Atlas of Genetics and Cytogenetics in Oncology and Haematology


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GNAS (GNAS complex locus)

Identity

Other namesAHO
C20orf45
GNAS1
GPSA
GSA
GSP
NESP
PHP1A
PHP1B
PHP1C
POH
HGNC (Hugo) GNAS
LocusID (NCBI) 2778
Location 20q13.32
Location_base_pair Starts at 57466426 and ends at 57486250 bp from pter ( according to hg19-Feb_2009)  [Mapping]
 
  Figure 1. Organization and imprinting of the GNAS complex locus. The general organization and imprinting patterns of the paternal (above) and maternal (below) GNAS alleles are shown, with the exons of sense transcripts (NESP55, XL, A/B, and Gαs) depicted as black boxes, the common exons 2 to 13 represented as green boxes, the five exons of the antisense transcript (AS) represented as grey boxes and the eight exons of the STX16 gene represented as orange boxes. The active sense and antisense promoters (arrows), as well as the splicing patterns of their respective paternal (blue) and maternal (pink) transcripts, are shown above and below the paternal and maternal exons, respectively. The dotted arrow for the paternal Gαs transcription indicates that the promoter is fully active in most tissues but is presumed to be silenced in some tissues, such as renal proximal tubules. Regions that are differentially methylated are represented as stars (red, methylated and white, unmethylated).
Note The gene encoding the Gsα protein gene GNAS (Guanine Nucleotide binding protein, Alpha Stimulating) is located in one of the most complex locus of the human genome, the GNAS locus, on the long arm of chromosome 20 (20q13.32) (Gejman et al., 1991). The complexity of this locus does not lie only in the four alternative first exons splicing onto common exons 2 to 13, or the antisense transcript that resides in this locus, but this locus also presents an elaborated imprinting pattern. The genomic imprinting is an epigenetic process in which a specific imprint mark is erased in primordial germ cells and then reestablished during oogenesis or spermatogenesis, resulting in suppression of gene expression from one parental allele (Reik and Walter, 2001). This differential gene expression may take whole lifetime or just a limited developmental stage, and can be generalized to all tissues that express the gene or may be tissue dependent (Latham, 1995; Solter, 1998). In most cases, the methylation of the allele is the imprinting mark (addition of methyl groups on cytosine in the CpG dinucleotides), but other times, the imprinting mechanism remains unknown.

DNA/RNA

 
  Figure 2. Gsα protein isoforms. Two long (Gsα-1 and Gsα-2) and two short (Gsα-3 and Gsα-4) forms of Gsα result from alternative splicing of exon 3. Use of an alternative splice acceptor site for exon 4 leads to insertion of an extra serine residue in Gsα-2 and Gsα-4. Introns are represented as dash lines, exons as orange boxes; UTRs as black boxes, serine residue as blue hexagons and splicing pattern as a solid line
Description The GNAS gene spans over 20-kilobase pair and contains thirteen exons and codifies the α-subunit of the stimulatory G protein (Gsα) (Kozasa et al., 1988).
Transcription The GNAS locus produces multiple gene products as it has four alternative first exons (NESP55 (Ischia et al., 1997), XLαs (Kehlenbach et al., 1994), A/B (Ishikawa et al., 1990; Swaroop et al., 1991) and E1-Gsα) that splice onto a common exons 2 to 13. These first alternative exons lie within CpG islands and are differently imprinted, while to increase its complexity this locus also has an antisense transcript to NESP55, referred as NESPas (Hayward and Bonthron, 2000) (Figure 1).
Exon A/B or exon 1A, located 2.5 kb centromeric from Gsα exon 1, splices onto common exons 2-13, and is methylated on the maternal allele. In this case, because there is no consensus AUG translational start site in exon A/B, it is thought that the resulting transcript is not translated (Ishikawa et al., 1990; Liu et al., 2000). It has been suggested that this region has a negative regulatory cis-acting element that suppresses the paternal Gsα allele in a tissue specific manner (i.e. renal proximal tubules) (Williamson et al., 2004; Liu et al., 2005).
XLαs alternative first exon, is located about 35 kb centromeric from Gsα exon 1, join exons 2-13 leading a transcript that encodes the extra large protein (XLαs), an isoform of Gsα with similar functions but slightly longer, and its promoter is imprinted on the maternal allele (Hayward et al., 1998b).
Finally, the farthest alternative exon (49kb centromeric from exon 1), together with the other common exons 2-13, makes the transcript encoding the protein NESP55, chromogranin-like protein that is expressed mostly in neuroendocrine tissues and only from the maternal allele, due to methylation on the paternal allele (Hayward et al., 1998b).
Regarding GNAS gene transcripts, by different splicing of exon 3 and/or use of two 5'splice sites of exon 4, two long (Gsα-L) and two short (Gsα-S) transcript variants are created, which contain alternatively exon 3 and/or a CAG sequence, respectively (Figure 2) (Bray et al., 1986; Robishaw et al., 1986; Kozasa et al., 1988). It is not methylated on either allele (Kozasa et al., 1988; Hayward et al., 1998a; Peters et al., 1999; Liu et al., 2005).
Pseudogene No pseudogenes have been identified.

