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Physiology 23: 221-229, 2008; doi:10.1152/physiol.00010.2008
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Physiology, Vol. 23, No. 4, 221-229, August 2008
© 2008 Int. Union Physiol. Sci./Am. Physiol. Soc.

REVIEW

Physiological Dysfunctions Associated with Mutations of the Imprinted Gnas Locus

Stefan Krechowec and Antonius Plagge

Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Liverpool, United Kingdom a.plagge{at}liv.ac.uk


   Abstract
 
The ubiquitous G{alpha}s-subunit of the trimeric, stimulatory G-protein plays a central role in receptor-mediated signal transduction, coupling receptor activation with the production of cAMP. The G{alpha}s-encoding locus Gnas is now known to consist of a complex arrangement of several protein-coding and noncoding transcripts. We provide an overview of its genomic organization, its regulation by genomic imprinting, and a summary of the physiological roles of the alternative protein variants G{alpha}s and XL{alpha}s as determined from deficient mouse models.


   Introduction
Top
 Introduction
The Transcripts and Proteins...
 Neuroendocrine and Metabolic...
 Concluding Remarks
 References
 
Signal transduction from a large number of activated seven-pass transmembrane receptors to adenylyl cyclases and subsequent generation of the second messenger cAMP requires the "{alpha}-stimulatory" subunit of the trimeric G-protein, G{alpha}s (70). Although this classical signaling protein has been studied in detail, the significance of an NH2-terminal splice variant, termed XL{alpha}s (eXtra Large {alpha}s), and the complexity of the genomic locus (Gnas) encoding these proteins has only recently been recognized (4, 32, 34, 49, 56, 68). The identification of alternative promoters and 5' exons within the locus and the discovery that genomic imprinting regulates their activity has played a fundamental role in forming our current understanding of what physiological functions depend on the different proteins of the Gnas locus (29, 30, 33, 53–56). The term genomic imprinting describes a regulatory mechanism, present in mammals, that controls gene dosage through the silencing of one parental allele in a parent-of-origin-dependent manner (46, 58, 73). Thus some imprinted genes are only expressed from the maternally inherited allele, whereas others are exclusively active on the paternally derived chromosome. Epigenetic changes, including DNA methylation and chromatin modifications, mediate the specific silencing of imprinted parental alleles. The establishment of maternal/paternal epigenetic and imprinting patterns occurs in the developing germ cells of the parents and is maintained in the embryo after fertilization and into adulthood (18, 62). Although the number of imprinted genes currently identified in the human and mouse genomes is relatively small (~90 transcripts) (databases: http://www.har.mrc.ac.uk/research/genomic_imprinting/; http://igc.otago.ac.nz/home.html), many of them play essential roles in typical mammalian physiological adaptations, e.g., placenta functions, fetal and postnatal growth, resource acquisition, and energy homeostasis (9, 14, 21, 64). Notably, an increasing body of evidence suggests that maternally and paternally imprinted genes have opposite effects on a number of converging/overlapping pathways involved in determining early growth dynamics and energy acquisition. In this light, genomic imprinting is regarded as a mechanism through which conflicting parental influences can affect the growth and development of offspring. Whereas paternally expressed alleles typically stimulate growth and nutrient acquisition, maternally expressed alleles have a limiting or restricting role (26). The characterization of a potential network of imprinted genes regulating the development of these crucial physiological pathways has become the current focus of research in the field of imprinting and epigenetic control of energy homeostasis (9, 65).


   The Transcripts and Proteins Encoded by the Gnas Locus and Their Regulation by Genomic Imprinting
Top
 Introduction
 The Transcripts and Proteins...
Neuroendocrine and Metabolic...
 Concluding Remarks
 References
 
