Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: GNAS
SNOMEDCT: 237659007, 404074003, 58833000, 71304002, 717792007, 719271000;
Cytogenetic location: 20q13.32 Genomic coordinates (GRCh38): 20:58,839,748-58,911,192 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.32 | ACTH-independent macronodular adrenal hyperplasia | 219080 | Somatic mutation | 3 |
| McCune-Albright syndrome, somatic, mosaic | 174800 | 3 | ||
| Osseous heteroplasia, progressive | 166350 | Autosomal dominant | 3 | |
| Pituitary adenoma 3, multiple types, somatic | 617686 | 3 | ||
| Pseudohypoparathyroidism Ia | 103580 | Autosomal dominant | 3 | |
| Pseudohypoparathyroidism Ib | 603233 | Autosomal dominant | 3 | |
| Pseudohypoparathyroidism Ic | 612462 | Autosomal dominant | 3 | |
| Pseudopseudohypoparathyroidism | 612463 | Autosomal dominant | 3 |
GNAS is a complex imprinted locus that produces multiple transcripts through the use of alternative promoters and alternative splicing. The most well-characterized transcript derived from GNAS, Gs-alpha, encodes the alpha subunit of the stimulatory guanine nucleotide-binding protein (G protein). Gs-alpha is expressed biallelically in nearly all tissues and plays essential roles in a multitude of physiologic processes. Other transcripts produced by GNAS are expressed exclusively from either the paternal or the maternal GNAS allele (Bastepe and Juppner, 2005).
Overview of Transcripts Produced by GNAS
The GNAS locus is imprinted and encodes 4 main transcripts, Gs-alpha, XLAS, NESP55, and the A/B transcript, as well as an antisense GNAS transcript (GNASAS; 610540). The 4 main transcripts are produced through the use of alternative promoters and splicing of 4 unique first exons onto the shared exons 2 through 13. Gs-alpha is ubiquitously expressed and encodes a protein that stimulates adenylyl cyclase when activated by an agonist-occupied G protein-coupled receptor, thereby generating the second messenger cAMP. Gs-alpha is biallelically expressed except in a small number of tissues, including renal proximal tubules, thyroid, gonads, and pituitary, where it is predominantly expressed from the maternal GNAS allele. XLAS is a large variant of Gs-alpha that is expressed exclusively from the paternal GNAS allele, primarily in neuroendocrine tissues and the nervous system. The XLAS and Gs-alpha proteins are identical over their C-terminal portions, but they have distinct N termini. NESP55 is exclusively expressed from the maternal GNAS allele and encodes a chromogranin (see 118910)-like neuroendocrine secretory protein that, due to a stop codon in its unique first exon, shares no amino acid sequence with Gs-alpha. The A/B transcript, which uses the alternative first exon A/B (also referred to as exon 1A or 1-prime), and the antisense GNAS transcript, which consists of exons that do not overlap with any other GNAS exons, are ubiquitously expressed noncoding transcripts that are derived exclusively from the paternal GNAS allele. Consistent with their parent-specific expression, the promoters of the XLAS, NESP55, A/B, and antisense transcripts are within differentially methylated regions (DMRs), and in each case the nonmethylated promoter drives expression. In contrast, the promoter for Gs-alpha lacks methylation and is biallelically active in most tissues (Bastepe and Juppner, 2005).
Gs-Alpha Transcript
Using oligonucleotide probes for recombinants that code for alpha subunits of G signal transduction proteins, Bray et al. (1986) screened human brain cDNA libraries and identified 11 clones corresponding to 4 species of Gs-alpha cDNA. One of the clones was predicted to encode a 384-amino acid protein with homology to the bovine and rat Gs-alpha proteins. The 4 clones differed in nucleotide sequence in the region that codes for amino acid residues 71 to 88. Two forms corresponded to proteins with molecular masses of 52 and 45 kD. The authors suggested alternative splicing of a single precursor mRNA.
A/B Transcript
Ishikawa et al. (1990) reported a Gs-alpha mRNA that uses a different promoter and exon, which they termed exon 1-prime (later termed exon 1A or A/B) that is located 2.5 kb upstream of GNAS exon 1. Exon 1-prime does not contribute an in-frame ATG, and thus its mRNA may encode a truncated form of Gs-alpha.
