GNAS (GNAS complex locus)

Gene

• Entrez ID: 2778
• Gene name: GNAS complex locus
• Gene symbol: GNAS
• Synonyms: AHO, C20orf45, GNAS1, GPSA, GSA, GSP, NESP, PITA3, POH, SCG6, SgVI
• Chromosome: 20
• Chromosome location: 20q13.32
• Summary: 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. [provided by RefSeq, Aug 2012]

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs11554273	C>A,G,T	Likely-pathogenic, pathogenic	Missense variant, non coding transcript variant, genic downstream transcript variant, coding sequence variant, 3 prime UTR variant
rs111541229	G>C,T	Likely-pathogenic	Splice donor variant, intron variant
rs113029858	G>C,T	Pathogenic	Genic downstream transcript variant, splice donor variant
rs121913494	A>G,T	Likely-pathogenic, pathogenic	Coding sequence variant, genic downstream transcript variant, 3 prime UTR variant, downstream transcript variant, non coding transcript variant, missense variant
rs121913495	G>A,T	Likely-pathogenic, pathogenic	Coding sequence variant, genic downstream transcript variant, 3 prime UTR variant, non coding transcript variant, missense variant
rs137854530	A>G,T	Likely-pathogenic, pathogenic	Upstream transcript variant, 5 prime UTR variant, intron variant, genic upstream transcript variant, non coding transcript variant, missense variant, initiator codon variant
rs137854531	T>C	Pathogenic	Coding sequence variant, genic downstream transcript variant, 3 prime UTR variant, non coding transcript variant, missense variant
rs137854532	C>T	Pathogenic	Coding sequence variant, genic downstream transcript variant, 3 prime UTR variant, non coding transcript variant, missense variant
rs137854533	G>C,T	Pathogenic	Coding sequence variant, genic downstream transcript variant, 3 prime UTR variant, downstream transcript variant, non coding transcript variant, missense variant
rs137854534	C>G	Pathogenic	Coding sequence variant, genic downstream transcript variant, 3 prime UTR variant, downstream transcript variant, non coding transcript variant, missense variant
rs137854535	C>T	Uncertain-significance, pathogenic	Coding sequence variant, genic downstream transcript variant, 3 prime UTR variant, downstream transcript variant, non coding transcript variant, missense variant
rs137854536	CG>GC	Pathogenic	Coding sequence variant, genic downstream transcript variant, 3 prime UTR variant, downstream transcript variant, non coding transcript variant, missense variant
rs137854537	G>A,T	Uncertain-significance, pathogenic	Coding sequence variant, genic downstream transcript variant, 3 prime UTR variant, non coding transcript variant, missense variant
rs137854538	G>A	Pathogenic	Coding sequence variant, genic downstream transcript variant, 3 prime UTR variant, downstream transcript variant, non coding transcript variant, missense variant
rs137854539	C>T	Likely-pathogenic, pathogenic	Coding sequence variant, genic downstream transcript variant, 3 prime UTR variant, non coding transcript variant, missense variant
rs201332059	T>G	Not-provided, conflicting-interpretations-of-pathogenicity	Coding sequence variant, missense variant, genic upstream transcript variant, intron variant
rs397514456	G>A,T	Pathogenic	Stop gained, missense variant, genic downstream transcript variant, coding sequence variant, 3 prime UTR variant, non coding transcript variant