Genome-wide screens for novel imprinted genes in the human and mouse have revealed the complex structural arrangement of the Gnas locus (29, 30, 33, 53). In addition to the core exons and promoter of Gnas itself, the locus is now known to contain several alternative upstream promoters that initiate further coding and noncoding transcripts. The gene structure, and pattern of imprinted expression are largely conserved between the murine and human loci on distal chromosome 2 and chromosome 20q13.2–13.3, respectively, with only some minor differences as mentioned below. At the center of the locus, Gnas itself comprises 12 exons, which encode the G{alpha}s protein (13 exons in human, due to an additional intron interrupting exon 9) (FIGURE 1Go). However, only exon 1, which contains the 5'-UTR and 46 codons, is specific to Gnas, since the remaining exons are also utilized by several other transcripts. Gnas is widely expressed in most tissues and generally transcribed from both chromosomes, that is, except in a specific subset of tissue types, where it is expressed preferentially from the maternally inherited allele (69). Silencing of the paternally inherited allele occurs in proximal renal tubule cells, thyroid gland, anterior pituitary, and ovaries (23–25, 27, 40, 44, 45, 79). Reports on Gnas imprinting in adipose tissue are currently contradictory; some studies have shown preferential expression from the maternal allele, whereas others indicated biallelic transcription (11, 25, 45, 71, 79). Regarding the adipose imprinting of Gnas, differences in species and developmental stages need to be carefully considered before solid conclusions can be reached. The tissue-specific silencing of the paternal allele is highly relevant for disorders associated with mutations on the maternal allele as described in more detail below.


Figure 1
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  		FIGURE 1. Scheme of the imprinted Gnas locus and summary of the main phenotypical features associated with mutant mouse models
The maternal and paternal alleles of the locus are depicted in the center, coding exons as filled boxes, and noncoding exons as light gray boxes. Active promoters and transcriptional directions of the RNAs for Gnas, exon 1A, Gnasxl, Nespas, and Nesp are marked by arrows. Although Gnas is expressed biallelically in most tissues, silencing of the promoter in some cell types is indicated by the light blue exon 1 box on the paternal allele. The splicing patterns of the various transcripts are shown above and below the maternal and paternal alleles, respectively. Nespas transcripts exist in multiple spliced and unspliced forms. In humans, GNAS consists of 13 exons and NESP only comprises one 5'-exon; exon 1A is termed exon A/B. MMM indicates DNA methylation at differentially methylated regions (DMRs) of the respective alleles; the DMRs at Nespas and exon 1A constitute imprinting control regions (ICRs) of the locus. The locations of various mutations in mice are indicated by X, and the major phenotypical features upon maternal or paternal transmission are mentioned above and below the respective alleles.

 
Gnasxl, the second protein-coding transcript of the Gnas locus, is initiated at a separate promoter ~30 kb upstream of Gnas exon 1 (FIGURE 1Go) (29, 33, 53). The transcript splices onto Gnas exons 2–12, whereby the open reading frame remains conserved, resulting in the NH2-extended protein variant of G{alpha}s, termed XL{alpha}s (32). In contrast to Gnas, the Gnasxl transcript is consistently imprinted and only expressed from the paternally inherited allele. Furthermore, Gnasxl shows a highly restricted expression pattern, which comprises, at neonatal stages, adipose tissue, pancreas, heart, stomach, kidney as well as neuroendocrine tissues like adrenal medulla, pituitary, and defined areas of the brain stem (medulla oblongata, pons, hypothalamus) (48, 49, 54). Emerging evidence currently suggests that Gnasxl expression is downregulated in various adult tissues, e.g., adipose tissue, kidney, and heart, which might be relevant in the context of the phenotype of knockout mice described below (49, 76). Although its NH2-terminus varies, the XL{alpha}s protein retains a β, {gamma}-subunit-interacting domain and can stimulate, with almost identical characteristics to G{alpha}s, adenylyl cyclases on activation of several hormone/neuro-transmitter receptors (4, 38).

In neuroendocrine tissues, e.g., brain, pituitary, and adrenal glands, a truncated splice form of the Gnasxl transcript is generated through usage of the alternative exon N1, which is located between exons 3 and 4 (16, 49, 54). Whether the XLN1 protein, which lacks most of the functional domains of G{alpha}s-subunits, exerts any function is currently unclear.

Approximately 15 kb upstream of the Gnasxl exon, a third promoter initiates the Nesp transcript, which encodes the "neuroendocrine-specific protein of Mr 55,000" (Nesp55) (30, 31, 33, 53). The Nesp transcript is also imprinted, but in contrast to Gnasxl it is expressed from the maternally inherited chromosome only. The Nesp-specific upstream exons (2 exons in mouse, 1 in human) are also spliced onto exons 2–12 of Gnas (FIGURE 1Go). However, in this case, the latter only constitute 3'-UTR, since the Nesp55 open reading frame remains confined to the upstream exon. Little is known about the molecular functions of the Nesp55 protein, although it has been associated with secretory vesicles and can be processed into smaller peptides (20, 43).