XLAS Transcript
By restriction landmark genomic scanning, Hayward et al. (1998) identified a differentially methylated locus containing a previously undescribed GNAS1 exon. This exon was included within transcripts homologous to an mRNA encoding the large G protein XL-alpha (s) in the rat (Kehlenbach et al., 1994). Two restriction sites flanking this exon were methylated on a maternal allele and unmethylated on a paternal allele. RT-PCR of human fetal tissues showed that in contrast to Gs-encoding transcripts, which were biallelic, mRNAs encoding XLAS were derived exclusively from the paternal allele. The paternally active alternative promoter was located 35 kb upstream of exon 1.
In rat, the paternally expressed XLAS gene is a splice variant of GNAS, consisting of exon 1 of XL and exons 2 to 13 of GNAS. A second open reading frame in XL exon 1, which completely overlaps the XL domain ORF, encodes ALEX (alternative gene product encoded by the XL exon), which is translated from the XLAS mRNA and binds the XL domain of XLAS (Klemke et al., 2001).
NESP55 Transcript
Hayward et al. (1998) identified a second promoter upstream of the Gs-alpha site in addition to that for XLAS. Both upstream promoters were associated with a large coding exon and showed opposite patterns of allele-specific methylation and monoallelic transcription. The more 5-prime of these exons encoded the neuroendocrine secretory protein-55 (NESP55), which was expressed exclusively from the maternal allele. The NESP55 exon is 11 kb 5-prime to the paternally expressed XLAS exon. The transcripts from these 2 promoters both splice onto GNAS1 exon 2, yet share no coding sequences. Despite their structural unrelatedness, the encoded proteins, of opposite allelic origin, have both been implicated in regulated secretion in neuroendocrine tissues. Hayward et al. (1998) concluded that maternally (NESP55), paternally (XLAS), and biallelically (Gs-alpha)-derived proteins are produced by different patterns of promoter use and alternative splicing of GNAS1, a gene showing simultaneous imprinting in both the paternal and maternal directions.
By sequencing clones obtained from human pheochromocytoma and rat pituitary cDNA libraries, Weiss et al. (2000) identified 2 main splice variants that included NESP55 sequences. In the 2,400-bp variant, NESP55 exons were spliced onto GNAS exons 2 to 13, and in the shorter 1800-bp variant, NESP55 exons were spliced onto GNAS exons 2, 3, and N1. Several cDNA clones contained inverted repeats on either the 5-prime or 3-prime terminus, and heterogeneity in the GNAS region, such as deletion of exon 3 or insertion of a CAG trinucleotide after exon 3, was also found. The 2,400-bp variant contains an open reading frame (ORF) encoding the NESP55 protein and an ORF encoding a truncated form of GNAS lacking exon 1. The sequence TAATG encodes the stop codon (TAA) of the NESP55 ORF as well as the initiating methionine (ATG) of the truncated GNAS. The human NESP55 ORF encodes a protein of about 28 kD, which has high homology with rat Nesp55, particularly in the first 70 amino acids. Northern blot analysis and RT-PCR detected the longer transcript in rat adrenal medulla, pituitary, and locus ceruleus, and the shorter transcript only in pituitary. Biochemical analysis indicated that rat Nesp55 is a keratan sulfate proteoglycan, and like other chromogranins, Nesp55 was proteolytically processed into smaller peptides in several rat tissues, including a predominant GPIPIRRH peptide that is also found in human NESP55.
GNAS Antisense Transcript
Hayward and Bonthron (2000) described a spliced polyadenylated antisense transcript (GNASAS; 610540) arising from the maternally methylated region upstream of the XL-alpha-s exon, which spans the upstream NESP55 region. The antisense transcript is imprinted, and expressed only from the paternal allele, suggesting to the authors that it may have a specific role in suppressing in cis the activity of the paternal NESP55 allele. For further information on the GNAS antisense transcript, see 610540,
Rickard and Wilson (2003) provided a schematic representation of the GNAS locus. Exons 1 through 13 of GNAS produce the Gs-alpha transcript. Imprinted first exons specifically used for the NESP55, XLAS, and exon 1A transcripts are located approximately 35, 14, and 2.5 kb upstream of GNAS exon 1, respectively. These exons are spliced to GNAS exons 2 through 13. The GNAS antisense transcript originates upstream of the XLAS exon. An alternative 3-prime exon, located within GNAS intron 3, includes an alternative stop codon and polyadenylation site.
