GNAS Complex Locus
In 1942, Fuller Albright and his colleagues described a disease characterized by hypocalcemia and hyperphosphatemia, which appeared similar to hypoparathyroidism. However, injection of a parathyroid hormone (PTH) extract did not lead to increased urinary phosphate excretion or normalize serum calcium in the patients. Based on these findings, resistance to the actions of PTH was postulated, and the term pseudohypoparathyroidism (PHP) was coined (Albright et al. 1942). The patients additionally displayed a constellation of phenotypic features including short stature, obesity with round face, brachydactyly, subcutaneous ossifications, and cognitive impairment (Albright et al. 1942), which are now collectively called Albright’s hereditary osteodystrophy (AHO). Decades later, elevated serum PTH has been detected – consistent with endogenous PTH being ineffective (Chase and Aurbach 1968), and it was shown that exogenous synthetic PTH injection fails to rise urinary excretion of cAMP (Chase et al. 1969). This type of PHP is currently classified as PHP type-I, involving impaired urinary excretion of both cAMP and phosphate in response to PTH. The presence of AHO in this setting defines the subtype PHP-Ia. Another PHP subtype was later defined, characterized by normal cAMP response in the urine with blunted phosphaturic effect of exogenous PTH (PHP type-II) (Drezner et al. 1973).
As shown more than 40 years ago, guanine nucleotides play a critical role for ligand-induced generation of cAMP (Pohl et al. 1971; Rodbell et al. 1971). Guanine nucleotide binding proteins (G proteins) are a family of heterotrimeric proteins that are critically involved in cell signaling by transducing cell-surface receptor signals to intracellular messengers. Each G protein is defined by its α-subunits, which has an intrinsic GTP hydrolase activity. The stimulatory G protein transduces receptor activation to cAMP generation and is essential for the actions of numerous hormones, neurotramsmitters, and paracrine/autocrine factors. The α-subunit of the stimulatory G protein (Gsα) was purified in 1980 (Northup et al. 1980), allowing careful characterization of its biochemical properties. Consistent with the importance of the stimulatory G protein in many developmental processes, it has been shown that homozygous ablation of Gsα causes embryonic lethality during mid-gestation in mice (Chen et al. 2005; Germain-Lee et al. 2005; Yu et al. 1998).
Similar to other Gα subunits, Gsα has a guanosine diphosphate (GDP) molecule bound in the basal, inactive state. When a ligand binds to the G protein-coupled receptor, GDP is replaced with guanosine triphosphate (GTP), resulting in the dissociation of Gsα from the Gβ and Gγ subunits (Cabrera-Vera et al. 2003; Bourne et al. 1991; Syrovatkina et al. 2016). The GTP-bound Gsα can then activate its effectors, including Src tyrosine kinase and certain Ca-channels. The most ubiquitous and best-studied Gsα effector, however, is the membrane-bound adenylyl cyclase, which catalyzes the synthesis of cAMP from ATP (Cabrera-Vera et al. 2003; Bourne et al. 1991; Syrovatkina et al. 2016). The activation of Gsα is tightly regulated and time-limited, as the intrinsic GTP hydrolase activity regenerates GDP-bound Gsα and, thereby, allows reassembly of the heterotrimer, thus returning the system to the basal state (Cabrera-Vera et al. 2003; Bourne et al. 1991; Syrovatkina et al. 2016).
The actions of PTH are mediated by a G protein-coupled receptor, PTHR1, and the deficiency of PTH-induced cAMP generation in PHP-Ia reflects a defect in the stimulatory G protein. Accordingly, the activity of this G protein could be measured in erythrocytes and cultured fibroblasts from patients with PHP-Ia, revealing an approximately 50% activity compared to the normal population (Levine et al. 1986; Patten and Levine 1990; Levine et al. 1988). Furthermore, it was shown that the protein and mRNA levels of the α-subunit of Gs (Gsα) were reduced in most cases with this disorder (Patten and Levine 1990; Levine et al. 1988).
In 1990, Patten et al. identified a heterozygous inactivating mutation in the gene encoding Gsα (GNAS) in a patient with PHP-Ia and his affected mother (Patten et al. 1990). In the same year, Weinstein et al. also revealed a heterozygous mutation in the GNAS gene in a kindred with PHP-Ia (Weinstein et al. 1990).