Apart from these three protein-coding transcripts, two additional RNAs are expressed from the paternally inherited allele (FIGURE 1Go). The exon 1A transcript initiates ~2.4 kb upstream of the first Gnas exon and is spliced onto exon 2 (41). The other noncoding RNA starts ~2.1 kb upstream of Gnasxl but is transcribed in multiple spliced and unspliced forms in the opposite direction, i.e., antisense to Nesp, and is therefore termed Nespas (28, 74). These two noncoding RNAs are most likely part of the regulatory mechanisms that control the imprinting of the protein-coding transcripts (50–52). Both transcripts originate in DNA regions (imprinting control regions, ICRs), which show differential cytosine methylation within maternal and paternal alleles (differentially methylated regions, DMRs) (FIGURE 1Go) (15, 41). Functionally, exon 1A DMR is responsible for the tissue-specific imprinting of Gnas. A paternal deletion of exon 1A, its promoter and start site, results in the upregulation of the normally silenced paternal Gnas transcript in imprinted tissues (39, 71). Similarly, paternal deletion of the Nespas DMR and transcriptional start site affects all transcripts of the locus (72). The role of a third DMR at Nesp remains to be clarified (3). Our current understanding of the precise imprinting regulatory mechanisms at the Gnas locus is limited and awaits further investigation; for a more detailed discussion of these aspects, the reader is referred to recent excellent reviews (51, 52).

The discovery of mutations in the highly conserved human GNAS locus gave the first indications that the encoded gene products influenced important physiological processes. The genetic disorders Albright’s Hereditary Osteodystrophy (AHO) and pseudohypoparathyroidism (PHP) were found to be due to missense or nonsense mutations in GNAS exons (1, 36, 37, 67). AHO is characterized by a range of symptoms, including short stature, brachydactyly, subcutaneous ossifications, obesity, and variable mental retardation (Table 1Go) (57, 69). In some cases, additional symptoms of hypocalcemia, hyperphosphatemia, and end-organ resistance to parathyroid hormone (PTH) in the proximal renal tubules are associated with AHO. This observation has led to the condition being termed PHP-type Ia (5, 35, 57, 69). AHO symptoms without hormone resistance and normal calcaemia are referred to as "pseudopseudohypoparathyroidism" (PPHP). Upon Davies and Hughes’ observation, it became clear that AHO plus PTH resistance (as well as other hormone resistances), i.e., PHP-Ia, only occurred after maternal inheritance of a GNAS mutation (17). By contrast, AHO without hormone resistances (PPHP) is found after paternal transmission of the same GNAS mutations (Table 1Go). This pattern of inheritance reflects the tissue-specific imprinting of GNAS, with hormone resistance arising from imprinted tissues, where the paternal allele is naturally silenced and the inheritance of an inactivating mutation in the maternal allele leads to an almost complete absence of GNAS expression. Thus the common AHO symptoms can be attributed to haploinsufficiency of GNAS in a subset of cell types demonstrating biallelic expression. It is beyond the scope of this review to describe the human disorders in more detail, but many of those symptoms are reproduced in recently generated mouse models, and we will refer to them in the following discussion of physiological phenotypes of mutant mice. The human disorders have recently been reviewed elsewhere (5, 35, 57, 69).


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  		Table 1. General physiological characteristics affected by mutations at the GNAS/Gnas imprinted locus in human and mouse
 

   Neuroendocrine and Metabolic Phenotypes in Mice Lacking G{alpha}s or XL{alpha}s and Their Relevance to Human Disease
Top
 Introduction
 The Transcripts and Proteins...
 Neuroendocrine and Metabolic...
Concluding Remarks
 References
 