Protein

 
  Figure 3. Schematic representation of GNAS gene and Gsα protein. (A) Schematic scaled representation of the 13 coding exons for GNAS gene (Black rectangles represent the exons, grey rectangles the untranslated regions, and the black line the intronic region). (B) Schematic representation of Gsα protein, where the blue rectangles represents the 4 different domains located in the protein (exons 1 and 2 encode for the GTPase activity domain; exons 4 and 5 for the adenylyl cyclase activity domain; exon 9 for the GTP dependent conformational change domain; and exons 12 and 13 for the G-protein coupled receptor interaction domain). The figure also shows the localization of the activating mutations in exon 8 (R201) and exon 9 (Q227).
Description The Gsα protein has 394 aminoacids with a mass of about 46 kDa. Gα-subunits contain two domains: a GTPase domain that is involved in the binding and hydrolysis of GTP and a helical domain.
The α subunit guanine nucleotide pocket consists of five distinct, highly conserved stretches (G1-G5). The G1, G4 and G5 regions are important for the binding of GTP while the G2 and G3 regions determine the intrinsic GTPase activity of the α subunit. The GDP-bound form binds tightly to bg and is inactive, whereas the GTP-bound form dissociates from bg and serves as a regulator of effector proteins. The receptor molecules cause the activation of G proteins by affecting several steps of the GTP cycle, resulting in the facilitation of the exchange of GTP for GDP on the α subunit (Lania et al., 2001; Cherfils and Chabre, 2003).
Expression GNAS is biallelically expressed in most tissues studied (Hayward et al., 1998a; Hayward et al., 1998b; Zheng et al., 2001; Mantovani et al., 2004); however, in some tissues (thyroid, renal proximal tubule, pituitary and ovaries) primarily maternal expression is observed leading to a parental-of-origin effect (Davies and Hughes, 1993; Campbell et al., 1994; Hayward et al., 2001; Weinstein, 2001; Mantovani et al., 2002; Germain-Lee et al., 2002; Liu et al., 2003) (Yu et al., 1998).
Localisation Cytoplasmatic membrane-associated
Function Heterotrimeric G proteins are membrane bound GTPases that are linked to seven-transmembrane domain receptors (Kleuss and Krause, 2003). Each G protein contains an alpha-, beta- and gamma-subunit and is bound to GDP in the "off" state (Olate and Allende, 1991). Ligand-receptor binding results in detachment of the G protein, switching it to an "on" state and permitting Gα activation of second messenger signalling cascades (Cabrera-Vera et al., 2003). Gsα mediates the simulation of adenylate cyclase regulated by various peptide hormones (PTH, TSH, gonadotropins, ACTH, GHRH, ADH, glucagon, calcitonin, among others) (Spiegel, 1999; Spiegel and Weinstein, 2004). Gsα-subunits contain two domains: a GTPase domain that is involved in the binding and hydrolysis of GTP and a helical domain that buries the GTP within the core of the protein (Cabrera-Vera et al., 2003).
Exon 5 is thought to codify the highly conserved domain of Gsa that interacts with adenylate cyclase, while exon 13 is responsible for the interaction with the receptor (Pennington, 1994).
Homology There are several types of Gα proteins; Gsα, Gqα, Gi/oα and G12/13α (Riobo and Manning, 2005). Members of Gsα bind directly to adenylyl cyclase and stimulate its activity, whereas their effects on ion channel activity are restricted to selected cell types; Gi/oα are involved in adenylyl cyclase inhibition, ion channel modulation and phosphatase activation. Finally, G12/13α family is implicated in processes of determination and cell proliferation. Subunits of the Gq/11 class are putative mediators of phospholipase C activation (Landis et al., 1989; Lania et al., 2001).

