Disease relevance of GNAS

• Increased cyclic AMP (cAMP) signaling has been associated with PRKAR1A or GNAS mutations and leads to adrenocortical tumors and Cushing syndrome [1].
• Common polymorphisms of the GNAS and GNB3 (which encodes Gbeta3) genes have been associated with multigenic disorders (e.g. hypertension and metabolic syndrome) [2].
• Distinct patterns of abnormal GNAS imprinting in familial and sporadic pseudohypoparathyroidism type IB [3].
• The patients were found to have a heterozygous mutation at nucleotide 305 in exon 4 (c305C-->A) of the GNAS gene, which has not been previously linked to congenital hypothyroidism [4].
• RESULTS: Polymorphisms in the three betaAR genes, GNAS1, and GNB3 were not associated with BMI, WHR, waist circumference, or obesity [5].

Psychiatry related information on GNAS

• Association of the GNAS1 gene variant with hypertension is dependent on alcohol consumption [6].
• In this report, we describe two unrelated patients with mental retardation and brachydactyly E classified as patients suffering from Albright hereditary osteodystrophy-like (AHO-like) syndrome [7].
• As a result of the potential relevance of NESP55 to serotoninergic neurotransmission, we screened its sequence using genomic DNA pools from autistic disorder, obsessive-compulsive disorder (OCD) probands and control subjects [8].
• The results demonstrated that framing paradigms and methods can be usefully applied to the study of cognitive processes in social phobia and indicated that research to examine how GSP patients process specific types of social information is needed [9].
• Individuals with Generalized Social Phobia (GSP, N = 25) and community controls (N = 26) participated in a social interaction task [10].

High impact information on GNAS

• Epigenetic defects in the imprinted GNAS cluster are associated with pseudohypoparathyroidism type Ib [11].
• In two kindreds with this disorder, we now report deletions that remove the differentially methylated region encompassing exon NESP55 and exons 3 and 4 of the antisense transcript [11].
• Hence, XL alpha s may mediate the effects of cholera toxin on secretory vesicle formation [12].
• XL alpha s is specifically associated with the trans-Golgi network and occurs selectively in cells containing both the regulated and the constitutive pathway of protein secretion [12].
• Interestingly, paternal transmission of GNAS1 mutations leads to the AHO phenotype alone (pseudopseudohypoparathyroidism), while maternal transmission leads to AHO plus resistance to several hormones (e.g., PTH, TSH) that activate G(s) in their target tissues (pseudohypoparathyroidism type IA) [13].

Chemical compound and disease context of GNAS

• These data indicate that POH has a weakly promoting effect early in nitrosamine-induced esophageal tumorigenesis and suggest that POH may not be an effective chemopreventive agent for esophageal cancer in humans [14].
• In addition, POH treatment resulted in a dose-dependent sensitization to cisplatin and doxorubicin induced cytotoxicity in glioma cells, highlighting its usefulness as a potent radio/chemosensitizer in the treatment of malignant glioma [15].
• We conducted a phase I dose-escalation trial of perillyl alcohol (POH; NSC 641066) given p.o. on a continuous four times a day basis to characterize the maximum tolerated dose, toxicities, pharmacokinetic profile, and antitumor activity [16].
• Metformin treatment significantly improved hyperandrogenism, menstrual cyclicity, body weight, and insulin resistance independent of GNAS1 genotype [17].
• To establish the molecular mechanisms of POH and its major metabolite perillic acid (PA) as anti-proliferative agents, their effects on cell proliferation, cell cycle and cell cycle regulatory proteins were studied in HCT 116 human colon cancer cells [18].

Biological context of GNAS

• We have now performed a detailed analysis of the GNAS methylation profile in 20 unrelated PHPIB probands [3].
• Neuroendocrine secretory protein 55 (NESP55): alternative splicing onto transcripts of the GNAS gene and posttranslational processing of a maternally expressed protein [19].
• PHP-Ia is caused by heterozygous mutations affecting one of the 13 GNAS exons encoding Gsalpha or by large intragenic deletions [20].
• However, an imprinted autosomal dominant form of PHP-Ib (AD-PHP-Ib) has been mapped to a region of chromosome 20q13.3 containing GNAS [21].
• MAS is caused by sporadic, postzygotic, activating mutations in the GNAS gene, which codes for the cAMP-regulating protein, G(s)alpha (gsp oncogene) [22].