Bastepe and Juppner (2005) noted that the promoter regions associated with the imprinted NESP55, XLAS, exon A/B, and antisense transcripts are located within differentially methylated regions. In each case, the nonmethylated promoter drives expression of the transcript. In contrast, the Gs-alpha promoter lacks methylation and is biallelically active in most tissues.
Using a cDNA probe in connection with a mouse/human somatic cell hybrid panel, Sparkes et al. (1987) mapped the gene encoding the alpha-stimulating polypeptide of G protein to chromosome 20. (See also Blatt et al. (1988).) Ashley et al. (1987) mapped the corresponding gene in the mouse to chromosome 2 which, by the argument of homology of synteny, supports the assignment of the human stimulatory G protein gene to chromosome 20.
Gejman et al. (1991) mapped the GNAS1 gene to the distal long arm of chromosome 20 by linkage studies using a polymorphism detected by denaturing gradient gel electrophoresis (DGGE). A maximum lod score of 9.31 was obtained at a theta of 0.042 with the locus D20S15, previously reported to be on the long arm of chromosome 20 (Donis-Keller et al., 1987).
By in situ hybridization, Rao et al. (1991) assigned the GNAS1 gene to chromosome 20q12-q13.2. Using the same method, Levine et al. (1991) mapped the GNAS1 gene to chromosome 20q13.2-q13.3.
G Protein Family
G proteins transduce extracellular signals received by transmembrane receptors to effector proteins. The activity of hormone-sensitive adenylate cyclase is regulated by at least 2 G proteins, 1 stimulatory (Gs) and 1 inhibitory (Gi; see 139310). A third G protein, Go (139311), is abundant in brain. Each G protein is a heterotrimer composed of an alpha, beta, and gamma subunit. The GNAS locus encodes Gs-alpha, the alpha subunit of the G stimulatory protein. Each of the 3 G protein subunits is encoded by a member of 1 of 3 corresponding gene families. Hurowitz et al. (2000) counted 16 different members of the alpha subunit family, 5 different members of the beta subunit family, and 11 different members of the gamma subunit family, as described in mammals. Using BACs, they determined the gene structure and chromosome location of each gene. The G protein family includes transducin (189970).
Crystal Structure
Rasmussen et al. (2011) presented the crystal structure of the active state ternary complex composed of agonist-occupied monomeric beta-2-adrenergic receptor (AR) (ADRB2; 109690) and nucleotide-free Gs heterotrimer. The principal interactions between the beta-2-AR and Gs involve the amino- and carboxy-terminal alpha-helices of Gs, with conformational changes propagating to the nucleotide-binding pocket. The largest conformational changes in the beta-2-AR include a 14-angstrom outward movement at the cytoplasmic end of transmembrane segment 6 and an alpha-helical extension of the cytoplasmic end of transmembrane segment 5. The most surprising observation is a major displacement of the alpha-helical domain of G-alpha-s relative to the Ras-like GTPase domain.
Chung et al. (2011) applied peptide amide hydrogen-deuterium exchange mass spectrometry to probe changes in the structure of the heterotrimeric bovine G protein, Gs, on formation of a complex with agonist-bound human beta-2-AR, and reported structural links between the receptor-binding surface and the nucleotide-binding pocket of Gs that undergo higher levels of hydrogen-deuterium exchange than would be predicted from the crystal structure of the beta-2-AR-Gs complex. Together with x-ray crystallographic and electron microscopic data of the beta-2-AR-Gs complex, Chung et al. (2011) provided a rationale for a mechanism of nucleotide exchange, whereby the receptor perturbs the structure of the amino-terminal region of the alpha-subunit of Gs and consequently alters the 'P-loop' that binds the beta-phosphate in GDP.
Function of Gs-Alpha Protein
Mehlmann et al. (2002) demonstrated that meiotic arrest of the oocyte can be released in mice by microinjecting the oocyte within the follicle with an antibody that inhibits Gs. This indicates that Gs activity in the oocyte is required to maintain meiotic arrest within the ovarian follicle and suggests that the follicle may keep the cell cycle arrested by activating Gs.