GNAS Complex Locus
Gsα transcripts are subject to alternative splicing that generates several variants. There is a long and a short Gsα transcript generated by alternative splicing of the 45-bp exon 3 that encodes 15 amino acids. These transcript variants lead to proteins with electrophoretic motilities of 52 and 45 kDa, respectively. Biochemical characterizations have indicated minor, but potentially significant, differences between the activities of these two Gsα variants. For example, it has been shown, by using partially purified proteins from rabbit liver, that the long Gsα variant has a greater ability to transduce receptor activation than does the short variant (Sternweis et al. 1981), although another study suggested the opposite upon experiments using cultured pancreatic islet cells (Walseth et al. 1989). It remains currently unclear whether the long and the short Gsα variants differ from one another in a biologically significant manner. Additionally, another alternative Gsα transcript occurs by the use of a noncanonical TG 3′-splice site preceding exon 4, leading to inclusion of an extra triplet coding for a serine residue after amino acids 87 and 72 of the long and short forms of Gsα, respectively. These four alternative transcripts show tissue-dependent alternative splicing and may provide different regulatory properties (Kozasa et al. 1988; Novotny and Svoboda 1998). In addition, an alternative splicing of exon 3 occurs onto exon N1, which is located in intron 3, leading to the formation of a C-terminally truncated Gsα protein that is expressed in neural tissues (Crawford et al. 1993).
The promoter of Gsα does not have CpG dinucleotide methylation, unlike the promoters of other GNAS transcripts (see below). Accordingly, Gsα expression is biallelic in most tissues, including bone, white adipose tissue, and blood lymphocytes. However, the expression is predominantly from the maternal GNAS allele in a small set of tissues including renal proximal tubules, thyroid, testes, pituitary, and some parts of the brain (Hayward et al. 1998a, b, 2001; Campbell et al. 1994; Mantovani et al. 2002). Histone methylation status at the Gsα promoter is consistent with the expression profile of Gsα. The Gsα promoter and first exon have similar levels of histone acetylation and H3K4 methylation in both parental alleles and no H3K9 methylation. In liver, where Gsα is biallelically expressed, Gsα first exon shows similar levels of tri- and dimethylated H3K4 in both parental alleles. In contrast, in renal proximal tubules, where the paternal allele is silenced, a greater ratio of tri- to dimethylated H3K4 of Gsα exon 1 exists on maternal as compared with the paternal allele. Thus, the allele-specific differences in histone modifications are tissue-specific, and activation of the Gsα promoter is correlated with trimethylation of H3K4 (Sakamoto et al. 2004). The tissue-specific, monoallelic expression of Gsα plays an important role in the phenotypes resulting from genetic or epigenetic alterations of GNAS (see below).
Extra Large αs (XLαs) Transcript
XLαs is a large variant of Gsα, which was first identified as a novel target of cholera toxin in the pheochromocytoma-derived cell line PC12 cells (Kehlenbach and Huttner 1994). XLαs is abundantly expressed in brain, cerebellum, and neuroendocrine tissues, such as pituitary and adrenal medulla; however, its expression is readily detectable in multiple other tissues, including pancreas, kidney, bone, and muscle (Kehlenbach and Huttner 1994; Liu et al. 2011a; Krechowec et al. 2012; Pasolli and Huttner 2001; Pasolli et al. 2000). XLαs is partly identical to Gsα, since the first exon of XLαs splices onto exons 2–13 encoding Gsα. The promoter and the first exon of XLαs are located in a differentially methylated region (DMR), and it has been shown that XLαs expression is exclusively driven by the unmethylated paternal promoter in most tissues (Hayward et al. 1998a). However, a single study demonstrated biallelic XLαs expression in clonal human bone marrow stromal cells (Michienzi et al. 2007).