Advances in our understanding of the complexities of the Gnas locus have led to a need to characterize the in vivo functions of its different protein products. This has initiated the development of different mouse lines carrying transcript-specific deletions. In turn, these new mutants have prompted a re-interpretation of earlier findings described in older mouse models, which carried less specific Gnas mutations. Earlier mutational models, involving mice with uniparental duplications/deficiencies of distal chromosome 2 and the Oed-Sml point mutation, typically affected both Gnas and Gnasxl transcripts and demonstrated a remarkably consistent parent-of-origin effect on neonatal and adult phenotypes (FIGURE 1Go) (7, 8). Thus mice that carry two copies of a paternally inherited distal chromosome 2 (and no maternal copy), i.e., paternal duplication distal chromosome 2 (PatDp.dist2), show a phenotype that is similar to maternally inherited G{alpha}s deficiency. Vice versa, mice that carry two copies of a maternally inherited distal chromosome 2 (no paternal copy, i.e., MatDp.dist2) largely reproduce a XL{alpha}s-deficient phenotype (7, 54). Furthermore, a point mutation in exon 6, termed Oed-Sml, causes symptoms reminiscent of lack of maternal G{alpha}s expression when inherited maternally (FIGURE 1Go). On the other hand, the same mutation, when inherited paternally, results in a phenotype similar to XL{alpha}s deficiency (7, 63). Further phenotype characterizations of these nonspecific mutants and detailed comparisons with transcript-specific knockouts are currently under way, and, therefore, we will focus on a description of the transcript-specific mutants here, which indicate distinct and possibly opposite physiological roles for G{alpha}s and XL{alpha}s in determining postnatal and adult metabolic functions (57, 68).

G{alpha}s deficiency
From its global pattern of expression, G{alpha}s had been thought to have an essential and non-redundant function in normal development and adult physiology. This hypothesis has been confirmed by the various Gnas knockout models, which show that homozygous G{alpha}s mutations are invariably embryonically lethal (11, 25, 79). Such mutant embryos fail to develop beyond gestational day 10.5. Significantly, heterozygous knockouts also demonstrate a high degree of lethality, indicating the critical nature of G{alpha}s in development.

A disruption of Gnas exon 2 was used to generate the original Gnas knockout mouse (FIGURE 1Go) (79). As we now know, this E2 mutation, when maternally inherited, effectively eliminates the expression of G{alpha}s in imprinted tissues, as well as causing a 50% reduction in tissues with biallelic expression. It also has the potential to disturb the Nesp transcript in its 3'-UTR. By contrast, when the E2 mutation is paternally inherited, it affects the transcripts Gnasxl, Gnas (to 50% in cells with biallelic expression), and the noncoding exon-1A. The phenotype of heterozygotes carrying a maternally inherited exon 2 mutation (E2m–/p+) was later confirmed to be comparable to a Gnas exon 1 mutation, specific for G{alpha}s (E1m–/p+) (FIGURE 1Go) (11, 25). A heterozygous, maternal allele-specific deficiency of G{alpha}s has severe neonatal consequences, resulting in a high (~50–80%) preweaning mortality rate, which notably varies with the genetic background of different mouse strains (11, 25, 79). Characteristic features of the maternal Gnas mutants include a transient subcutaneous edema immediately after birth, an increased level of interscapular brown adipose tissue (BAT), and a wide, square body shape. Despite an increased adiposity (adipocyte hypertrophy), Gnasm–/p+ mutants remain underweight in the immediate neonatal period (78). However, toward adulthood, they experience accelerated catch-up growth, increased adiposity, and enhanced obesity development (11, 25, 78). The metabolic phenotype of adult Gnasm–/p+ mutants has now been characterized in detail (FIGURE 2Go). In the absence of changes in food intake, the obesity phenotype is associated with reductions in energy expenditure and metabolic rate (reduced oxygen consumption) (11, 68, 78). A trend toward reduced urinary catecholamine metabolites suggests that this shift in metabolic rate reflects a decrease in overall neural sympathetic output (78). In contrast to a close similarity in obesity phenotypes, E1m–/p+ and E2m–/p+ mutants display marked differences in glucose tolerance and insulin sensitivity. In E1m–/p+ mice, obesity development is accompanied by hyperglycemia, glucose intolerance, hyperinsulinemia, and insulin resistance, as well as hyperlipidemia and a tendency toward reduced locomotor activity (11). By contrast, obese E2m–/p+ mice were found to be glucose tolerant and insulin sensitive (77). This apparent discrepancy between the two mouse models remains unresolved for the time being, since there is no other maternal allele-specific Gnas product known that could account for it (68).