Harrison et al. (2003) demonstrated that signaling via the erythrocyte ADRB2 and heterotrimeric G-alpha-s regulated the entry of the human malaria parasite Plasmodium falciparum. Agonists that stimulate cAMP production led to an increase in malarial infection that could be blocked by specific receptor antagonists. Moreover, peptides designed to inhibit G-alpha-s protein function reduced parasitemia in P. falciparum cultures in vitro, and beta-antagonists reduced parasitemia of P. berghei infections in an in vivo mouse model. Harrison et al. (2003) suggested that signaling via erythrocyte ADRB2 and G-alpha-s may regulate malarial infection across parasite species.
Adams et al. (2009) demonstrated that hematopoietic stem and progenitor cell (HSPC) engraftment of bone marrow in fetal development is dependent on G-alpha-S. The authors observed that HSPCs from adult mice deficient in G-alpha-S differentiated and underwent chemotaxis, but did not home to or engraft in the bone marrow in adult mice, and demonstrated a marked inability to engage the marrow microvasculature. Deletion of G-alpha-S after engraftment did not lead to lack of retention in the marrow; rather, cytokine-induced mobilization into the blood was impaired. In tests of the effect of G-alpha-S activation on HSPCs, pharmacologic activators enhanced homing and engraftment in vivo. Adams et al. (2009) concluded that G-alpha-S governs specific aspects of HSPC localization under physiologic conditions in vivo and may be pharmacologically targeted to improve transplantation efficiency.
Imprinting of GNAS
Hall (1990) noted that the region of chromosome 20 occupied by the Gs-alpha gene is homologous to an area of mouse chromosome 2 involved in both maternal and paternal imprinting.
Campbell et al. (1994) presented evidence suggesting that GNAS1 is biallelically expressed in a wide range of human fetal tissues. Of 75 fetuses genotyped, 13 heterozygous for a FokI polymorphism in GNAS1 were identified whose mothers were homozygous for one or another allele. Analysis of GNAS1 RNA from each fetus showed expression from both parental alleles. No tissue-specific pattern of expression was discerned. Campbell et al. (1994) concluded that if genomic imprinting regulates the expression of the GNAS1 gene, the effect must either be subtle and quantitative or be confined to a small subset of specialized hormone-responsive cells within the target tissues.
Hayward et al. (2001) investigated GNAS1 imprinting in the normal adult pituitary and found that Gs-alpha was monoallelically expressed from the maternal allele in this tissue. They found that this monoallelic expression of Gs-alpha was frequently relaxed in somatotroph tumors regardless of GNAS1 mutation status. These findings implied a possible role for loss of Gs-alpha imprinting during pituitary somatotroph tumorigenesis and also suggested that Gs-alpha imprinting is regulated separately from that of the other GNAS1 products, NESP55 and XL-alpha-s, which retain maternal and paternal imprinting, respectively, in these tumors.
To establish if the GNAS1 gene is imprinted in human endocrine tissues, Mantovani et al. (2002) selected 14 thyroid, 10 granulosa cell, 13 pituitary (3 normal glands, 7 GH-secreting adenomas, and 3 nonfunctioning adenomas), 3 adrenal, and 11 lymphocyte samples shown to be heterozygous for a known polymorphism in exon 5. RNA from these tissues was analyzed by RT-PCR, and expression from both parental alleles was evaluated by enzymatic digestion and subsequent quantification of the resulting fragments. Most thyroid, ovarian, and pituitary samples showed an almost exclusive or significantly predominant expression of the maternal allele over the paternal one, whereas in lymphocyte and adrenal samples both alleles were equally expressed. The authors concluded that their results provided evidence for a predominant maternal origin of GNAS1 transcripts in different human adult endocrine tissues, particularly thyroid, ovary, and pituitary.