The alternative splicing of exon 3 or exon N1 that occurs in the Gsα transcript also takes place in the XLαs transcript, leading to various different XLαs variants. No studies have been conducted regarding the functional significance of these variants in the XLαs backbone. In addition, the first exon of XLαs comprises a second open reading frame (ORF), giving rise to another translated protein termed ALEX. Thus, the XLαs mRNA produces both XLαs and ALEX at the same time (Klemke et al., 2001). Strikingly, XLαs and ALEX interact with each other. A study has suggested that the interaction between XLαs and ALEX diminishes the ability of XLαs to mediate cAMP generation (Freson et al. 2003). XLαs transcription starts in the middle of an ORF based on the genomic sequence in this region (Kehlenbach and Huttner 1994). Addition of those in-frame N-terminal residues, which are highly conserved, generates another XLαs variant, termed XXLαs, which shows a different tissue distribution profile (Abramowitz et al. 2004; Aydin et al. 2009). This extended ORF also includes a larger second ORF, resulting in an N-terminally extended ALEX, termed ALEXX (Abramowitz et al. 2004).
The N-terminal domain of XLαs, encoded by its first exon, comprises multiple proline-rich amino acid motifs, a highly conserved proline-rich region, and a highly conserved region of charged residues. While these features are unique to XLαs, the remaining portion of XLαs protein is identical to Gsα protein over a long stretch of amino acids encoded by exons 2–13. Accordingly, XLαs is able to bind to G protein beta and gamma subunits and mediate receptor-stimulated cAMP production (Klemke et al. 2000; Bastepe et al. 2002). It has been clearly shown that XLαs, when overexpressed, mimics Gsα in transfected cells and transgenic mice (Liu et al. 2011b; Linglart et al. 2006). XLαs seems to have a higher basal activity than Gsα and remains localized to the plasma membrane after activation, as opposed to Gsα, which is subject to activation-induced redistribution to the cytosol (Liu et al. 2011a; Mariot et al. 2011). However, ablation of XLαs in mice leads to a phenotype that markedly differs from the phenotype observed in mice in which either paternal or the maternal allele of Gsα is ablated (Chen et al. 2005; Germain-Lee et al. 2005; Plagge et al. 2004). While Gsα ablation alone (by deleting exon 1) phenocopies PHP-Ia and PPHP depending on the parental inheritance, XLαs ablation leads to early postnatal lethality with poor feeding, hypoglycemia, and growth retardation. Thus, XLαs is predicted to have cellular roles that are entirely distinct from the roles of Gsα. It has recently been shown that XLαs ablation in mice causes, at least in renal proximal tubules, reduced signaling downstream of phospholipase C, which is an effector stimulated typically by Gq/11 (He et al. 2015). Accordingly, overexpression of XLαs in transfected cells or in mouse proximal tubule also increases IP3 generation and PKC expression levels (He et al. 2015), indicating that XLαs could have a similar function to Gq/11α, as well.
It has been suggested that XLαs deficiency plays a role in the pathogenesis of progressive osseous heteroplasia (see below) because of the almost exclusive paternal inheritance of GNAS mutations in this disorder. Loss of XLαs activity has also been implicated in the intrauterine growth retardation observed often in patients with pseudo-pseudohypoparathyroidism and in patients with either large paternal GNAS deletions or maternal uniparental disomy of chromosome 20. Moreover, altered XLαs expression/activity is associated with certain platelet defects, congenital hyperinsulinism, 20q-amplified breast cancers, and some tumors seen in patients with McCune-Albright syndrome. In addition, XLαs hyperactivity may contribute to other tumors with increased GNAS copy number and those carrying activating GNAS mutations (Turan and Bastepe 2015; Weinstein et al. 2004).
Neuroendocrine secretory protein of Mr 55,000 (NESP55) is another GNAS transcript. NESP55 is a member of the granin family, a group of proteins that play important roles in endocrine and neuronal secretory pathways, involved in neuroendocrine, cardiovascular, and endocrine systems, as well as inflammatory responses (Bauer et al. 1999; Weiss et al. 2000). NESP55 transcript uses its first exon located 47 kb upstream of exon 1, which also splices onto Gsα exons 2–13; however, the latter exons constitute the 3′-untranslated region. Thus, NESP55 shares no amino acid identity with Gsα. The promoter and the first exon of NESP55 are located in a DMR, but in contrast to XLαs, NESP55 is expressed exclusively from the maternal allele (Hayward et al. 1998b).