Anatomical context of GNAS

• Instead, the region of overlap between the two microdeletions likely harbors a cis-acting imprinting control element that is necessary for establishing and/or maintaining methylation at GNAS exon A/B, thus allowing normal G alpha(s) expression in the proximal renal tubules [23].
• Well-described GNAS mutations like fibrous dysplasia or Albright hereditary osteodystrophy are linked to abnormality in osteoblast function, and numerous evidences showed that Gsalpha coupled adrenergic receptors increase the expression of osteotrophic factors and regulate bone mass [24].
• We therefore used PNA-clamping to detect low copy numbers of mutant GNAS alleles in DNA from peripheral blood cells from patients with McCune-Albright syndrome and fibrous dysplasia [25].
• Nevertheless, his circulating fibroblast growth factor 23 (FGF-23) level was elevated, likely functioning as a "phosphatonin," yet no activating mutations in GNAS previously reported in fibrous dysplasia or McCune-Albright syndrome were detected in his leukocytes or affected skin [26].
• Because in MAS patients, tissues as diverse as melanocytes, gonads and bone are affected, it is generally accepted that the GNAS mutation in this disease must have occurred early in development [27].

Associations of GNAS with chemical compounds

• Purity, as assessed by GCMS, was shown to be greater than 95% for SNAS, SaMT, and GaMT and to be 88% for GNAS [28].
• Accordingly, here we investigated the effect of GSP on mitogenic signaling and regulators of cell cycle and apoptosis as molecular targets for the growth arrest, apoptotic death, and/or differentiation of estrogen-independent MDA-MB468 human breast carcinoma cells [29].
• Additional studies assessing the biological fate of GSP-treated cells showed that they do not undergo apoptotic death, as evidenced by a lack of DNA fragmentation, poly (ADP ribose) polymerase cleavage, and apoptotic morphology of the cells [29].
• Polymorphisms of genes CYP2D6, ADRB1 and GNAS1 in pharmacokinetics and systemic effects of ophthalmic timolol. A pilot study [30].
• The GNAS1 gene encodes the alpha subunit of the G protein Gs, which couples receptor binding by several hormones to activation of adenylate cyclase [31].

Regulatory relationships of GNAS

• A novel STX16 deletion in autosomal dominant pseudohypoparathyroidism type Ib redefines the boundaries of a cis-acting imprinting control element of GNAS [23].
• Runx2 regulates the expression of GNAS on SaOs-2 cells [24].
• A highly sensitive polymerase chain reaction method detects activating mutations of the GNAS gene in peripheral blood cells in McCune-Albright syndrome or isolated fibrous dysplasia [25].
• Moreover, overexpression of human XLalphas or Gsalpha markedly enhanced the PTH-induced cAMP accumulation in opossum kidney cells that endogenously express PTH receptor type 1 [32].

Other interactions of GNAS

• All five probands with familial disease had a deletion mutation within the closely linked STX16 gene and a GNAS imprinting defect involving only the exon 1A region [3].
• Several human disorders that result from genetic G-protein abnormalities involve the imprinted GNAS gene, which encodes Gs alpha, the ubiquitously expressed alpha-subunit that couples receptors to adenylyl cyclase and cAMP generation [2].
• PHP-Ia and PPHP are caused by heterozygous inactivating mutations in those exons of GNAS encoding the alpha subunit of the stimulatory guanine nucleotide-binding protein (Gsalpha), and the autosomal dominant form of PHP-Ib (AD-PHP-Ib) is caused by heterozygous mutations disrupting a long-range imprinting control element of GNAS [33].
• In FRTL5, expression of GSP or mutant (m) TSHR induced a 2 - 3-fold increase in basal levels of cAMP [34].
• In primary cultures, expression of mTSHR, but not GSP, consistently induced formation of colonies with epithelial morphology and thyroglobulin expression, capable of 10 - 15 population doublings (PD) compared to less than three in controls [34].

Analytical, diagnostic and therapeutic context of GNAS

• MATERIALS AND METHODS: Using nested polymerase chain reaction, enzyme digestions, laser microdissection and direct sequencing we looked for activating mutations on GNAS codons 201 and 227, and inhibiting mutations on the Gialpha gene in 30 consecutive patients with clear cell renal cell carcinoma between January 2003 and January 2004 [35].
• Expression of NESP55 in pancreatic endocrine tumours and pheochromocytomas was confirmed by Western and Northern blot analysis [36].
• Mapping of the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase (GNAS1) to 20q13.2----q13.3 in human by in situ hybridization [37].
• Three hundred and four severely obese patients (mean +/- SEM age, 42 +/- 1 years; 245 women and 59 men; mean +/- SEM body mass index, 43.9 +/- 0.3 kg/m2) followed prospectively for at least 3 years after surgery were genotyped for the GNB3 C825T, G814A, and GNAS1 T393 polymorphisms [38].
• We analyzed the GNAS1 gene in five patients with pseudohypoparathyroidism type 1a (PHP1a) by performing polymerase chain reaction, followed by sequencing all 13 exons of the gene, single-stranded conformational polymorphism (SSCP) or heteroduplex analysis (HD) [39].

References