Mutations

Note Both germinal and somatic, activating and inactivating, genetic and epigenetic alterations have been described at GNAS locus associated with different entities.
Activating mutations: Mutations at Arg201 or Gln227 inhibits the GTPase activity, maintaining Gsα in its active form. The mutant Gsα protein carrying these activating mutations is termed the gsp oncogene (Landis et al., 1989).
In McCune-Albright syndrome, the somatic mutation at Arg201, leading to its change into cysteine or histidine (even serine or glycine), occurs in early embryogenesis, resulting in widespread tissue distribution of abnormalities. The post zygotic mutation is responsible for the mosaic pattern of tissue distribution and the extreme variability of clinical changes (Weinstein et al., 1991).
Endocrine and non-endocrine tumors: Somatic mutations of Arg201 or Gln227 have been identified in human growth hormone-secreting pituitary adenomas, (Landis et al., 1989; Landis et al., 1990), ACTH-secreting pituitary adenomas (Williamson et al., 1995; Riminucci et al., 2002), nonfunctioning pituitary tumors (Tordjman et al., 1993), thyroid tumors (Suarez et al., 1991), Leydig cell tumor (Libe et al., 2012), ovarian granulosa cell tumors (Kalfa et al., 2006a), renal cell carcinoma (Kalfa et al., 2006b), hepatocellular carcinoma (Nault et al., 2012) and myelodysplastic syndromes (Bejar et al., 2011). The mutation at codon 201 (Arg into Cys or His) is more frequent that the mutation at 227 (Gln into Arg, His, Lys or Leu).
Fibrous dysplasia of the bone: Fibrous dysplasia (FD) is a benign intramedullary osteofibrous lesion that may involve either one (monostotic FD) or several (polyostotic FD) bones. FD may occur in isolation or as part of the McCune-Albright syndrome or within Mazabraud's syndrome. Some cases of FD have been found to have a somatic GNAS mutation, mainly R201C and R201H (Riminucci et al., 1997), though R201S (Candeliere et al., 1997) and Q227L (Idowu et al., 2007) has also been reported.
Inactivating mutations: The first reports of germ-line inactivating Gsα mutations were reported in 1990 (Patten et al., 1990; Weinstein et al., 1990). Latter on, many different mutations have been described in literature and summarized in the Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff (www.hgmd.cf.ac.uk) as a cause of a hormonal disorder coupled to Gsα activity characterized by PTH renal resistance called Pseudohypoparathyroidism (PHP).
Mutation types include translation initiation mutations, amino acid substitutions, nonsense mutations, inversions, splice site mutations, insertions or deletions (even intragenic or encompassing the whole gene). Mutations are distributed throughout the Gsα coding region. Although each mutation is usually associated to a single kindred, a mutational hot-spot involving 20% of all mutations so far described has been identified within exon 7 (Weinstein et al., 1992; Yu et al., 1995; Yokoyama et al., 1996; Ahmed et al., 1998; Mantovani et al., 2000; Aldred and Trembath, 2000). It is a 4 bp deletion which coincides with a defined consensus sequence for arrest of DNA polymerase a, a region known to be prone to sporadic deletion mutations (Krawczak and Cooper, 1991; Yu et al., 1995). In most cases it has been found as a de novo mutation, thus representing a recurring new mutation rather than a founder effect.
As mentioned above, in some tissues paternal GNAS allele is silenced, leading to a parental-of-origin effect. In case of maternally inherited mutation, AHO is associated with end-organ resistance to the Gsα-mediated action of different hormones, primarily PTH, TSH, gonadotropin, and GHRH. AHO with endocrinopathy is then termed pseudohypoparathyroidism type Ia (PHP-Ia; MIM: 103580) or pseudohypoparathyroidism type Ic (PHP-Ic; MIM: 612462). In contrast, AHO due to paternally inherited mutation transmission lacks biochemical evidence of hormone resistance and is designated as pseudopseudohypoparathyroidism (PPHP; MIM 612463) (Davies and Hughes, 1993; Campbell et al., 1994; Weinstein, 2001; Weinstein et al., 2004) (see below for further details).
An intriguing missense mutation (Iiri et al., 1994; Nakamoto et al., 1996) localized within the highly conserved G5 region of the Gsα, has been identified in two unrelated males who presented with AHO, PTH resistance and testotoxicosis (Iiri et al., 1994). This substitution (A366S) leads to constitutive activation of adenylyl cyclase by causing accelerated release of GDP, thus increasing the fraction of active GTP-bound Gsα. However, while this mutant protein is stable at the reduced temperature of the testis, it is thermolabile at 37°C, resulting in reduced Gsα activity in almost tissues and AHO phenotype.
Progressive Osseous Heteroplasia (POH; MIM: 166350) is defined by cutaneous ossification, characteristically presenting during childhood, that progresses to involve subcutaneous and deep connective tissues, including muscle and fascia, in the absence of multiple features of Albright hereditary osteodystrophy (AHO) or hormone resistance (Kaplan et al., 1994). Most cases of POH are caused by heterozygous paternally-inherited inactivating mutations of GNAS (Shore et al., 2002; Adegbite et al., 2008).
Epigenetic alterations: Loss of methylation at GNAS exon A/B, sometimes combined with epigenetic defects at other GNAS differentially methylated regions has been associated with pseudohypoparathyroidism type Ib (PHP-Ib; MIM: 603233). The familial form of the disease has been shown to be mostly associated with an exon A/B-only methylation defect and a heterozygous 3-kb or 4.4-kb deletion mutation within the closely linked STX16 gene (Bastepe et al., 2003; Linglart et al., 2005), although four families of AD-PHP-Ib associated with NESP55 and NESPas deletions have also been described, the latter leading to the loss of all maternal GNAS imprints (Bastepe et al., 2005; Chillambhi et al., 2010; Richard et al., 2012). The exon A/B region is known as an imprinting control region and is believed to be critical for the tissue-specific imprinting of Gsα in the renal proximal tubules (Weinstein et al., 2001). The sporadic form of PHP-Ib show complete loss of methylation at the NESPas, XLαs and A/B regions, and no other changes in cis- or trans-acting elements have been found to explain this loss of methylation. In the scientific literature six cases have been described in which there is an association between the complete loss of methylation and partial or complete paternal isodisomy of chromosome 20q covering the GNAS locus (Bastepe et al., 2001; Bastepe et al., 2010; Fernandez-Rebollo et al., 2010). And on the other hand, it has been recently published a new trait of inheritance, an autosomal recessive form, explaining the molecular mechanism underlying the sporadic PHP-Ib in five families (Fernandez-Rebollo et al., 2011).