Two main splice variants of NESP55 have been identified from sequencing clones obtained from human pheochromocytoma and rat pituitary cDNA libraries. When NESP55 exon is spliced onto GNAS exons 2 to 13, the 2400-bp variant, and when NESP55 exon is spliced onto GNAS exons 2, 3, and N1, the shorter 1800-bp variant is produced (Weiss et al. 2000). The human NESP55 ORF encodes a protein in the size of about 28 kD, which shows high homology to rat Nesp55, especially over the first 70 amino acids. The longer transcript is expressed in adrenal medulla, pituitary, and locus coeruleus and the shorter transcript only in pituitary in rats (Bauer et al. 1999). Additional biochemical analysis of rat Nesp55 protein suggests that NESP55 is a keratan sulfate proteoglycan, similar to the other chromogranins. Nesp55 is proteolytically processed into smaller peptides in several rat tissues including a predominant GPIPIRRH peptide, which is also found in human NESP55 (Bauer et al. 1999; Weiss et al. 2000; Kim et al. 2000).
In mice, ablation of Nesp55 results in mild behavioral defects, including abnormal reactivity to novel environments (Plagge et al. 2005). In humans, on the other hand, no discernible defects seem to result from the loss of NESP55, as judged by the findings in patients with PHP type-Ib (PHP-Ib), who display GNAS methylation abnormalities (see below). Nevertheless, a study has shown that transcription from the NESP55 promoter is required for the establishment of maternal methylation imprints at the GNAS locus, indicating the importance of this transcript in the regulation of GNAS imprinting (Chotalia et al. 2009).
Exon A/B is the closest upstream first exon to those encoding Gsα, located ~2.5 kb upstream from exon 1 (Ishikawa et al. 1990; Liu et al. 2000, Swaroop et al. 1991). It has been shown that the promoter of A/B is maternally methylated, driving expression of this transcript from the nonmethylated paternal allele (Liu et al. 2000). The methylation at this site is present in the oocyte, that is, it is a germ-line imprint, unlike the methylation imprints at the promoters of NESP55 and XLαs (Liu et al. 2000). The exon A/B DMR shows allele-specific histone acetylation and methylation, with histone acetylation and H3K4 methylation of the paternal allele, and H3K9 methylation of the maternal allele in mice (Sakamoto et al. 2004).
An amino-terminally truncated Gsα variant can be translated from the A/B transcript, and it has been suggested that this protein variant can inhibit Gsα signaling (Ishikawa et al. 1990; Puzhko et al. 2011). Nevertheless, the A/B transcript per se may have a regulatory role within GNAS. Ablation of the paternal exon A/B derepresses Gsα transcription in cis in those tissues in which Gsα is monoallelic, indicating that the first exon of A/B or the A/B transcript is a critical regulator of allelic Gsα expression (Liu and Weinstein 2005; Williamson et al. 2004). Eaton et al. have prematurely truncated the A/B transcript in mice to address the role of A/B transcription in this regulation (Eaton et al. 2012). Although the results were consistent with a mechanism whereby transcription from the paternal A/B promoter silences the downstream Gsα promoter in cis, the findings did not entirely rule out the possible involvement of a trans-acting factor that binds to the region comprising exon of A/B (Eaton et al. 2012).
Adding further complexity to the GNAS locus, another transcript is derived from the antisense strand (Hayward and Bonthron 2000; Wroe et al. 2000). The first exon of GNAS-AS1 is located just upstream of XLαs, such that the promoter regulatory regions of the two transcripts are overlapping (Williamson et al. 2006). The mature GNAS1-AS1 transcript, which is detected in all tissues, is spliced and contains at least five exons; however, this transcript is noncoding. The promoter of GNAS-AS1 is also maternally methylated and comprises a region in which the methylation is present in the female germ line (Coombes et al. 2003). Accordingly, the GNAS-AS1 transcript is expressed exclusively from the paternal allele (Hayward and Bonthron 2000; Wroe et al. 2000). The primary transcript traverses the first exon and the promoter of NESP55. Williamson et al. have shown by generating a mouse model that GNAS-AS1 is required for the silencing of NESP55 on the paternal allele (Williamson et al. 2006). The same group of investigators has also shown that the action of GNAS-AS1 in this regard involves reduction of H3K4 methylation at the NESP55 promoter that likely precedes the gain of DNA methylation (Williamson et al. 2011).