rs397514457	T>G	Pathogenic	Missense variant, genic downstream transcript variant, coding sequence variant, 3 prime UTR variant, non coding transcript variant
rs587776829	GACT>-	Pathogenic	3 prime UTR variant, coding sequence variant, frameshift variant, genic downstream transcript variant, non coding transcript variant
rs774711025	CTG>-,CTGCTG	Pathogenic	Upstream transcript variant, inframe deletion, intron variant, non coding transcript variant, genic upstream transcript variant, 5 prime UTR variant, coding sequence variant, inframe insertion
rs797044895	A>G	Likely-pathogenic	Non coding transcript variant, 3 prime UTR variant, 5 prime UTR variant, missense variant, coding sequence variant
rs797045046	C>G,T	Pathogenic	Upstream transcript variant, stop gained, intron variant, non coding transcript variant, genic upstream transcript variant, 5 prime UTR variant, missense variant, coding sequence variant
rs797045203	C>A	Pathogenic	Non coding transcript variant, genic downstream transcript variant, 3 prime UTR variant, missense variant, coding sequence variant, downstream transcript variant
rs863224876	C>T	Likely-pathogenic	Stop gained, non coding transcript variant, genic downstream transcript variant, 3 prime UTR variant, coding sequence variant
rs886039383	A>G	Pathogenic	Genic downstream transcript variant, splice acceptor variant
rs886039677	C>T	Pathogenic	Stop gained, non coding transcript variant, genic downstream transcript variant, 3 prime UTR variant, coding sequence variant, downstream transcript variant
rs1057518224	T>-	Pathogenic	Coding sequence variant, non coding transcript variant, 3 prime UTR variant, frameshift variant, genic downstream transcript variant
rs1057518907	C>G,T	Pathogenic	Intron variant, coding sequence variant, upstream transcript variant, non coding transcript variant, 5 prime UTR variant, genic upstream transcript variant, stop gained, missense variant
rs1057520715	G>A	Pathogenic	Intron variant, coding sequence variant, upstream transcript variant, non coding transcript variant, 5 prime UTR variant, genic upstream transcript variant, missense variant
rs1064794045	G>C	Pathogenic	Intron variant, coding sequence variant, upstream transcript variant, non coding transcript variant, 5 prime UTR variant, genic upstream transcript variant, missense variant
rs1064795798	G>A	Likely-pathogenic	Coding sequence variant, non coding transcript variant, 3 prime UTR variant, missense variant, genic downstream transcript variant
rs1085307719	CGCCAT>-	Pathogenic	Intron variant, inframe deletion, upstream transcript variant, non coding transcript variant, 5 prime UTR variant, genic upstream transcript variant, initiator codon variant
rs1131691999	C>T	Likely-pathogenic	Coding sequence variant, non coding transcript variant, 3 prime UTR variant, missense variant, genic downstream transcript variant
rs1135401777	G>A	Likely-pathogenic	Intron variant, coding sequence variant, synonymous variant, genic upstream transcript variant, missense variant
rs1272546759	C>G,T	Likely-pathogenic	Missense variant, downstream transcript variant, genic downstream transcript variant, non coding transcript variant, synonymous variant, coding sequence variant, 3 prime UTR variant
rs1555883949	T>C	Pathogenic	Genic upstream transcript variant, non coding transcript variant, 5 prime UTR variant, missense variant, intron variant, upstream transcript variant, initiator codon variant
rs1555889031	G>A	Pathogenic	Non coding transcript variant, coding sequence variant, genic downstream transcript variant, missense variant, 3 prime UTR variant
rs1555889131	G>A	Pathogenic	Genic downstream transcript variant, downstream transcript variant, splice donor variant
rs1555891562	G>A	Likely-pathogenic	Non coding transcript variant, coding sequence variant, genic downstream transcript variant, missense variant, downstream transcript variant, 3 prime UTR variant
rs1555891584	G>A	Likely-pathogenic	Non coding transcript variant, coding sequence variant, genic downstream transcript variant, missense variant, downstream transcript variant, 3 prime UTR variant
rs1555891728	CGCTGAGAAAGTCCT>-	Likely-pathogenic	Non coding transcript variant, coding sequence variant, genic downstream transcript variant, 3 prime UTR variant, inframe deletion
rs1555891743	A>T	Pathogenic	Non coding transcript variant, coding sequence variant, genic downstream transcript variant, stop gained, 3 prime UTR variant
rs1569015549	A>C	Likely-pathogenic	Non coding transcript variant, coding sequence variant, genic downstream transcript variant, missense variant, 3 prime UTR variant
rs1569020396	C>T	Pathogenic	Non coding transcript variant, coding sequence variant, genic downstream transcript variant, stop gained, 3 prime UTR variant
rs1569031388	->C	Likely-pathogenic	Non coding transcript variant, coding sequence variant, genic downstream transcript variant, 3 prime UTR variant, frameshift variant
rs1569032751	CAT>-	Likely-pathogenic	Non coding transcript variant, coding sequence variant, genic downstream transcript variant, 3 prime UTR variant, inframe deletion
rs1601115202	A>T	Pathogenic	Stop gained, non coding transcript variant, coding sequence variant, genic downstream transcript variant, 3 prime UTR variant
rs1601115231	C>T	Pathogenic	Stop gained, non coding transcript variant, coding sequence variant, genic downstream transcript variant, 3 prime UTR variant
rs1601162438	C>T	Pathogenic	Non coding transcript variant, downstream transcript variant, coding sequence variant, missense variant, genic downstream transcript variant, 3 prime UTR variant
rs1601163749	C>-	Pathogenic	Non coding transcript variant, downstream transcript variant, coding sequence variant, genic downstream transcript variant, 3 prime UTR variant, frameshift variant
rs1601164303	->GG	Pathogenic	Non coding transcript variant, downstream transcript variant, coding sequence variant, genic downstream transcript variant, 3 prime UTR variant, frameshift variant
rs1601164378	G>C	Pathogenic	Downstream transcript variant, splice donor variant, genic downstream transcript variant
rs1601166850	T>C	Likely-pathogenic	Splice donor variant, genic downstream transcript variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT020904	hsa-miR-155-5p	Proteomics	18668040
MIRT020904	hsa-miR-155-5p	HITS-CLIP	22473208
MIRT036192	hsa-miR-320b	CLASH	23622248
MIRT039683	hsa-miR-615-3p	CLASH	23622248
MIRT040832	hsa-miR-18a-3p	CLASH	23622248
MIRT042911	hsa-miR-324-3p	CLASH	23622248
MIRT043309	hsa-miR-331-3p	CLASH	23622248
MIRT044478	hsa-miR-320a	CLASH	23622248
MIRT051047	hsa-miR-17-5p	CLASH	23622248
MIRT051047	hsa-miR-17-5p	HITS-CLIP	22473208
MIRT052019	hsa-let-7b-5p	CLASH	23622248