Using hot-stop PCR analysis on total RNA from 6 normal human thyroid specimens, Liu et al. (2003) showed that the majority of the Gs-alpha mRNA (72 +/- 3%) was derived from the maternal allele. This was considered consistent with the presence of TSH (see 188540) resistance in patients with maternal Gs-alpha-null mutations (PHP 1a; 103580) and the absence of TSH resistance in patients with paternal Gs-alpha mutations (pseudopseudohypoparathyroidism). Patients with PTH (168450) resistance in the absence of Albright hereditary osteodystrophy (PHP1B; 603233) have an imprinting defect of the Gs-alpha gene resulting in both alleles having a paternal epigenotype, which would lead to a more moderate level of thyroid-specific Gs-alpha deficiency. The authors found evidence of borderline TSH resistance in 10 of 22 PHP Ib patients. The authors concluded that their study provided further evidence for tissue-specific imprinting of Gs-alpha in humans and provided a potential mechanism for mild to moderate TSH resistance in PHP Ia and borderline resistance in some patients with PHP Ib.
Liu et al. (2000) showed that the human GNAS exon 1A promoter region (2.5 kb upstream from exon 1) is imprinted in a manner similar to that in the mouse: the region is normally methylated on the maternal allele and unmethylated on the paternal allele. In 13 patients with pseudohypoparathyroidism Ib, the exon 1A region was unmethylated on both alleles, and was thus biallelically expressed. Liu et al. (2000) proposed that the exon 1A differentially methylated region (DMR) is important for establishing or maintaining tissue-specific GNAS imprinting and that loss of exon 1A imprinting is the cause of PHP Ib. (See also Bastepe et al. (2001, 2001).)
Freson et al. (2002) described a PHP Ib patient with lack of methylation of the exon XL and 1A promoters, and biallelic methylation of the NESP55 promoter. Platelets of this patient showed a functional Gs defect, decreased cAMP formation upon Gs-receptor stimulation, and normal Gs-alpha sequence, but reduced Gs-alpha protein levels. The authors hypothesized that transcriptional deregulation between the biallelically active promoters of both exon 1A and exon 1 of Gs-alpha could explain the decreased Gs-alpha expression in platelets and presumably in the proximal renal tubules. Platelets demonstrated decreased NESP55 and increased XL-alpha-s protein levels, in agreement with the methylation status of their corresponding first exons. In a megakaryocytic cell line MEG-01, exon 1A is methylated on both alleles, in contrast to the normally maternally methylated exon 1A in leukocytes. Experimental demethylation of exon 1A in MEG-01 cells led to reduced Gs-alpha expression, in agreement with the observations in the patient. The authors proposed that platelet studies may allow more facile evaluation of disturbances of the GNAS1 cluster in PHP Ib patients.
Genomic imprinting, by which maternal and paternal alleles of some genes have different levels of activity, has profound effects on growth and development of the mammalian fetus. Plagge et al. (2004) disrupted a paternally expressed transcript at the Gnas locus, Gnasxl, which encodes the unusual Gs-alpha isoform XL-alpha-s. Mice with mutations in Gnasxl had poor postnatal growth and survival and a spectrum of phenotypic effects indicating that XL-alpha-s controls a number of key postnatal physiologic adaptations, including suckling, blood glucose, and energy homeostasis. Increased cAMP levels in brown adipose tissue of Gnasxl mutants and phenotypic comparison with Gnas mutants suggested that XL-alpha-s can antagonize Gs-alpha-dependent signaling pathways. The opposing effects of maternally and paternally expressed products of the Gnas locus provided tangible molecular support for the parental conflict hypothesis of imprinting.
Two candidate imprinting control regions (ICRs) have been identified at the compact imprinted Gnas cluster on distal mouse chromosome 2: one at exon 1A upstream of Gnas itself and one covering the promoters of Gnasxl and the antisense Gnas transcript, also called Nespas (Coombes et al., 2003). Gnas itself is mainly biallelically expressed but is weakly paternally repressed in specific tissues. Williamson et al. (2004) showed that a paternally-derived targeted deletion of the germline differentially methylated region at exon 1A abolished tissue-specific imprinting of Gnas, which rescued the abnormal phenotype of mice with a maternally-derived Gnas mutation. Imprinting of alternative transcripts, Nesp, Gnasxl, and Nespas in the cluster was unaffected. The results established that the differentially methylated region in exon 1A contains an imprinting control element that specifically regulates Gnas and comprises a characterized ICR for a gene that is only weakly imprinted in a minority of tissues. Williamson et al. (2004) concluded that there must be a second ICR regulating the alternative transcripts.