The Genetic and Epigenetic Changes of GNAS in Human Disease
Activating-Inactivating Mutations in Gsα-Coding GNAS Exons
Classification of PHP according to phenotypic and biochemical features
Additional hormone resistances
Urinary cAMP and phosphate to PTH
Erythrocyte Gsα activity
(OMIM # 612463)
(OMIM # 603233)
Inactivating Gsα mutations are scattered all through Gsα-coding GNAS exons; however, a 4-bp deletion in exon 7 is the most common defect (Aldred and Trembath 2000). Inactivating Gsα mutations have also been identified in patients with progressive osseous heteroplasia (POH), a disorder characterized by heterotopic ossifications that not only occur in the skin and subcutis but also invade the deep connective tissue and skeletal muscle (Kaplan and Shore 2000). The same Gsα mutation can cause either POH or PHP-Ia/PPHP, and thus, POH appears to be an extreme presentation of ectopic ossifications observed in patients with AHO. However, a recent study has shown that POH lesions often affect one side of the body and follow dermomyotomes, suggesting that additional defects acquired during embryonic development contribute to the pathogenesis (Cairns et al. 2013). Moreover, there seems to be a significant bias in the parental origin of mutations that lead to POH, as it was shown in a number of families that POH develops after inheriting the GNAS mutation from a father (Shore et al. 2002).
The spectrum of phenotypes associated with loss-of-function Gsα mutations have been expanded with additionally described patients. It was shown that two male patients with PHP-Ia and testotoxicosis had a Gsα A366S mutation, which confers low affinity for GDP and thus constitutive activity. The hormone-independent cAMP generation at baseline results in the overproduction of testosterone in testis, in which the ambient temperature is lower than 37 °C. The mutant, however, is rapidly degraded at 37 °C, thus causing Gsα deficiency and hormone resistance in other tissues (Iiri et al. 1994; Nakamoto et al. 1996). Another example of both activating and inactivating functional outcome is a 12-bp in-frame insertion. The patients with this mutation (insertion of AVDT amino acids) displayed PHP-Ia in combination with neonatal diarrhea. Biochemical and intact cell studies showed that the mutant protein is unstable but constitutively active due to rapid GDP release and reduced GTP hydrolysis. The PHP-Ia phenotype is due to the instability of the Gsα-AVDT mutant, and the concomitant neonatal diarrhea is related to enhanced constitutive Gsα activity in the intestine (Makita et al. 2007). Gsα-AVDT is predominantly localized to the cytosol, but in the small intestine epithelial cells, it is localized to the plasma membrane – where adenylyl cyclase is localized – due to reduced depalmitylation of Gsα upon activation (Makita et al. 2007).
Gsα-activating mutations in the GNAS gene cause McCune-Albright Syndrome (MAS, OMIM # 174800), isolated polyostotic fibrous dysplasia (POFD), and several endocrine tumors, such as growth hormone-secreting pituitary adenomas. These Gsα mutations have also been identified in a number of nonendocrine tumors, such as intrapancreatic mucinous neoplasms and renal clear cell carcinoma. MAS is characterized by POFD combined with hyperpigmented skin lesions (café-au-lait spots) and overactive endocrine hormones (McCune and Bruch 1937; Albright et al. 1937). The mutations, specific to codons 201 and 227, lead to constitutive activation of Gsα protein (Landis et al. 1989). Patients with MAS and POFD are mosaic for these activating mutations, which are acquired postzygotically during early embryonic development. Germline activating mutations are considered to be lethal for the embryo, since no patient with germline activating mutation has been detected (Aldred and Trembath 2000; Lumbroso et al. 2004; Happle 1986).
