helical domain
  • conjugated LipoP , Other
    mono polymer heteromer , trimer
    HOMOLOGY
    interspecies ortholog to murine Gnas
    Homologene
    FAMILY
  • G-alpha family
  • G(s) subfamily
  • NESP55 family
  • CATEGORY regulatory , secretory , protooncogene , signaling , receptor membrane G
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,endosome
    text
  • GNAS and CCDC88A localize to EEA1 early endosomes
  • basic FUNCTION
  • putatively involved in secretory vesicle formation
  • involved in hormonal regulation of adenylate cyclase: activation of the cyclase in response to beta-adrenergic stimuli
  • proteolytically derived peptide (LSAL) antagonizing serotonergic receptor 5HT1RB
  • involved as modulators or transducers in various transmembrane signaling systems
  • primarily mediating the differential effects of parathyroid hormone on trabecular and cortical bone in osteoblasts
  • negatively regulating chondrocyte differentiation and acting as critical signaling mediator of the PTH/PTH-rP receptor in growth plate chondrocytes
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling signal transduction
    a component
  • composed of 3 units (beta, gamma and alpha chain containing the guanine nucleotide binding site)
  • INTERACTION
    DNA
    RNA
    small molecule nucleotide,
  • GTP
  • protein
  • ALEX1
  • GNAS facilitates EEA1 endosome maturation, limits EGFR signaling from EEA1 endosomes, and inhibits cell proliferation
  • GNAS facilitates dissociation of EEA1 from membranes, which is a key step in EEA1 endosome maturation and EGFR signal down-regulation
  • GNAS and CCDC88A functionally interact to facilitate endosome maturation, EGFR degradation, and down-regulation of EGFR proliferative signaling
  • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) MCAS , PHP1A , PHP1B , PHP1C , PPHP , POH , PAD , DEL20Q13
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --low  
    by partial and complete hypomethylation in Beckwith-Wiedemann syndrome (Bliek (2009)
    Susceptibility
  • to severe malaria
  • to vasovagal syncope
  • Variant & Polymorphism SNP
  • three SNP presenting significant associations with severe malaria were clustered at the 5-prime end (Auburn 2008)
  • mutation T/C inside codon 131 causes the increased activation of adenyl cyclase, which plays an important role in cardiovascular regulation, and predisposes to vasovagal syncope (Lelonek 2008)
  • Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS