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Endocrinology Vol. 145, No. 12 5459-5464
Copyright © 2004 by The Endocrine Society

MINIREVIEW

Minireview: GNAS: Normal and Abnormal Functions

Lee S. Weinstein, Jie Liu, Akio Sakamoto, Tao Xie and Min Chen

Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892

Abstract

GNAS is a complex imprinted gene that uses multiple promoters to generate several gene products, including the G protein {alpha}-subunit (Gs{alpha}) that couples seven-transmembrane receptors to the cAMP-generating enzyme adenylyl cyclase. Somatic activating Gs{alpha} mutations, which alter key residues required for the GTPase turn-off reaction, are present in various endocrine tumors and fibrous dysplasia of bone, and in a more widespread distribution in patients with McCune- Albright syndrome. Heterozygous inactivating Gs{alpha} mutations lead to Albright hereditary osteodystrophy. Gs{alpha} is imprinted in a tissue-specific manner, being primarily expressed from the maternal allele in renal proximal tubules, thyroid, pituitary, and ovary. Maternally inherited mutations lead to Albright hereditary osteodystrophy (AHO) plus PTH, TSH, and gonadotropin resistance (pseudohypoparathyroidism type 1A), whereas paternally inherited mutations lead to AHO alone. Pseudohypoparathyroidism type 1B, in which patients develop PTH resistance without AHO, is almost always associated with a GNAS imprinting defect in which both alleles have a paternal-specific imprinting pattern on both parental alleles. Familial forms of the disease are associated with a mutation within a closely linked gene that deletes a region that is presumably required for establishing the maternal imprint, and therefore maternal inheritance of the mutation results in the GNAS imprinting defect. Imprinting of one differentially methylated region within GNAS is virtually always lost in pseudohypoparathyroidism type 1B, and this region is probably responsible for tissue-specific Gs{alpha} imprinting. Mouse knockout models show that Gs{alpha} and the alternative Gs{alpha} isoform XL{alpha}s that is expressed from the paternal GNAS allele may have opposite effects on energy metabolism in mice.

GNAS: Normal Function

GNAS IS A COMPLEX imprinted gene that generates multiple gene products through the use of multiple promoters and first exons that splice onto a common set of downstream exons (exons 2–13; see Fig. 1Go) (1, 2). The major GNAS gene product, which is generated by the most downstream promoter (exon 1), is the ubiquitously expressed G protein {alpha}-subunit (Gs{alpha}) that couples numerous hormonal and other seven-transmembrane receptors to adenylyl cyclase and is required for the receptor-stimulated intracellular cAMP production. The most upstream GNAS promoter generates transcripts for the chromogranin-like protein NESP55, which is structurally and functionally unrelated to Gs{alpha}. The NESP55 coding region is limited to its specific first exon, and Gs{alpha} exons 2–13 form the majority of its 3'-untranslated region (3, 4). The next promoter generates transcripts encoding the neuroendocrine-specific Gs{alpha} isoform XL{alpha}s, which structurally is identical to Gs{alpha}, except for the presence of an extra-long amino-terminal extension encoded by its specific first exon (5). NESP55 and XL{alpha}s are oppositely imprinted (6, 7, 8). NESP55 is only expressed from the maternally inherited allele, and its promoter is DNA methylated at CpG dinucleotides on the paternally inherited allele. In contrast, XL{alpha}s is only expressed from the paternal allele, and its promoter is methylated on the maternal allele. Both XL{alpha}s and NESP55 are expressed primarily in neuroendocrine tissues (9, 10, 11, 12). Although the biological functions of these two gene products have not been fully established, it seems likely that NESP55 and XL{alpha}s deficiency have little effect in humans, but that XL{alpha}s deficiency leads to a severe phenotype in mice (see below). The XL{alpha}s promoter region probably contains a primary imprinting center in which maternal-specific methylation is established during gametogenesis and maintained throughout development (13). This region also generates paternally expressed antisense transcripts that may be important for NESP55 imprinting (14, 15), which is a secondary event that occurs during postimplantation development (16, 17).



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  		FIG. 1. General organization and imprinting patterns of the human GNAS (and mouse Gnas) locus. The maternal (Mat) and paternal (Pat) alleles of GNAS are depicted with alternative first exons for NESP55 (NESP), XL{alpha}s, untranslated (exon 1A), and Gs{alpha} (exon 1) mRNAs splicing to a common exon (exon 2). Common downstream exons 3–13 in the sense direction are not shown. Differentially methylated regions (METH) are shown above, and splicing patterns are shown below each panel. Transcriptionally active promoters are indicated by horizontal arrows in the direction of transcription. Transcription from the paternal Gs{alpha} (exon 1) promoter is suppressed in some tissues, which is indicated with a dashed arrow. The XL{alpha}s promoter also generates paternally expressed antisense transcripts, and the first antisense exon is shown (NESPAS). The diagram is not drawn to scale.

 
The Gs{alpha} promoter lies 35 kb downstream of the XL{alpha}s promoter. The Gs{alpha} promoter is within a CpG island and is unmethylated on both parental alleles (16) despite the fact that Gs{alpha} is imprinted in a tissue-specific manner, being expressed primarily from the maternal allele in specific hormone target tissues (e.g. renal proximal tubules, thyroid, pituitary, and ovaries) (18, 19, 20, 21, 22). Tissue-specific Gs{alpha} imprinting in mice is associated with tissue-specific differences in the extent of histone H3 lysine 4 methylation in Gs{alpha} exon 1, an epigenetic modification that has been shown to be associated with transcriptional activity in lower species (23). Just upstream of the Gs{alpha} promoter is another differentially methylated region (DMR) that is methylated only on the maternal allele and contains a promoter and first exon (exon 1A or A/B) that generates paternally expressed untranslated mRNA transcripts (16, 24). The exon 1A DMR also appears to be a primary imprint mark, because its methylation is established during gametogenesis and is maintained throughout development (16). The exon 1A DMR can be deleted without affecting NESP55-XL{alpha}s imprinting (25) (Weinstein, L. S., and J. Liu, unpublished observations), indicating that the GNAS locus contains two independent imprinting domains (NESP55/XL{alpha}s and exon 1A DMR/ Gs{alpha}). Both the human gene, located at 20q13, and the mouse ortholog Gnas, which is located within a syntenic region in distal chromosome 2, have similar overall structure and imprinting patterns.

The most well characterized function of Gs{alpha} is as a signal transducer between seven-transmembrane receptors and generation of cAMP by adenylyl cyclase. cAMP is known to mediate many of its effects by stimulating protein kinase A (PKA), but more recently cAMP has been shown to have other effectors in certain cell types, such as cAMP-regulated guanine nucleotide exchange factors for Rap1 (26) and calcium channels (27). These diverse effectors lead to mitogenic and antimitogenic effects in different cell types (2). There is also evidence that Gs{alpha} itself may have other effectors, such as Src kinase (28) and calcium channels (29), and that Gs{alpha} may be activated by growth factor receptors (30, 31). In addition to residing on the inner leaf of cell membranes, Gs{alpha} is localized to intracellular membranes and therefore may have a role in membrane trafficking (32).

Gs{alpha}, like all G protein {alpha}-subunits, consists of two domains: a GTPase domain that includes the sites for guanine nucleotide binding and receptor and effector interaction and a helical domain that may be important to maintain guanine nucleotide binding (33, 34). Long and short forms of Gs{alpha} result from alternative splicing of exon 3. In the inactive state, Gs{alpha} exists as a Gs{alpha}-ß{gamma} heterotrimer with GDP bound to its binding pocket. Ligand-bound receptors promote GDP release and binding of ambient GTP, which results in a switch to an active conformation and dissociation from ß{gamma}. GTP-Gs{alpha} directly activates adenylyl cyclase and its other effectors. The turn-off mechanism is an intrinsic GTPase that hydrolyzes bound GTP to GDP. The GTPase cycle may also be regulated by RGS proteins and effectors (35, 36). Unlike Gs{alpha}, XL{alpha}s has a more limited tissue distribution, being primarily expressed in the pars intermedia of the pituitary, brain, adrenal, heart, and pancreatic islets (12). XL{alpha}s is able to bind to ß{gamma}-subunits and mediate receptor-stimulated cAMP production (37, 38).