Figure 2
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  		FIGURE 2. Opposite metabolic effects in G{alpha}s and XL{alpha}s knockouts
Model showing the main metabolic dysfunctions of Gnasm–/p+ and Gnasxlm+/p– mice, favoring antagonistic roles of G{alpha}s and XL{alpha}s in sympathetic nervous system (SNS) outflow as the most important influence on overall phenotypes. The expression of the two proteins is indicated within each tissue, and a deficiency is marked by an X. A: loss of G{alpha}s expression from the maternal allele impairs signaling within brain, resulting in reduced SNS activity (light green arrows), which might potentially be exacerbated by inhibitory effects of XL{alpha}s on this system. Reduced sympathetic output has a major effect on the development of an obesity phenotype. Loss of maternal G{alpha}s expression in peripheral tissues might contribute to the net systemic effect, although heterozygous deficiency specifically in liver or pancreatic β-cells did not show the major phenotypical effects that were described in general Gnasm–/p+ mice. Brain or adipose tissue-specific knockouts have not yet been reported. Secondary effects of the knockout are symbolized by arrows between peripheral tissues. Despite mild resistance to TSH, thyroid hormone levels are unchanged in Gnasm–/p+ mice and, therefore, unlikely to contribute significantly to the metabolic phenotype. B: loss of paternally expressed XL{alpha}s leads to an increased SNS outflow, contributing to the development of a lean, hypermetabolic phenotype. A role of XL{alpha}s in peripheral tissues is currently unclear since no tissue-specific knockout exists, but it might add to the net phenotypic effect. XL{alpha}s is downregulated in adult adipose tissue.

 
Both maternal E1 and E2 Gnasm–/p+ mutants demonstrate multiple hormone resistances due to disrupted receptor signaling in imprinted tissues. This feature recapitulates the defining aspects of PHP-Ia patients, with Gnasm–/p+ mice exhibiting a resistance to parathyroid hormone (PTH) in the renal proximal tubules (Table 1Go) (25, 79). Consistent with Gnas imprinting in the thyroid, Gnasm–/p+ mutants also demonstrate a mild resistance to thyroid-stimulating hormone (TSH) as indicated by elevated plasma TSH levels, but this does not impact on plasma T4 or T3 levels and is therefore unlikely to contribute significantly to the change in metabolic rate (11, 25, 79). There are also further indications for a resistance to gonadotropins, since both male and female Gnasm–/p+ mice show reduced fertility rates (25). Female m–/p+ mice are also less successful in rearing offspring to weaning age, which potentially reflects deficits in hormone-mediated mothering behavior. These observations are in line with clinical findings in PHP-Ia patients who variably present with hypogonadism, delayed sexual development, amenorrhoea or oligomenorrhoea, and occasionally elevated LH and FSH levels (47, 57). Evidence showing Gnas transcripts being derived predominantly from the maternal allele in human ovarian granulosa cells further supports the notion of gonadotropin resistance as an additional symptom of a maternal allele-specific deficiency of G{alpha}s (44).

In contrast to the significant physiological deficiencies described for maternally inherited Gnas mutations, heterozygous mice carrying a paternally derived mutation show a much milder phenotype (11). Postnatal development has been described as normal in a CD1 genetic background, although a 30–40% mortality occurred in the 129Sv strain (11, 25). In adult E1m+/p– mice, mild metabolic abnormalities can be found, including a moderate increase in adipose tissue, mild hyperinsulinemia, glucose intolerance, and insulin resistance. The presence of obesity and insulin resistance in both maternal and paternal E1 mutants suggests that the haploinsufficiency of G{alpha}s in biallelic tissues has a significant effect on the regulation of energy homeostasis. In light of G{alpha}s’s ubiquitous expression, possible obesogenic mechanisms are likely to involve a number of subtle widespread changes across multiple tissues. However, a greater degree of obesity can be observed in mice inheriting maternal G{alpha}s-specific mutations compared with mice inheriting the matched paternal mutation. On this basis, it is possible to speculate that the loss of maternal G{alpha}s expression within imprinted tissues may act to further amplify obesogenic pathways. In humans, significant obesity has long been viewed as a classic feature of both PHP-Ia and PPHPs (57, 69). Consistent with the findings above, a recent clinical study has now found that not only is obesity more common in patients with PHP-Ia, inheriting maternal GNAS mutations, but the degree of weight gain is also significantly greater compared with patients with PPHP who inherit paternal GNAS mutations (Table 1Go) (42). Together, these findings strongly suggest that the loss of maternal G{alpha}s within imprinted tissues plays a key role in the development of human obesity. Chen et al. propose a specific reduction in hypothalamic melanocortin-G{alpha}sm–/+ signaling in E1 mice as one potential mechanism (11). However, it is not presently known whether G{alpha}s is imprinted within the hypothalamic nuclei or other brain regions involved in regulating energy homeostasis.