Williamson et al. (2006) identified a second ICR at the mouse Gnas cluster. They showed that a paternally-derived targeted deletion of the germline DMR associated with the antisense Nespas transcript unexpectedly affected both the expression of all transcripts in the cluster and methylation of 2 DMRs. The results established that the Nespas DMR is the principal ICR at the Gnas cluster and functions bidirectionally as a switch for modulating expression of the antagonistically acting genes Gnasxl and Gnas. Uniquely, the Nespas DMR acts on the downstream ICR at exon 1A to regulate tissue-specific imprinting of the Gnas gene.
Mantovani et al. (2004) investigated the presence of a parent specificity of Gs-alpha mutations in 10 patients affected with McCune-Albright syndrome (MAS; 174800) and 12 isolated tumors (10 GH-secreting adenomas, 1 toxic thyroid adenoma, and 1 hyperfunctioning adrenal adenoma). The parental origin of Gs-alpha mutations was assessed by evaluating NESP55 and exon 1A transcripts, which are monoallelically expressed from the maternal and paternal alleles, respectively. By this approach, Mantovani et al. (2004) demonstrated that in isolated GH-secreting adenomas, as well as in MAS patients with acromegaly, Gs-alpha mutations were on the maternal allele. By contrast, the involvement of other endocrine organs in MAS patients was not associated with a particular parent specificity, as precocious puberty and hyperthyroidism were present in patients with mutations on either the maternal or the paternal allele. Moreover, isolated hyperfunctioning thyroid and adrenal adenomas displayed the mutation on the maternal and paternal alleles, respectively. Mantovani et al. (2004) concluded that their data confirmed the importance of Gs-alpha imprinting in the pituitary gland and demonstrated the high degree of tissue specificity of this phenomenon.
To establish whether Gs-alpha is imprinted also in tissues that are site of alteration both in PHP Ia and PPHP, Mantovani et al. (2004) selected 20 bone and 10 adipose tissue samples that were heterozygous for a known polymorphism in exon 5. Expression from both parental alleles was evaluated by RT-PCR and enzymatic digestion of the resulting fragments. By this approach, the great majority of the samples analyzed showed an equal expression of the 2 alleles. The authors concluded that their results provided evidence for the absence of Gs-alpha imprinting in human bone and fat and suggested that the clinical finding of osteodystrophy and obesity in PHP Ia and PPHP patients despite the presence of a normal Gs-alpha allele is likely due to Gs-alpha haploinsufficiency in these tissues.
By analyzing 30 polymorphic sites across the Gnas1 gene region in C57BL/6J x Mus spretus F1 mice, Li et al. (2004) identified 2 allelic switch regions (ASRs) that marked boundaries of epigenetic information. Activating signals consisting of histone acetylation and methylation of H3 lys4 (see 602810) and silencing signals consisting of histone methylation of H3 lys9 and DNA methylation segregated independently across the ASRs. The authors suggested that these ASRs may allow the transcriptional elongation to proceed through the silenced domain of nearby imprinted promoters.
Sakamoto et al. (2004) examined the chromatin state of each parental allele within the exon 1A-Gs-alpha promoter region by chromatin immunoprecipitation of samples derived from mice with heterozygous deletions within the region using antibodies to covalently modified histones. The exon 1A DMR had allele-specific differences in histone acetylation and methylation, with histone acetylation and H3 lysine-4 (H3K4) methylation of the paternal allele, and H3 lysine-9 (H3K9) methylation of the maternal allele. Both parental alleles had similar levels of histone acetylation and H3K4 methylation within the Gs-alpha promoter and first exon, with no H3K9 methylation. In liver, where Gs-alpha is biallelically expressed, both parental alleles had similar levels of tri- and dimethylated H3K4 within the Gs-alpha first exon. In contrast, in renal proximal tubules there was a greater ratio of tri- to dimethylated H3K4 of Gs-alpha exon 1 in the more transcriptionally active maternal as compared with the paternal allele. The authors concluded that allele-specific differences in Gs-alpha expression correlate in a tissue-specific manner with allele-specific differences in the extent of H3K4 methylation, and chronic transcriptional activation in mammals is correlated with trimethylation of H3K4.