GNAS-Activating Mutations

GNAS-activating mutations (also known as gsp mutations) are missense mutations that lead to amino acid substitution of either residue Arg201 or Gln227 within the long form of Gs{alpha} (39). These two residues are catalytically important for GTPase activity; therefore, these mutations cause constitutive activation by disrupting the turn-off mechanism. The exotoxin secreted by Vibrio cholera catalyzes a posttranslational modification (ADP ribosylation) of Gs{alpha} Arg201, and the resulting increased cAMP in intestinal lining cells leads to severe secretory diarrhea. Gsp mutations are dominant acting, and such somatic mutations were originally found in approximately 40% of GH-secreting pituitary tumors, a small number of thyroid tumors, and rarely in other endocrine tumors (2, 40). Growth and hormone release in many endocrine glands are stimulated by trophic hormones that activate Gs{alpha}-cAMP pathways. The GHRH-Gs{alpha}-cAMP-PKA pathway stimulates growth and hormone release in somatotrophs via phosphorylation of cAMP response element-binding protein and induction of the somatotroph-specific transcription factor GH factor-1 (41, 42). The glycoprotein hormones TSH, ACTH, and gonadotropins stimulate growth and hormone release in their target tissues by both PKA-dependent and -independent mechanisms (2).

More widespread distribution of cells bearing Arg201 mutations, presumably due to somatic mutation occurring during early prenatal development, leads to the McCuneAlbright syndrome (MAS). MAS is classically defined as the triad of gonadotropin-independent sexual precocity, café-au-lait skin lesions, and fibrous dysplasia (FD) of bone (43, 44, 45). Some MAS patients do not develop all three features of the triad, whereas others develop other characteristic endocrine and nonendocrine features, such as TSH-independent functional thyroid nodules, ACTH-independent adrenal hyperplasia with hypercortisolism, acromegaly, hypophosphatemia, cardiomyopathy, sudden death, and effects on other nonendocrine tissues (46). Somatic gsp mutations are also present in FD lesions from patients with or without other features of MAS (47, 48). MAS is virtually never inherited, and germline gsp mutations are considered lethal (49), although a possible germline Arg201 to Gly mutation was reported in one patient with severe manifestations (50). In the vast majority of patients with sporadic acromegaly or acromegaly associated with MAS, the mutation is present on the active maternal allele, although there does not appear to be a parental allele bias in patients with MAS who do not have acromegaly (19, 51).

The hyperpigmentary lesions in MAS results from increased cAMP in melanocytes (52). cAMP production is normally stimulated in melanocytes by MSH, and cAMP induces the expression of tyrosinase, the rate-limiting enzyme for melanin production. FD results from hyperproliferation and incomplete differentiation of marrow stromal cells to osteoblasts, which is the direct result of excess cAMP in these cells (44, 53, 54, 55, 56). cAMP stimulates the expression of Fos by PKA-dependent phosphorylation and activation of cAMP response element-binding protein. Fos overexpression in FD cells (57) inhibits the expression of osteoblast-specific genes and stimulates the expression of cytokines such as IL-6, which promotes bone resorption by osteoclasts (58). Recent studies show that hypophosphatemia in FD/MAS results from excess secretion of the phosphatonin fibroblast growth factor 23 from FD lesions (59).