Apart from these global heterozygous knockouts, several tissue-specific, homozygous Gnas mouse models have been generated (6, 10, 12, 59, 60, 75). A detailed description of dysfunctions due to complete lack of G{alpha}s in specific cell types is beyond the scope of this article but is summarized in a recent excellent review (68). With regard to the metabolic and obesity phenotypes, crucial tissue-specific knockouts (i.e., adipose tissue- and/or brain-specific) have not yet been reported but will be very informative for the clarification of G{alpha}s functions in energy homeostasis. It should be noted, however, that heterozygous G{alpha}s deficiency (maternal allele), specifically in pancreatic β-cells, contributes little to the general E1m–/p+ phenotype (impaired first-phase insulin release and initial glucose intolerance only) (FIGURE 2Go) (75). In addition, no effects have been described in heterozygotes carrying a liver-specific Gnas knockout (12).

XL{alpha}s deficiency
In the original Gnas exon 2 knockout model, maternal and paternal transmission of the mutation caused opposite metabolic phenotypes: maternal transmission (E2m–/p+) led to adult obesity, whereas paternal transmission (E2m+/p–) resulted in a lean, hypermetabolic phenotype (FIGURE 1Go) (78). The paternally inherited exon 2 mutation affected both G{alpha}s and XL{alpha}s, and we now know from the Gnasxl-specific knockout that this latter phenotype can be attributed to XL{alpha}s deficiency, which has a dominant effect over paternal G{alpha}s haploinsufficiency (54, 76). The XL{alpha}s-specific knockout model was generated through the targeted deletion of a small (60 bp) part of the Gnasxl exon. This deletion specifically terminates the expression of XL{alpha}s while preserving the paternal expression of G{alpha}s. As can be expected from a maternally silenced gene, the Gnasxl mutation is without phenotypic effects when passed through the maternal line. However, offspring receiving the paternal mutation (Gnasxlm+/p–) demonstrate a phenotype closely comparable to E2m+/p– mice. Gnasxlm+/p– mice typically show a high level of neonatal mortality due to an inability to suckle successfully (54). This is immediately apparent within the first few days after birth. On an inbred background, mortality rates reach 100% by P9, whereas on an outbred background there is an ~10–20% survival rate, which can be improved by reducing wild-type littermate competition. The observation of Gnasxl expression within the facial, hypoglossal, and trigeminal brain nuclei, which provide motor innervation to the orofacial muscles, indicates that suckling problems may involve a localized motor deficit. Notably, this characteristic feeding deficiency is confined to the neonatal period, with adult mutants demonstrating a significantly increased food intake (76). Other key features of the Gnasxlm+/p– mutation include low birth weight, severe postnatal growth retardation, a narrow body shape, low neonatal blood glucose and insulin levels, reduced levels of BAT and WAT, and a lean, hypermetabolic adult phenotype, featuring increased adipose lipid oxidation (FIGURE 2Go) (54, 76). Unsurprisingly, reduced adiposity and an enhanced mobilization of lipid stores are associated with improved glucose tolerance and increased insulin sensitivity in adult Gnasxlm+/p– mice. Enhanced insulin-stimulated glucose uptake is observed within WAT, BAT, and skeletal muscle. Currently, improvements in skeletal muscle insulin sensitivity are believed to be secondary to a dramatic reduction in tissue triglycerides brought about by the increased oxidative flux within the adipose tissue (76).