Implicated in

Entity McCune-Albright syndrome
Note The McCune-Albright syndrome (MAS) is a rare, sporadic disease characterized by a classical triad of clinical signs: polyostotic fibrous dysplasia (FD), skin hyperpigmentation (cafe-au-lait spots) and endocrine dysfunction. The major endocrine disorders include autonomous hyperfunction of several endocrine glands, such as gonads, thyroid, pituitary and adrenal cortex, i.e. glands sensitive to trophic agents acting through cAMP dependent pathway. Moreover, increasing data drive the attention to non-endocrine affections, including hepatobiliary dysfunction and cardiac disease, which are probably important risk factors for early death.
As mutation detection rates may vary considerably according to the type of tissue analyzed and the detection method used, sensitive and specific molecular methods must be used to look for the mutation from all available affected tissues and from easily accessible tissues, particularly in the presence of atypical and monosymptomatic forms of MAS (Weinstein, 2006; Chapurlat and Orcel, 2008).
Prognosis The prognosis depends on the severity of each individual endocrine and non-endocrine manifestation and on the age at which each affection appears.
Bisphosphonates are used in the treatment of FD to relieve bone pain and improve lytic lesions, but they are still under clinical evaluation. Calcium, vitamin D and phosphorus supplements may be useful in some patients. Surgery is also helpful to prevent and treat fracture and deformities.
Oncogenesis Postzygotic, somatic mutations at Arginine 201 of the GNAS gene that results in cellular mosaicism, thus leading to a broad spectrum of clinical manifestations.
  
Entity Mazabraud syndrome
Note Very rare association of fibrous dysplasia and myxomas of the soft tissues (Biagini et al., 1987; Dreizin et al., 2012).
  
Entity Various endocrine and non-endocrine tumors
Note Growth hormone-secreting pituitary adenomas (Landis et al., 1989; Landis et al., 1990), ACTH-secreting pituitary adenomas (Williamson et al., 1995; Riminucci et al., 2002), nonfunctioning pituitary tumors (Tordjman et al., 1993), thyroid tumors (Suarez et al., 1991), Leydig cell tumor (Libe et al., 2012), ovarian granulosa cell tumors (Kalfa et al., 2006a), ACTH-independent macronodular adrenal hyperplasia (AIMAH) (Fragoso et al., 2003), renal cell carcinoma (Kalfa et al., 2006b), hepatocellular carcinoma (Nault et al., 2012) and myelodysplastic syndromes (Bejar et al., 2011).
Activating GNAS mutations are a common feature of the above-mentioned endocrine tumors with a maximum frequency in growth hormone-secreting pituitary adenomas (about 30-40%) (Landis et al., 1989), while the same mutations have been only occasionally reported in the other cited tumors.
Oncogenesis Activating mutations of the α subunit of the stimulatory G protein (Gsα) gene (the gsp oncogene) leading to amino acid substitution of either residue Arg201 or Gln227. These two residues are catalytically important for GTPase activity, their mutation thus causing constitutive activation by disrupting the signalling turn-off mechanism. Growth and hormone release in many endocrine glands are stimulated by trophic hormones that activate Gsα-cAMP pathways, therefore GNAS activating mutations affect those glands sensitive to trophic agents acting through the cAMP-dependent pathway, leading to autonomous hyperfunction in addition to tumorigenesis.
  
Entity Pseudohypoparathyroidism
Note Pseudohypoparathyroidism (PHP) is a term applied to a heterogeneous group of disorders whose common feature is end-organ resistance to parathyroid hormone (PTH) (Mantovani, 2011).
PTH resistance, the most clinically evident abnormality, usually develops over the first years of life, with hyperphosphatemia and elevated PTH generally preceding hypocalcemia. Renal function is conserved through life and so seems to be bone mineral density.
Diagnostic Criteria for PHP:
- elevated PTH levels
- hypocalcemia
- hyperphosphatemia
- absence of hypercalciuria or impaired renal function
- reduced calcemic and phosphaturic response to injected exogenous PTH
Disease PHP-Ia: in addition to PTH resistance, is characterized by resistance to other hormones, including TSH, gonadotrophins and GHRH. It is associated with Albright's hereditary osteodystrophy (AHO), which includes short stature, obesity, round facies, subcutaneous ossifications, brachydactyly, and other skeletal anomalies. Some patients have mental retardation. Laboratory studies show a decreased cAMP response to infused PTH and defects in activity of the erythrocyte Gs protein (Mantovani, 2011).
Pseudo-PHP (PPHP): is characterized by the physical findings of AHO without hormone resistance. Laboratory studies show a defect in Gs protein activity in erythrocytes (Weinstein et al., 2001).
PHP-Ib: is characterized clinically by isolated renal PTH resistance. Patients usually lack the physical characteristics of AHO and typically show no other endocrine abnormalities, although resistance to TSH has been reported. However, patients may rarely show some features of AHO. Laboratory studies show a decreased cAMP response to infused PTH and, most recently reported, sometimes defects in Gs protein activity similarly to PHP-Ia patients (Zazo et al., 2011; Mantovani et al., 2012).
PHP-Ic: is clinically indistinguishable from PHP-Ia, therefore being characterized by the association of multi-hormone resistance and AHO. Laboratory studies show a decreased cAMP response to infused PTH, but typically no defect in activity of the erythrocyte Gs protein (Thiele et al., 2011).
Progressive Osseous Heteroplasia (POH): is characterized by ectopic dermal ossification beginning in infancy, followed by increasing and extensive bone formation in deep muscle and fascia. These patients typically do not show any endocrine abnormality (Shore et al., 2002; Shore and Kaplan, 2010).
Prognosis In general, PHP patients should be monitored annually for both blood biochemistries (PTH, calcium, phosphate, TSH) and urinary calcium excretion. Particular attention must be given in children to height, growth velocity and pubertal development. Increasing evidences suggest that, independently of growth curve, children should be screened with appropriate provocative tests for GH deficiency in order to eventually start treatment as soon as possible. Weight and BMI should be checked in order to start dietary/exercise intervention when appropriate. Careful physical examination and, when necessary, specific psychological investigations should be performed annually in order to detect and follow the presence/evolution of specific AHO features (in particular heterotopic ossifications and mental retardation). Initial screening should include radiological evaluation of brachydactyly.
The long-term therapy of hypocalcemia, in order to maintain normocalcemia, is with active vitamin D metabolites, preferentially calcitriol, with or without oral calcium supplementation. Patients should be also routinely screened and eventually treated for any associated endocrinopathy, in particular hypothyroidism and hypogonadism. Levothyroxine and sex hormones should be given following the same criteria, doses and follow-up as in any other form of hypothyroidism or hypogonadism.
There are no specific treatments for the various manifestations of AHO, even if subcutaneous ossifications may be surgically removed when particularly large or bothersome.
While prognosis of correctly treated hormone disturbances is very good, POH may end up with deeply invalidating lesions.
 