MIRT154852	hsa-miR-205-5p	HITS-CLIP	22473208
MIRT154852	hsa-miR-205-5p	HITS-CLIP	23313552
MIRT154853	hsa-miR-212-5p	HITS-CLIP	23313552
MIRT154856	hsa-miR-188-3p	HITS-CLIP	23313552
MIRT154857	hsa-miR-376a-3p	HITS-CLIP	23313552
MIRT154858	hsa-miR-376b-3p	HITS-CLIP	23313552
MIRT154861	hsa-miR-532-3p	HITS-CLIP	23313552
MIRT154876	hsa-miR-5196-3p	PAR-CLIP	23592263
MIRT154876	hsa-miR-5196-3p	PAR-CLIP	21572407
MIRT154876	hsa-miR-5196-3p	HITS-CLIP	23313552
MIRT154882	hsa-miR-142-3p	HITS-CLIP	22473208
MIRT154882	hsa-miR-142-3p	PAR-CLIP	23592263
MIRT154882	hsa-miR-142-3p	PAR-CLIP	21572407
MIRT154884	hsa-miR-875-3p	PAR-CLIP	23592263
MIRT154885	hsa-miR-1299	PAR-CLIP	23592263
MIRT154885	hsa-miR-1299	PAR-CLIP	21572407
MIRT154889	hsa-miR-4280	PAR-CLIP	23592263
MIRT154889	hsa-miR-4280	PAR-CLIP	21572407
MIRT154891	hsa-miR-3664-3p	PAR-CLIP	23592263
MIRT154891	hsa-miR-3664-3p	PAR-CLIP	21572407
MIRT154894	hsa-miR-4433a-3p	PAR-CLIP	23592263
MIRT154894	hsa-miR-4433a-3p	PAR-CLIP	21572407
MIRT154895	hsa-miR-4459	PAR-CLIP	23592263
MIRT154895	hsa-miR-4459	PAR-CLIP	21572407
MIRT154897	hsa-miR-4540	PAR-CLIP	23592263
MIRT154898	hsa-miR-3978	PAR-CLIP	23592263
MIRT154900	hsa-miR-4768-3p	PAR-CLIP	23592263
MIRT154900	hsa-miR-4768-3p	PAR-CLIP	21572407
MIRT154901	hsa-miR-6073	PAR-CLIP	23592263
MIRT440552	hsa-miR-432-3p	HITS-CLIP	24374217
MIRT440553	hsa-miR-136-5p	HITS-CLIP	24374217
MIRT440554	hsa-miR-432-5p	HITS-CLIP	24374217
MIRT440555	hsa-miR-377-5p	HITS-CLIP	24374217
MIRT440556	hsa-miR-218-5p	HITS-CLIP	23212916
MIRT440557	hsa-miR-20a-5p	HITS-CLIP	22473208
MIRT440558	hsa-miR-106b-5p	HITS-CLIP	22473208
MIRT493757	hsa-miR-219b-5p	PAR-CLIP	23592263
MIRT493757	hsa-miR-219b-5p	PAR-CLIP	23446348
MIRT493758	hsa-miR-888-3p	PAR-CLIP	23592263
MIRT493758	hsa-miR-888-3p	PAR-CLIP	23446348
MIRT493759	hsa-miR-4735-3p	PAR-CLIP	23592263
MIRT493759	hsa-miR-4735-3p	PAR-CLIP	23446348
MIRT493760	hsa-miR-18b-5p	PAR-CLIP	23592263
MIRT493760	hsa-miR-18b-5p	PAR-CLIP	23446348
MIRT493761	hsa-miR-18a-5p	PAR-CLIP	23592263
MIRT493761	hsa-miR-18a-5p	PAR-CLIP	23446348
MIRT493762	hsa-miR-3665	PAR-CLIP	23592263
MIRT493763	hsa-miR-6804-5p	PAR-CLIP	23592263
MIRT493764	hsa-miR-6786-3p	PAR-CLIP	23592263
MIRT493765	hsa-miR-203a-3p	PAR-CLIP	23592263
MIRT493766	hsa-miR-125a-3p	PAR-CLIP	23592263
MIRT493767	hsa-miR-6755-5p	PAR-CLIP	23592263
MIRT493768	hsa-miR-4519	PAR-CLIP	23592263
MIRT493769	hsa-miR-4274	PAR-CLIP	23592263
MIRT493770	hsa-miR-1252-3p	PAR-CLIP	23592263
MIRT493771	hsa-miR-199a-3p	PAR-CLIP	23592263
MIRT493772	hsa-miR-199b-3p	PAR-CLIP	23592263
MIRT493773	hsa-miR-3129-5p	PAR-CLIP	23592263
MIRT493774	hsa-miR-5706	PAR-CLIP	23592263
MIRT493774	hsa-miR-5706	PAR-CLIP	21572407
MIRT493775	hsa-miR-4782-5p	PAR-CLIP	23592263
MIRT493775	hsa-miR-4782-5p	PAR-CLIP	21572407
MIRT493776	hsa-miR-516b-5p	PAR-CLIP	23592263
MIRT493776	hsa-miR-516b-5p	PAR-CLIP	21572407
MIRT493777	hsa-miR-6128	PAR-CLIP	23592263
MIRT493778	hsa-miR-6838-3p	PAR-CLIP	23592263
MIRT703277	hsa-miR-4642	HITS-CLIP	23313552
MIRT703278	hsa-miR-6771-5p	HITS-CLIP	23313552
MIRT703279	hsa-miR-425-3p	HITS-CLIP	23313552
MIRT703280	hsa-miR-3622b-5p	HITS-CLIP	23313552
MIRT703281	hsa-miR-6847-3p	HITS-CLIP	23313552
MIRT703282	hsa-miR-4793-5p	HITS-CLIP	23313552
MIRT727560	hsa-miR-519d-3p	HITS-CLIP	22473208
MIRT727561	hsa-miR-93-5p	HITS-CLIP	22473208
MIRT727562	hsa-miR-20b-5p	HITS-CLIP	22473208