Morison et al. (2005) reported a census of known imprinted genes in humans and mice. They listed 83 transcriptional units, of which 29 are imprinted in both species. They noted that there is a high level of discordance of imprinting status between the mouse and human and that a high proportion of imprinted genes are noncoding RNAs or genes derived by retrotransposition.
Inactivating Mutations in the GNAS Gene
Inactivating loss-of-function mutations in the GNAS1 gene result in pseudohypoparathyroidism Ia (PHP1A; 103580), pseudopseudohypoparathyroidism (PPHP; 612463), and progressive osseous heteroplasia (POH; 166350) (Aldred and Trembath, 2000).
In a patient with PHP Ia and his affected mother, Patten et al. (1989, 1990) identified a heterozygous mutation in the GNAS gene (139320.0001).
Ahmed et al. (1998) performed mutation analysis in 13 unrelated families, 8 with PHP Ia and PPHP patients, and 5 with PPHP patients only. GNAS1 mutations were detected in 4 of the 8 families with PHP Ia: 2 novel de novo missense mutations and an identical frameshift deletion in 2 unrelated families (139320.0011). GNAS1 mutations were not detected in any of the families with PPHP only.
Aldred and Trembath (2000) found that a recurring 4-bp deletion in exon 7 of the GNAS1 gene (139320.0011) was common among patients with PHP1A. The authors noted that inactivating mutations are scattered throughout the GNAS gene with some evidence of clustering.
In 4 unrelated Italian families with PHP Ia, Mantovani et al. (2000) identified heterozygous mutations in GNAS: 2 families had 2 previously reported deletions in exons 5 and 7, whereas the other 2 families had 2 novel frameshift deletions (139320.0025 and 139320.0026). No mutations were detected in the families in which PPHP was the only clinical manifestation.
Ahrens et al. (2001) investigated 29 unrelated patients with Albright hereditary osteodystrophy and PHP Ia or pseudopseudohypoparathyroidism and their affected family members. All patients showed a reduced GNAS1 protein activity (mean 59% compared with healthy controls). In 21 of 29 patients (72%), 15 different mutations in GNAS1, including 11 novel mutations, were detected. There were 8 instances in which a mother had PPHP and her offspring had PHP Ia with AHO due to the same mutation (see, e.g., 139320.0028). They also reported 5 unrelated patients with a previously described 4-bp deletion in exon 7 (139320.0011), confirming the presence of a hotspot for loss-of-function mutations in GNAS1. In 8 patients, no molecular abnormality was found in the GNAS1 gene despite a functional defect of Gs-alpha.
Shore et al. (2002) identified heterozygous inactivating GNAS1 mutations in 13 of 18 probands with progressive osseous heteroplasia. The defective allele in POH was inherited exclusively from fathers, a result consistent with a model of imprinting for GNAS1. Direct evidence that the same mutation can cause either POH or PPHP was observed in a single family; in this family 5 sisters had POH due to a frameshift deletion of 4 nucleotides (139320.0011) inherited from the father in whom the mutation was nonpenetrant. Three offspring of these sisters had PPHP, including traces of subcutaneous ossification. Shore et al. (2002) described a second family in which the unaffected father was heterozygous for the same GNAS1 mutation associated with POH in his 3 affected daughters. Shore et al. (2002) noted that hormone resistance, such as that in PHP Ia, is strongly correlated with GNAS1 mutations in the maternally derived allele, indicating that the maternal allele is critical in some tissues for cellular functions required for signal transduction. In contrast, severe, progressive heterotopic ossification, such as that found in POH, correlates with paternal inheritance of the GNAS1 mutation, suggesting that the paternal allele specifically influences progressive osteoblastic differentiation, proliferation of cells in soft connective tissues, or both.