Table1. Legend: PHP, pseudohypoparathyroidism; PPHP, Pseudo-pseudohypoparathyroidism; AHO, Albright hereditary osteodystrophy; POH, Progressive Osseous Heteroplasia; Gn, gonadotropins; NA, not available.
  

Other Solid tumors implicated (Data extracted from papers in the Atlas)

Solid Tumors AmeloblastomID5945 MedulloblastomaID5065

External links

Nomenclature
HGNC (Hugo)GNAS   4392
Cards
AtlasGNASID40727ch20q13
Entrez_Gene (NCBI)GNAS  2778  GNAS complex locus
GeneCards (Weizmann)GNAS
Ensembl (Hinxton)ENSG00000087460 [Gene_View]  chr20:57466426-57486250 [Contig_View]  GNAS [Vega]
ICGC DataPortalENSG00000087460
cBioPortalGNAS
AceView (NCBI)GNAS
Genatlas (Paris)GNAS
WikiGenes2778
SOURCE (Princeton)NM_000516 NM_001077488 NM_001077489 NM_001077490 NM_016592 NM_080425 NM_080426
Genomic and cartography
GoldenPath (UCSC)GNAS  -  20q13.32   chr20:57466426-57486250 +  20q13.2-q13.3   [Description]    (hg19-Feb_2009)
EnsemblGNAS - 20q13.2-q13.3 [CytoView]
Mapping of homologs : NCBIGNAS [Mapview]
OMIM102200   103580   139320   166350   174800   219080   603233   612462   612463   
Gene and transcription
Genbank (Entrez)AF064092 AF088184 AF088185 AF105253 AF493897
RefSeq transcript (Entrez)NM_000516 NM_001077488 NM_001077489 NM_001077490 NM_016592 NM_080425 NM_080426
RefSeq genomic (Entrez)AC_000152 NC_000020 NC_018931 NG_016194 NT_011362 NW_001838667 NW_004929418
Consensus coding sequences : CCDS (NCBI)GNAS
Cluster EST : UnigeneHs.125898 [ NCBI ]
CGAP (NCI)Hs.125898
Alternative Splicing : Fast-db (Paris)GSHG0018870
Alternative Splicing GalleryENSG00000087460
Gene ExpressionGNAS [ NCBI-GEO ]     GNAS [ SEEK ]   GNAS [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ5JWF2 (Uniprot)
NextProtQ5JWF2  [Medical]
With graphics : InterProQ5JWF2
Splice isoforms : SwissVarQ5JWF2 (Swissvar)
Domains : Interpro (EBI)Gprotein_alpha_S [organisation]   Gprotein_alpha_su [organisation]   GproteinA_insert [organisation]   P-loop_NTPase [organisation]  
Related proteins : CluSTrQ5JWF2
Domain families : Pfam (Sanger)G-alpha (PF00503)   
Domain families : Pfam (NCBI)pfam00503   
Domain families : Smart (EMBL)G_alpha (SM00275)  
DMDM Disease mutations2778
Blocks (Seattle)Q5JWF2
Human Protein AtlasENSG00000087460 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasQ5JWF2
HPRD00761
IPIIPI00009881   IPI00514055   IPI00219835   IPI00644936   IPI00790404   IPI00095891   IPI00646491   IPI00154366   IPI00385033   IPI00006762   IPI00871191   IPI00640867   IPI00644474   IPI00792774   IPI00647637   IPI00030939   IPI00941962   IPI00853318   IPI00853238   
Protein Interaction databases
DIP (DOE-UCLA)Q5JWF2
IntAct (EBI)Q5JWF2
FunCoupENSG00000087460
BioGRIDGNAS
InParanoidQ5JWF2
Interologous Interaction database Q5JWF2
IntegromeDBGNAS
STRING (EMBL)GNAS
Ontologies - Pathways
Ontology : AmiGOruffle  tissue homeostasis  endochondral ossification  molecular_function  GTPase activity  GTPase activity  adenylate cyclase activity  signal transducer activity  signal transducer activity  insulin-like growth factor receptor binding  protein binding  GTP binding  extracellular region  nucleus  cytoplasm  cytosol  cytosol  heterotrimeric G-protein complex  heterotrimeric G-protein complex  heterotrimeric G-protein complex  plasma membrane  plasma membrane  energy reserve metabolic process  energy reserve metabolic process  cAMP biosynthetic process  GTP catabolic process  DNA methylation  water transport  adenylate cyclase-activating G-protein coupled receptor signaling pathway  adenylate cyclase-activating G-protein coupled receptor signaling pathway  activation of adenylate cyclase activity  adenylate cyclase-activating dopamine receptor signaling pathway  adenylate cyclase-activating dopamine receptor signaling pathway  female pregnancy  blood coagulation  sensory perception of chemical stimulus  sensory perception of smell  protein secretion  membrane  membrane  transport vesicle  dendrite  positive regulation of cAMP biosynthetic process  intrinsic component of membrane  G-protein beta/gamma-subunit complex binding  G-protein beta/gamma-subunit complex binding  beta-2 adrenergic receptor binding  D1 dopamine receptor binding  mu-type opioid receptor binding  positive regulation of Ras GTPase activity  trans-Golgi network membrane  embryonic hindlimb morphogenesis  ionotropic glutamate receptor binding  multicellular organism growth  negative regulation of multicellular organism growth  post-embryonic body morphogenesis  response to drug  positive regulation of cAMP-mediated signaling  small molecule metabolic process  positive regulation of osteoblast differentiation  positive regulation of osteoclast differentiation  metal ion binding  intracellular transport  perinuclear region of cytoplasm  developmental growth  developmental growth  embryonic cranial skeleton morphogenesis  regulation of insulin secretion  cognition  cognition  cartilage development  corticotropin-releasing hormone receptor 1 binding  transmembrane transport  bone development  bone development  hair follicle placode formation  hair follicle placode formation  extracellular vesicular exosome  platelet aggregation  platelet aggregation  response to parathyroid hormone  cellular response to glucagon stimulus  cellular response to prostaglandin E stimulus  genetic imprinting  cellular response to catecholamine stimulus  adenylate cyclase-activating adrenergic receptor signaling pathway  