Transcription factors

Transcription factor	Regulation	Reference
GATA1	Unknown	11418466
YY1	Unknown	18458536

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0001664	Function	G protein-coupled receptor binding	IBA	21873635
GO:0001894	Process	Tissue homeostasis	IEA
GO:0001958	Process	Endochondral ossification	IEA
GO:0003924	Function	GTPase activity	IBA	21873635
GO:0005159	Function	Insulin-like growth factor receptor binding	IBA	21873635
GO:0005515	Function	Protein binding	IPI	12719376, 23353685
GO:0005525	Function	GTP binding	IEA
GO:0005829	Component	Cytosol	IDA	12719376
GO:0005829	Component	Cytosol	ISS
GO:0005834	Component	Heterotrimeric G-protein complex	IBA	21873635
GO:0006112	Process	Energy reserve metabolic process	IEA
GO:0006306	Process	DNA methylation	IEA
GO:0007188	Process	Adenylate cyclase-modulating G protein-coupled receptor signaling pathway	IBA	21873635
GO:0007189	Process	Adenylate cyclase-activating G protein-coupled receptor signaling pathway	IMP	12719376
GO:0007191	Process	Adenylate cyclase-activating dopamine receptor signaling pathway	IBA	21873635
GO:0007606	Process	Sensory perception of chemical stimulus	IBA	21873635
GO:0010856	Function	Adenylate cyclase activator activity	ISS
GO:0016020	Component	Membrane	HDA	19946888
GO:0016020	Component	Membrane	IDA	12719376
GO:0016020	Component	Membrane	ISS
GO:0016324	Component	Apical plasma membrane	IEA
GO:0030425	Component	Dendrite	IEA
GO:0031683	Function	G-protein beta/gamma-subunit complex binding	IBA	21873635
GO:0031698	Function	Beta-2 adrenergic receptor binding	IBA	21873635
GO:0031748	Function	D1 dopamine receptor binding	IBA	21873635
GO:0031852	Function	Mu-type opioid receptor binding	IBA	21873635
GO:0035116	Process	Embryonic hindlimb morphogenesis	IEA
GO:0035255	Function	Ionotropic glutamate receptor binding	IBA	21873635
GO:0035264	Process	Multicellular organism growth	IEA
GO:0040032	Process	Post-embryonic body morphogenesis	IEA
GO:0042493	Process	Response to drug	IEA
GO:0043588	Process	Skin development	IEA
GO:0045669	Process	Positive regulation of osteoblast differentiation	IEA
GO:0045672	Process	Positive regulation of osteoclast differentiation	IEA
GO:0046872	Function	Metal ion binding	IEA
GO:0048589	Process	Developmental growth	IMP	12719376
GO:0048701	Process	Embryonic cranial skeleton morphogenesis	IEA
GO:0050790	Process	Regulation of catalytic activity	IEA
GO:0051216	Process	Cartilage development	IEA
GO:0051430	Function	Corticotropin-releasing hormone receptor 1 binding	IBA	21873635
GO:0060348	Process	Bone development	IMP	12719376
GO:0070062	Component	Extracellular exosome	HDA	19199708, 20458337, 23533145
GO:0070527	Process	Platelet aggregation	IMP	12719376
GO:0071514	Process	Genetic imprinting	IEA
GO:0120162	Process	Positive regulation of cold-induced thermogenesis	ISS	20374964
GO:2000828	Process	Regulation of parathyroid hormone secretion	IEA

Other IDs

• MIM: 139320
• HGNC: 4392
• e!Ensembl: ENSG00000087460

Protein

• UniProt ID: Q5JWF2
• Protein name: Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas (Adenylate cyclase-stimulating G alpha protein) (Extra large alphas protein) (XLalphas)
• Protein function: Guanine nucleotide-binding proteins (G proteins) function as transducers in numerous signaling pathways controlled by G protein-coupled receptors (GPCRs). Signaling involves the activation of adenylyl cyclases, resulting in increased levels of the signaling molecule cAMP. GNAS functions downstream of several GPCRs, including beta-adrenergic receptors. XLas isoforms interact with the same set of receptors as GNAS isoforms (By similarity).
• UniProt ID: P63092
• Protein name: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short (Adenylate cyclase-stimulating G alpha protein)
• Protein function: 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).
• PDB: 5G53, 5UZ7, 5VAI, 6AU6, 6B3J, 6E3Y, 6E67, 6EG8, 6GDG, 6LI3, 6LMK, 6LPB, 6M1H, 6M1I, 6NI3, 6NIY, 6ORV, 6P9X, 6P9Y, 6PB0, 6PB1, 6UUN, 6UUS, 6UVA, 6VCB, 6VN7, 6WHC, 6WI9, 6WPW, 6WZG, 6X18, 6X19, 6X1A, 7BW0, 7BZ2, 7C2E, 7CFM, 7CFN, 7CKW, 7CKX, 7CKY, 7CKZ, 7CRH, 7CZ5, 7D3S, 7D7M, 7DHI, 7DHR, 7JV5, 7JVP, 7LCI
• UniProt ID: P84996
• Protein name: Protein ALEX (Alternative gene product encoded by XL-exon)
• Protein function: May inhibit the adenylyl cyclase-stimulating activity of guanine nucleotide-binding protein G(s) subunit alpha which is produced from the same locus in a different open reading frame.
• UniProt ID: O95467
• Protein name: Neuroendocrine secretory protein 55 (NESP55) [Cleaved into: LHAL tetrapeptide; GPIPIRRH peptide]
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF06390	NESP55	1 → 245	Neuroendocrine-specific golgi protein P55 (NESP55)	Family

• Sequence:

  MDRRSRAQQWRRARHNYNDLCPPIGRRAATALLWLSCSIALLRALATSNARAQQRAAAQQ
  RRSFLNAHHRSGAQVFPESPESESDHEHEEADLELSLPECLEYEEEFDYETESETESEIE
  SETDFETEPETAPTTEPETEPEDDRGPVVPKHSTFGQSLTQRLHALKLRSPDASPSRAPP
  STQEPQSPREGEELKPEDKDPRDPEESKEPKEEKQRRRCKPKKPTRRDASPESPSKKGPI
  PIRRH

• Sequence length: 245