GNAS-Inactivating Mutations

Heterozygous inactivating Gs{alpha} mutations result in Albright hereditary osteodystrophy (AHO), a congenital syndrome in which patients develop obesity, short stature, brachydactyly, subcutaneous ossifications, and neurobehavioral deficits (1, 60, 61). The severity of manifestations varies greatly, and some patients with mutations have minimal or no clinical features (62). Mutations that disrupt Gs{alpha} mRNA expression (e.g. premature stop codons and splice junction mutations) or missense mutations have been identified in all 13 Gs{alpha} coding exons, except exon 3, probably because splicing out this exon still produces a functional protein (63). Some missense mutations produce specific biochemical Gs{alpha} defects (1). These mutations result in Gs{alpha} haploinsufficiency (50% loss of expression or function) in many tissues, and this is the most likely molecular defect underlying the AHO phenotype. If NESP55 or XL{alpha}s deficiency were the underlying cause of AHO, one would expect different phenotypes resulting from mutations on the maternal and paternal alleles, respectively. Moreover, mutations in Gs{alpha} exon 1, which disrupt expression of Gs{alpha}, but not XL{alpha}s or NESP55, also lead to AHO. Some patients with identical Gs{alpha} mutations develop a severe form of ectopic ossification known as progressive osseous heteroplasia, possibly resulting from inappropriate expression of the osteoblast-specific transcription factor Cbfa1/RUNX2 in ectopic locations (64, 65). The opposite skeletal effects of activating and inactivating Gs{alpha} mutations in FD and AHO strongly implicate Gs{alpha}/cAMP as an important regulator of osteoblast differentiation.

AHO patients who inherit Gs{alpha} mutations from their mother also develop resistance to PTH, TSH, and gonadotropins [pseudohypoparathyroidism type 1A (PHP1A)], whereas patients who inherit mutations from their father inherit their mutations only develop AHO (also known as pseudopseudohypoparathyroidism) (1, 66). This is due to the fact that Gs{alpha} is primarily expressed from the maternal allele in the target tissues of these respective hormones (renal proximal tubules, thyroid, and ovaries) (18, 19, 20, 21, 22). Mutations in the active maternal allele lead to Gs{alpha} deficiency and hormone resistance, whereas mutation in the inactive paternal allele have little or no effect on Gs{alpha} expression or hormonal signaling (Fig. 2Go). Recent studies show these patients to also have GH deficiency due to GHRH resistance, although the short stature in these patients is probably the result of a primary skeletal growth plate defect rather than GH deficiency (67, 68). Olfactory defects and prolactin deficiency have also been reported in PHP1A patients (69, 70). Lack of Gs{alpha} imprinting in other hormone target tissues is one explanation for why PHP1A patients fail to develop resistance to other hormones that stimulate Gs{alpha}/cAMP pathways (e.g. ACTH and vasopressin) (18).



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  		FIG. 2. Tissue-specific Gs{alpha} imprinting and the effects of heterozygous inactivating Gs{alpha} mutations. Gs{alpha} is paternally imprinted (denoted with X) in renal proximal tubules (upper panels). Mutation (Mut) on the active maternal allele (left panel) leads to Gs{alpha} deficiency and PTH resistance, whereas mutation on the imprinted paternal allele (right panel) has little effect on Gs{alpha} expression or PTH sensitivity. Immunoblots of renal cortical membranes isolated from mice with disruption of the Gnas maternal (m–/+) and paternal (+/p–) alleles, respectively, as well as their wild-type mice (WT) littermates confirm the predicted Gs{alpha} expression patterns (18 ). In most other tissues (lower panels), Gs{alpha} is not imprinted, and therefore, both maternal and paternal mutations lead to an approximately 50% loss of Gs{alpha} expression (haploinsufficiency), as shown in immunoblots of renal inner medulla membranes from the same mice. Gs{alpha} haploinsufficiency is probably the underlying molecular defect that leads to the AHO phenotype in patients with heterozygous Gs{alpha} mutations Figure adapted from Weinstein et al. (1 ).

 
GNAS Imprinting Defects

PHP1B patients have renal PTH resistance similar to that in PHP1A, but lack the AHO phenotype. In PHPIB, Gs{alpha} expression in tissues such as blood cells is normal, ruling out the presence of typical Gs{alpha}-inactivating mutations. PHPIB results from a GNAS imprinting defect in which maternal-specific imprinting (methylation) of the exon 1A DMR is lost, with both alleles having a paternal imprinting pattern or epigenotype in this region (24). Presumably this leads to Gs{alpha} deficiency in renal proximal tubules due to the lack of an active maternal allele, but has no effect on Gs{alpha} expression in the majority of other tissues, where Gs{alpha} is normally expressed equally from both parental alleles. This is consistent with the fact that PHPIB patients have PTH resistance, but lack the AHO phenotype. Although TSH resistance was not considered to be a feature of PHPIB, it was recently shown that borderline to mild TSH resistance is present in almost half the patients with the imprinting defect (22).