Ontology : EGO-EBIruffle  tissue homeostasis  endochondral ossification  molecular_function  GTPase activity  GTPase activity  adenylate cyclase activity  signal transducer activity  signal transducer activity  insulin-like growth factor receptor binding  protein binding  GTP binding  extracellular region  nucleus  cytoplasm  cytosol  cytosol  heterotrimeric G-protein complex  heterotrimeric G-protein complex  heterotrimeric G-protein complex  plasma membrane  plasma membrane  energy reserve metabolic process  energy reserve metabolic process  cAMP biosynthetic process  GTP catabolic process  DNA methylation  water transport  adenylate cyclase-activating G-protein coupled receptor signaling pathway  adenylate cyclase-activating G-protein coupled receptor signaling pathway  activation of adenylate cyclase activity  adenylate cyclase-activating dopamine receptor signaling pathway  adenylate cyclase-activating dopamine receptor signaling pathway  female pregnancy  blood coagulation  sensory perception of chemical stimulus  sensory perception of smell  protein secretion  membrane  membrane  transport vesicle  dendrite  positive regulation of cAMP biosynthetic process  intrinsic component of membrane  G-protein beta/gamma-subunit complex binding  G-protein beta/gamma-subunit complex binding  beta-2 adrenergic receptor binding  D1 dopamine receptor binding  mu-type opioid receptor binding  positive regulation of Ras GTPase activity  trans-Golgi network membrane  embryonic hindlimb morphogenesis  ionotropic glutamate receptor binding  multicellular organism growth  negative regulation of multicellular organism growth  post-embryonic body morphogenesis  response to drug  positive regulation of cAMP-mediated signaling  small molecule metabolic process  positive regulation of osteoblast differentiation  positive regulation of osteoclast differentiation  metal ion binding  intracellular transport  perinuclear region of cytoplasm  developmental growth  developmental growth  embryonic cranial skeleton morphogenesis  regulation of insulin secretion  cognition  cognition  cartilage development  corticotropin-releasing hormone receptor 1 binding  transmembrane transport  bone development  bone development  hair follicle placode formation  hair follicle placode formation  extracellular vesicular exosome  platelet aggregation  platelet aggregation  response to parathyroid hormone  cellular response to glucagon stimulus  cellular response to prostaglandin E stimulus  genetic imprinting  cellular response to catecholamine stimulus  adenylate cyclase-activating adrenergic receptor signaling pathway  
Pathways : BIOCARTAChREBP regulation by carbohydrates and cAMP [Genes]    Erk1/Erk2 Mapk Signaling pathway [Genes]    Corticosteroids and cardioprotection [Genes]    Roles of _-arrestin-dependent Recruitment of Src Kinases in GPCR Signaling [Genes]    _-arrestins in GPCR Desensitization [Genes]    Ion Channels and Their Functional Role in Vascular Endothelium [Genes]    Attenuation of GPCR Signaling [Genes]    Role of _-arrestins in the activation and targeting of MAP kinases [Genes]    CCR3 signaling in Eosinophils [Genes]   
Pathways : KEGGRap1 signaling pathway    Calcium signaling pathway    Adrenergic signaling in cardiomyocytes    Vascular smooth muscle contraction    Gap junction    Circadian entrainment    Glutamatergic synapse    Serotonergic synapse    Dopaminergic synapse    Long-term depression    Taste transduction    Insulin secretion    GnRH signaling pathway    Ovarian steroidogenesis    Estrogen signaling pathway    Melanogenesis    Thyroid hormone synthesis    Endocrine and other factor-regulated calcium reabsorption    Vasopressin-regulated water reabsorption    Salivary secretion    Gastric acid secretion    Pancreatic secretion    Bile secretion    Cocaine addiction    Amphetamine addiction    Morphine addiction    Alcoholism    Vibrio cholerae infection    Chagas disease (American trypanosomiasis)    Amoebiasis    Dilated cardiomyopathy   
Protein Interaction DatabaseGNAS
Wikipedia pathwaysGNAS
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)GNAS
snp3D : Map Gene to Disease2778
SNP (GeneSNP Utah)GNAS
SNP : HGBaseGNAS
Genetic variants : HAPMAPGNAS
Exome VariantGNAS
1000_GenomesGNAS 
ICGC programENSG00000087460 
Cancer Gene: CensusGNAS 
Somatic Mutations in Cancer : COSMICGNAS 
CONAN: Copy Number AnalysisGNAS 
Mutations and Diseases : HGMDGNAS
Genomic VariantsGNAS  GNAS [DGVbeta]
dbVarGNAS
ClinVarGNAS
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM102200    103580    139320    166350    174800    219080    603233    612462    612463   
MedgenGNAS
GENETestsGNAS
Disease Genetic AssociationGNAS
Huge Navigator GNAS [HugePedia]  GNAS [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneGNAS
Homology/Alignments : Family Browser (UCSC)GNAS
Phylogenetic Trees/Animal Genes : TreeFamGNAS
Chemical/Protein Interactions : CTD2778
Chemical/Pharm GKB GenePA175
Drug Sensitivity GNAS
Clinical trialGNAS
Cancer Resource (Charite)ENSG00000087460
Other databases
Probes
Litterature
PubMed379 Pubmed reference(s) in Entrez
CoreMineGNAS
iHOPGNAS
OncoSearchGNAS