Almost 40% of growth hormone-secreting pituitary adenomas contain somatic mutations in GNAS either at R201 or Q227 (Hayward et al. 2001; Landis et al. 1989; Landis et al. 1990; Lyons et al. 1990; Yang et al. 1996). The mutation was found to be on the maternal allele in 21 of 22 GNAS-positive somatotroph adenomas, consistent with monoallelic maternal expression of Gsα in normal adult pituitary tissue. However, this monoallelic expression of Gsα was frequently relaxed in somatotroph tumors regardless of GNAS mutation status, suggesting a possible pathogenetic role for loss of Gsα imprinting in pituitary somatotroph tumor development (Hayward et al. 2001).
PHP-Ib is another subtype of PHP characterized by PTH resistance and associated biochemical abnormalities in the absence of AHO (Frame et al. 1972). Nearly all patients with this disorder demonstrate a loss of exon A/B methylation on the maternal allele, combined with biallelic A/B expression (Liu et al. 2000; Bastepe et al. 2001). Furthermore, broad methylation defects of GNAS DMRs with gain of methylation at the NESP55 promoter and loss of methylation at XLαs, GNAS-AS1, and A/B promoters have been shown in many sporadic cases of PHP-Ib (Liu et al. 2000; Liu and Weinstein 2005). In some cases with broad GNAS methylation defects, the underlying genetic defect is paternal uniparental disomy affecting chromosome 20 (Bastepe et al. 2001). In familial cases with PHP-Ib, a recurrent 3-kb heterozygous microdeletion approximately 220 kb centromeric of GNAS exon A/B has been detected, and the PHP-Ib cases carrying this deletion show isolated loss of A/B methylation and inherit the deletion from the mother; paternal transmission of the deletion do not cause the methylation defect and are, thus, not disease-causing (Bastepe et al. 2003). The 3-kb deletion also removes three of eight exons encoding syntaxin-16 (STX16), which is not an imprinted gene (Bastepe et al. 2003; Linglart et al. 2005). A 4.4-kb and a 24.6-kb microdeletion overlapping with the 3-kb deletion in STX16 has also been identified in two different families with isolated A/B loss of methylation, in whom affected individuals inherited the deletion from female obligate carriers (Linglart et al. 2005; Elli et al. 2014). These deletions likely disrupt a putative cis-acting element required for methylation at exon A/B in humans. Additionally, in a single kindred, individuals with isolated loss of A/B methylation without any STX16 deletions have been found to have a maternally inherited 19-kb deletion removing exon NESP55 and the upstream genomic region (Richard et al. 2012). Thus, the methylation at A/B is likely to be regulated by another cis-acting element in this region. This could be the NESP55 transcript itself, as premature truncation of this transcript in mice leads to loss of methylation at A/B in an isolated manner or in combination with other maternal Gnas imprints (Chotalia et al. 2009).
Some familial PHP-Ib cases show broad methylation defects in multiple GNAS DMRs. The deletions of all or part of the NESP55 DMR including exon NESP55 and exons 3 and 4 of the GNAS-AS1 transcript have been identified in three unrelated PHP-Ib families with affected individuals having broad methylation defects in all GNAS DMRs (Chillambhi et al. 2010; Bastepe et al. 2005). The deletions are nearly identical and remove the entire NESP55 DMR in two families (Bastepe et al. 2005). The deletion in the third family preserved the sequences of exon NESP55 but removed GNAS-AS1 exons 3–4 and a significant portion of intron 2 (Chillambhi et al. 2010). Although NESP55 was preserved genetically, patients with maternal deletions showed incomplete gain of NESP55 methylation. Moreover, paternal inheritance of the same deletion in the family members resulted in incomplete loss of NESP55 methylation and an incomplete gain of A/B methylation (Chillambhi et al. 2010). Based on these findings, it appears likely that the genomic region spanning GNAS-AS1 exons 3–4 comprises a cis-acting element necessary for the maintenance of all maternal GNAS methylation imprints.
Sporadic, nonfamilial PHP-Ib cases also show epigenetic changes involving multiple GNAS DMRs (Liu and Weinstein 2005). However, clinical features of sporadic PHP-Ib patients are similar to the familial PHP-Ib cases (Jüppner 2007). The genetic cause or other mechanisms underlying these methylation abnormalities, other than paternal uniparental disomy involving this chromosomal region, remain unknown.
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