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FLASH GENE

Symbol

GNAS

contributors: mct/npt - updated : 09-07-2019

HGNC name	GNAS complex locus
HGNC id	4392

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_000516 13 - 1926 NP_000507 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 NM_016592 13 splicing initiation site 2581 NP_057676 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 NM_080426 12 initiation site 1884 NP_536351 - 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 NM_001077490 13 splicing 3784 NP_001070958 - 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 NM_001077489 12 - 1881 NP_001070957 - 379 - Levine (1991) also known as variant 7, isoform g NM_001077488 13 - 1586 NP_001070956 - 395 - Levine (1991) also known as variant 6, isoform f NM_080425 13 - 3784 NP_536350 - 1037 - Levine (1991) also called alpha s XXL, alex, alexX

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive mouth tongue     predominantly   pancreas exocrine       highly   stomach       moderately Nervous brain       moderately Reproductive female system uterus cervix   moderately   female system breast mammary gland   moderately Respiratory respiratory tract larynx     highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Nervous peripherous

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
	GPR174 can signal via GNAS to modulate B cell gene expression

cell & other

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

MCAS , PHP1A , PHP1B , PHP1C , PPHP , POH , PAD , DEL20Q13

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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