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Concurrent hormone resistance (pseudohypoparathyroidism type Ia) and hormone independence (testotoxicosis) caused by a unique mutation in the G alpha s gene.
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A 4-base pair deletion mutation of Gs alpha gene in a Japanese patient with pseudohypoparathyroidism.
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Molecular cloning and characterization of NESP55, a novel chromogranin-like precursor of a peptide with 5-HT1B receptor antagonist activity.
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GNAS1 mutational analysis in pseudohypoparathyroidism.
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The human GNAS1 gene is imprinted and encodes distinct paternally and biallelically expressed G proteins.
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Bidirectional imprinting of a single gene: GNAS1 encodes maternally, paternally, and biallelically derived proteins.
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Variable and tissue-specific hormone resistance in heterotrimeric Gs protein alpha-subunit (Gsalpha) knockout mice is due to tissue-specific imprinting of the gsalpha gene.
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A cluster of oppositely imprinted transcripts at the Gnas locus in the distal imprinting region of mouse chromosome 2.
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Activating and inactivating mutations in the human GNAS1 gene.
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An imprinted antisense transcript at the human GNAS1 locus.
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A GNAS1 imprinting defect in pseudohypoparathyroidism type IB.
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Mutational analysis of GNAS1 in patients with pseudohypoparathyroidism: identification of two novel mutations.
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Paternal uniparental isodisomy of chromosome 20q--and the resulting changes in GNAS1 methylation--as a plausible cause of pseudohypoparathyroidism.
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The gsalpha gene: predominant maternal origin of transcription in human thyroid gland and gonads.
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Insights into G protein structure, function, and regulation.
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Activation of G-protein Galpha subunits by receptors through Galpha-Gbeta and Galpha-Ggamma interactions.
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Cushing's syndrome secondary to adrenocorticotropin-independent macronodular adrenocortical hyperplasia due to activating mutations of GNAS1 gene.
Fragoso MC, Domenice S, Latronico AC, Martin RM, Pereira MA, Zerbini MC, Lucon AM, Mendonca BB.
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Galpha(s) is palmitoylated at the N-terminal glycine.
Kleuss C, Krause E.
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The stimulatory G protein alpha-subunit Gs alpha is imprinted in human thyroid glands: implications for thyroid function in pseudohypoparathyroidism types 1A and 1B.
Liu J, Erlichman B, Weinstein LS.
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Biallelic expression of the Gsalpha gene in human bone and adipose tissue.
Mantovani G, Bondioni S, Locatelli M, Pedroni C, Lania AG, Ferrante E, Filopanti M, Beck-Peccoz P, Spada A.
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Inherited diseases involving g proteins and g protein-coupled receptors.
Spiegel AM, Weinstein LS.
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Minireview: GNAS: normal and abnormal functions.
Weinstein LS, Liu J, Sakamoto A, Xie T, Chen M.
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A cis-acting control region is required exclusively for the tissue-specific imprinting of Gnas.
Williamson CM, Ball ST, Nottingham WT, Skinner JA, Plagge A, Turner MD, Powles N, Hough T, Papworth D, Fraser WD, Maconochie M, Peters J.
Nat Genet. 2004 Aug;36(8):894-9. Epub 2004 Jul 25.
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Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type Ib.
Bastepe M, Frohlich LF, Linglart A, Abu-Zahra HS, Tojo K, Ward LM, Juppner H.
Nat Genet. 2005 Jan;37(1):25-7. Epub 2004 Dec 12.
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A novel STX16 deletion in autosomal dominant pseudohypoparathyroidism type Ib redefines the boundaries of a cis-acting imprinting control element of GNAS.
Linglart A, Gensure RC, Olney RC, Juppner H, Bastepe M.
Am J Hum Genet. 2005 May;76(5):804-14. Epub 2005 Mar 30.
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Identification of the control region for tissue-specific imprinting of the stimulatory G protein alpha-subunit.
Liu J, Chen M, Deng C, Bourc'his D, Nealon JG, Erlichman B, Bestor TH, Weinstein LS.
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Receptors coupled to heterotrimeric G proteins of the G12 family.
Riobo NA, Manning DR.
Trends Pharmacol Sci. 2005 Mar;26(3):146-54. (REVIEW)
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Activating mutations of the stimulatory g protein in juvenile ovarian granulosa cell tumors: a new prognostic factor?
Kalfa N, Ecochard A, Patte C, Duvillard P, Audran F, Pienkowski C, Thibaud E, Brauner R, Lecointre C, Plantaz D, Guedj AM, Paris F, Baldet P, Lumbroso S, Sultan C.
J Clin Endocrinol Metab. 2006a May;91(5):1842-7. Epub 2006 Feb 28.
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Activating mutations of Gsalpha in kidney cancer.
Kalfa N, Lumbroso S, Boulle N, Guiter J, Soustelle L, Costa P, Chapuis H, Baldet P, Sultan C.
J Urol. 2006b Sep;176(3):891-5.
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G(s)alpha mutations in fibrous dysplasia and McCune-Albright syndrome.
Weinstein LS.
J Bone Miner Res. 2006 Dec;21 Suppl 2:P120-4. (REVIEW)
PMID 17229000
 