The reduced adiposity and increased lean body mass of Gnasxlm+/p– mice appears to result from an increase in energy expenditure (O2 consumption). Metabolically, this increased energy expenditure appears to be driven by enhanced rates of lipid oxidation within the adipose tissue. Morphological, biochemical, and gene-expression analysis of both BAT and WAT suggest that such an elevation in adipose tissue lipid mobilization is a consequence of enhanced β-adrenergic/G{alpha}s/cAMP signaling, stemming from increased basal sympathetic nervous activity (FIGURE 2Go) (76). The expression pattern of XL{alpha}s within the noradrenergic locus coeruleus, sympathetic trunk, and catecholamine-producing adrenal medulla supports this conclusion and suggests that XL{alpha}s plays a key role as a negative regulator of the sympathetic nervous system (48, 49, 54). Of further note, it is hypothesized that the neural-specific, alternatively spliced and truncated XLN1 protein may also be involved in the inhibition of central sympathetic output. One possible mechanism potentially mediating this inhibition of sympathetic activity involves the action of XL{alpha}s and/or XLN1 in a negative regulatory pathway, inhibiting G{alpha}s/SNS signaling within the brain (FIGURE 2Go). An alternative possibility also exists, i.e., a direct effect of XL{alpha}s deficiency within adipose tissue, although this is thought to be unlikely since XL{alpha}s expression is downregulated in adult adipose tissue (76). However, XL{alpha}s is expressed in adipose tissue at fetal and neonatal stages. Consequently, there remains the possibility that an absence of XL{alpha}s during early development may permanently alter adult adipose function.

Although mutational studies have clearly demonstrated a critical biological role for XL{alpha}s in the mouse, it is important to note that a possible role of XL{alpha}s in human disease remains uncertain. AHO/PPHP patients with various paternal GNAS exon 2–13 mutations, predicted to disrupt XL{alpha}s, generally fail to develop the defining hypermetabolic characteristics, which appear to predominate in the knockouts. Such a discrepancy suggests that, in contrast to G{alpha}s, the metabolic actions of XL{alpha}s might be species specific. However, some rare human chromosomal abnormalities that lead to a deficiency of XL{alpha}s (e.g., maternal uniparental disomies and paternally inherited deletions) appear to generate a phenotype that shares some of the defining aspects of Gnasxlm+/p– knockout mice, such as intractable neonatal feeding difficulties, prenatal and postnatal growth retardation, and abnormal adipose tissue deposition (Table 1Go) (2, 13, 19, 22, 61, 66). As much as this is feasible, future studies of human mutation carriers at postnatal stages should be encouraged to clarify species differences.

Nesp55 deficiency
A specific mutation of Nesp, which leads to loss of the protein but does not eliminate the transcript, showed that Nesp55 is not required for postnatal development or adult metabolic control (55). Corresponding with the expression of Nesp in the brain and endocrine system, a behavioral phenotype relating to novel environments was identified. However, although Nesp55 is associated with secretory vesicles, its molecular functions remain uncertain (20, 43). Since it was recently discovered that larger deletions in the NESP region, when inherited maternally in human kindreds, lead to changes in the imprinting status of the other downstream Gnas transcripts, it seems now likely that the DMR at Nesp and/or the transcript itself has a regulatory function in the control of imprinting of the locus (3). Modeling of these human NESP mutations in mice should provide us with highly valuable information on its potential roles in Gnas imprinting.


   Concluding Remarks
Top
 Introduction
 The Transcripts and Proteins...
 Neuroendocrine and Metabolic...
 Concluding Remarks
References
 
The development of Gnas knockout models has demonstrated many parallels between mouse phenotypes and human disease symptoms in AHO/PHP-Ia and PPHP (Table 1Go). These studies have greatly advanced our understanding of how the specific disruption of maternal or paternal alleles can lead to opposite phenotypes in knockout mice and clinically distinct disorders in humans. Yet it is important to note that differences have been observed between the phenotype of some knockouts and the presentation of human symptoms. Specifically, a role for XL{alpha}s in human disease remains uncertain and may be confirmed as species specific. The development of further tissue-specific knockouts, of both G{alpha}s and XL{alpha}s, is necessary to identify the tissues where disruption of different parental alleles leads to the development of parent-of-origin-specific phenotypes. A greater understanding of the tissue-specific contributions of Gnas mutations to phenotype development will provide a deeper insight into the complex molecular mechanisms that underlie the genetic disorders of AHO/PHP-Ia and PPHP. Apart from the analysis of the physiological functions, further work is also necessary to characterize mutations of the GNAS locus that impact its imprinting status and the genetic regulatory mechanisms that control the various coding and non-coding transcripts.


   Acknowledgments
 
Our work is supported by grants from the Royal Society and the Medical Research Council of the United Kingdom.


   References
Top
 Introduction
 The Transcripts and Proteins...
 Neuroendocrine and Metabolic...
 Concluding Remarks
 References
 

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