In familial PHPIB, patients almost always have a deletion mutation within the closely linked STX16 gene located upstream of GNAS, which has no effect when inherited paternally, but leads to the exon 1A DMR imprinting defect and PTH resistance when inherited maternally (71). Imprinting of NESP55/XL{alpha}s is unaffected in these patients. Presumably the deleted region contains cis-acting elements that are required to establish or maintain exon 1A DMR imprinting, but is not necessary for imprinting of the intervening NESP55/XL{alpha}s domain. Sporadic forms of PHPIB can be associated with loss of the maternal epigenotype within the exon 1A DMR alone or may also involve loss of the maternal epi-genotype within the NESP55/XL{alpha}s imprinting domain as well (24, 72). Whether these imprinting defects in sporadic PHPIB are caused by underlying mutations or result from a random failure of the imprinting process is unknown. NESP55 expression in patients with the more global GNAS imprinting defect is absent due to methylation of the NESP55 promoter on both parental alleles (24). This subset of patients does not have a more severe phenotype, suggesting that NESP55 expression is dispensable in humans. PTH resistance has also been described in a patient with paternal uniparental disomy of 20q, which leads to a similar GNAS imprinting defect (73). In one family a PHPIB phenotype was caused by maternal inheritance of a Gs{alpha} missense mutation (deletion of Ile382) that generates a Gs{alpha} protein, which is selectively uncoupled to the PTH/PTH-releasing peptide receptor (74).

We have proposed a model to explain how tissue-specific Gs{alpha} imprinting is controlled by the exon 1A DMR and how loss of exon 1A DMR imprinting leads to PHPIB (24). The fact that exon 1A-specific and Gs{alpha} mRNA transcripts have similar tissue distributions makes it unlikely that the exon 1A DMR controls Gs{alpha} by promoter competition or by a direct action of exon 1A-specific transcripts (16). Rather, the exon 1A DMR may contain a cis-acting, negative regulatory element (silencer or insulator) that is both methylation sensitive and tissue specific. In the example shown in Fig. 3Go, the exon 1A DMR has a silencer that binds a tissue-specific repressor protein. In proximal tubules, the repressor binds to the paternal allele and suppresses Gs{alpha} expression, but is unable to bind to the maternal allele because its site is methylated and heterochromatic (23), allowing Gs{alpha} to be maternally expressed. In most other tissues, the exon 1A DMR is methylated, but the repressor is not expressed; therefore, Gs{alpha} is biallelically expressed. In PHPIB, exon 1A DMR methylation is absent, allowing the repressor to bind to and suppress Gs{alpha} expression from both alleles in proximal tubules, leading to Gs{alpha} deficiency and PTH resistance. However, the methylation defect has no effect on Gs{alpha} expression in most other tissues because the repressor is absent. Support from this model comes from recent findings showing that paternal, but not maternal, deletion of the exon 1A DMR in mice leads to Gs{alpha} overexpression in renal proximal tubules and lower serum PTH levels, a sign of increased PTH sensitivity (25) (Weinstein, L. S., and J. Liu, unpublished observations).



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  		FIG. 3. Proposed model for the role of the exon 1A DMR in tissue-specific Gs{alpha} imprinting and the pathogenesis of PHP1B. Maternal (Mat) and paternal (Pat) alleles of the exon 1A DMR-Gs{alpha} exon 1 region are depicted. The exon 1A DMR is normally methylated on the maternal allele (Meth) and contains a cis-acting silencer (S; upper panels). In proximal tubules (left panel) a tissue-specific trans-acting repressor (R) binds to the silencer and suppresses Gs{alpha} expression on the paternal allele, but is unable to bind to the maternal allele due to methylation, allowing Gs{alpha} to be expressed from the maternal allele. In most other tissues (right panel) the repressor is not expressed, and therefore, Gs{alpha} is biallelically expressed. In PHP1B (lower panels), methylation is absent, allowing the repressor to bind to both alleles in proximal tubules, resulting in Gs{alpha} deficiency and PTH resistance. Gs{alpha} expression is unaffected in most other tissues because the repressor is absent.