A sensitive mutation-specific screening technique for GNAS1 mutations in cases of fibrous dysplasia: the first report of a codon 227 mutation in bone.
Idowu BD, Al-Adnani M, O'Donnell P, Yu L, Odell E, Diss T, Gale RE, Flanagan AM.
Histopathology. 2007 May;50(6):691-704.
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Diagnostic and mutational spectrum of progressive osseous heteroplasia (POH) and other forms of GNAS-based heterotopic ossification.
Adegbite NS, Xu M, Kaplan FS, Shore EM, Pignolo RJ.
Am J Med Genet A. 2008 Jul 15;146A(14):1788-96. doi: 10.1002/ajmg.a.32346.
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Fibrous dysplasia of bone and McCune-Albright syndrome.
Chapurlat RD, Orcel P.
Best Pract Res Clin Rheumatol. 2008 Mar;22(1):55-69. doi: 10.1016/j.berh.2007.11.004. (REVIEW)
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Deletion of the noncoding GNAS antisense transcript causes pseudohypoparathyroidism type Ib and biparental defects of GNAS methylation in cis.
Chillambhi S, Turan S, Hwang DY, Chen HC, Juppner H, Bastepe M.
J Clin Endocrinol Metab. 2010 Aug;95(8):3993-4002. doi: 10.1210/jc.2009-2205. Epub 2010 May 5.
PMID 20444925
 
New mechanisms involved in paternal 20q disomy associated with pseudohypoparathyroidism.
Fernandez-Rebollo E, Lecumberri B, Garin I, Arroyo J, Bernal-Chico A, Goni F, Orduna R; Spanish PHP Group, Castano L, de Nanclares GP.
Eur J Endocrinol. 2010 Dec;163(6):953-62. doi: 10.1530/EJE-10-0435. Epub 2010 Sep 13.
PMID 20837711
 
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Contributor(s)

Written10-2012Guiomar Pérez de Nanclares, Giovanna Mantovani, Eduardo Fernandez-Rebollo
Molecular (Epi)Genetics Laboratory, Research Unit, Hospital Universitario Araba-Txagorritxu, C/Jose Atxotegi s/n, Q2 Vitoria-Gasteiz, Alava, Spain (GPN); Endocrinology Unit, Deparment of Clinical Sciences and Community Health, University of Milan, Fondazione IRCCS Ca' Granda Policlinico, Milan, Italy (GM); Diabetes and Obesity Laboratory, Endocrinology and Nutrition Unit, Institut d'Investigations Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic de Barcelona, Spain (EFR)

Citation

This paper should be referenced as such :
Pérez, de Nanclares G ; Mantovani, G ; Fernandez-Rebollo, E
GNAS (GNAS complex locus)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(3):178-187.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/GNASID40727ch20q13.html

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