 
Gnas Knockout Models

Mice with heterozygous disruption of Gnas exon 2 on the maternal (m–/+) or paternal (+/p–) allele have distinct early phenotypes similar to mice with paternal uniparental disomy/maternal deletion and maternal uniparental disomy/paternal deletion of the distal chromosome 2 region including Gnas, respectively (18). These distinct phenotypes are consistent with the fact that Gnas has distinct maternally and paternally expressed gene products. Interestingly, m–/+ and +/p– mice have opposite metabolic phenotypes (18, 75, 76, 77). –/+ mice are obese, hypometabolic, and hypoactive, whereas +/p– mice are very lean, hypermetabolic, and hypoactive. Measurements of urinary norepinephrine suggest that the m–/+ and +/p– metabolic phenotypes may be secondary to decreased and increased sympathetic nerve activity, respectively (75). Interestingly, both groups of mice have increased whole body insulin sensitivity, although to a much greater extent in +/p– mice (76). Mice with paternal deletion of Gs{alpha} exon 1, a mutation that specifically disrupts expression of Gs{alpha}, but not other Gnas gene products, lack the +/p– exon 2 phenotype and, in fact, have the opposite metabolic phenotype (obesity and insulin resistance) (Weinstein, L. S., and M. Chen, unpublished observations). Recently, XL{alpha}s knockout mice were shown to have a phenotype similar to that of +/p– exon 2 mice (78). These findings suggest that Gs{alpha} and XL{alpha}s have opposite effects on whole body metabolism, and that the +/p– exon 2 phenotype is primarily caused by XL{alpha}s deficiency. One possibility is that XL{alpha}s normally acts as a negative regulator of sympathetic nerve activity, and therefore, XL{alpha}s deficiency in +/p– mice leads to a hyperadrenergic state (77). The biological importance of XL{alpha}s may be species specific, because loss of XL{alpha}s expression in pseudopseudohypoparathyroidism patients does not result in a similar phenotype.

Conclusions

GNAS is a complex imprinted locus whose major product is Gs{alpha}. Somatic Gs{alpha}-activating mutations produce MAS, endocrine tumors, and/or fibrous dysplasia of bone primarily through the effects of increased cAMP levels, which in some cell types can lead to proliferation. Inactivating Gs{alpha} mutations leads to AHO and in some cases progressive osseous heteroplasia. The opposite effects of activating and inactivating Gs{alpha} mutations on osteoblast differentiation in these disorders suggest that Gs{alpha}/cAMP pathways play a major role in regulating osteoblastogenesis. The AHO phenotype is most likely due to Gs{alpha} haploinsufficiency resulting from heterozygous Gs{alpha} mutations. Gs{alpha} is imprinted and expressed primarily from the maternal allele in various hormone target tissues, and therefore, maternal inheritance of Gs{alpha} mutations also leads to multihormone resistance (PHPIA). Hormone resistance in PHPIB can also result from loss of maternal imprinting of the exon 1A DMR region, a region within the GNAS locus that appears to contain elements important for establishing tissue-specific imprinting of Gs{alpha}. However, these patients do not develop AHO, because the imprinting defect has no effect on Gs{alpha} expression in the vast majority of tissues where Gs{alpha} is normally expressed biallelically. Gnas knockout mouse models demonstrate that both Gs{alpha} and XL{alpha}s, a neuroendocrine-specific Gs{alpha} isoform expressed only from the paternal allele, have important roles in the regulation of energy metabolism.

Footnotes

Address all correspondence and requests for reprints to: Dr. Lee S. Weinstein, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 8C101, Bethesda, Maryland 20892-1752. E-mail: leew{at}amb.niddk.nih.gov.

Abbreviations: AHO, Albright hereditary osteodystrophy; DMR, differentially methylated region; FD, fibrous dysplasia; Gs{alpha}, G protein {alpha}-subunit; MAS, McCune-Albright syndrome; PHP1A, pseudohypoparathyroidism type 1A; PKA, protein kinase A.

Received July 7, 2004.

Accepted for publication August 17, 2004.

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