Linglart et al. (2002) conducted clinical and biologic studies including screening for mutations in the GNAS1 gene in 30 patients from 21 families with PHP: 19 with PHP associated with decreased erythrocyte Gs activity (PHP Ia); 10 with AHO associated with decreased erythrocyte Gs activity (isolated AHO); and 1 with PHP, hormonal resistance, and AHO but normal erythrocyte Gs activity (PHP Ic). A heterozygous GNAS1 gene lesion was found in 14 of 17 (82%) of the PHP Ia index cases, including 11 new mutations and a mutation hotspot involving codons 189-190 (21%). These lesions led to a truncated protein in all but 3 cases with missense mutations. In the patient diagnosed with PHP Ic, Gs-alpha protein was shortened by just 4 amino acids, a finding consistent with the conservation of Gs activity in erythrocytes and the loss of receptor contact. No GNAS1 lesions were found in the 5 individuals with isolated AHO who were not related to the PHP Ia patients. Intrafamilial segregation analyses of the mutated GNAS1 allele in 9 PHP Ia patients established that the mutation had occurred de novo on the maternal allele in 4 and had been transmitted by a mother with a mild phenotype in the other 5. They concluded that imprinting of GNAS1 plays a role in the clinical phenotype of loss-of-function mutations and that a functional maternal GNAS1 allele has a predominant role in preventing the hormonal resistance of PHP Ia.
Aldred et al. (2002) reported 2 patients with Albright hereditary osteodystrophy and deletions of chromosome 20q, including complete deletion of the GNAS1 gene. One boy had a paternally inherited deletion of chromosome 20q13.13-q13.32 and a normal biochemical evaluation consistent with pseudopseudohypoparathyroidism. The other patient had a maternally derived deletion of chromosome 20q13.31-q13.33 and pseudohypoparathyroidism type Ia. Neither patient showed evidence of soft tissue ossification.
In patients with AHO, Rickard and Wilson (2003) searched the 3 overlapping upstream exons, NESP55, XL-alpha-s, and exon 1A. Analysis of the NESP55 transcripts revealed the creation of a novel splice site in 1 patient and an unusual intronic mutation that caused retention of the intron in another patient, neither of which could be detected by analysis of the cDNA of GNAS1.
In a brother and sister with a PHP-Ia phenotype, who also had neonatal diarrhea and pancreatic insufficiency, Aldred et al. (2000) identified heterozygosity for a 12-bp in-frame insertion in the GNAS1 gene (139320.0035). The mutation was inherited from the unaffected mother, who was found to have germline mosaicism. Makita et al. (2007) performed biochemical and intact cell studies of the 12-bp insertion (AVDT) and suggested that the PHP-Ia phenotype results from the instability of the Gs-alpha-AVDT mutant and that the accompanying neonatal diarrhea may result from its enhanced constitutive activity in the intestine.
Adegbite et al. (2008) reviewed the charts of 111 individuals with cutaneous and subcutaneous ossification. While most individuals with superficial or progressive ossification had inactivating mutations in GNAS, there were no specific genotype-phenotype correlations that distinguished the more progressive forms such as POH from the nonprogressive forms such as PPHP and PHP Ia/c.
Pseudohypoparathyroidism Type Ib
In 3 brothers with a clinical diagnosis of PHP Ib (603233), Wu et al. (2001) identified heterozygosity for a 3-bp deletion in the GNAS gene (139320.0033). The boys had decreased cAMP response to PTH infusion, but normal erythrocyte Gs activity. When expressed in vitro, the mutant Gs-alpha was unable to interact with PTHR1 (168468) but showed normal coupling to other coexpressed heptahelical receptors. Wu et al. (2001) noted that the absence of PTH resistance in the mother and maternal grandfather who carried the same mutation was consistent with models of paternal imprinting of the GNAS gene.
In affected members and obligate carriers of 12 unrelated families with PHP Ib, Bastepe et al. (2003) identified a 3-kb heterozygous microdeletion located approximately 220 kb centromeric of exon 1A, which they called exon A/B, of the GNAS gene. Four of 16 apparently sporadic PHP Ib patients also had the deletion. Affected individuals with the microdeletion showed loss of exon 1A methylation, but no other epigenetic abnormalities. In all examined cases, the deletion was inherited from the mother, consistent with the observation of PHP Ib developing only in offspring of female obligate carriers. The deletion also removed 3 of 8 exons encoding syntaxin-16 (STX16; 603666.0001), but Bastepe et al. (2003) considered the involvement of STX16 in the molecular pathogenesis of PHP Ib unlikely. They postulated that the microdeletion disrupts a putative cis-acting element required for methylation at exon 1A and that this epigenetic defect underlies the pathogenesis of PHP Ib.
In all affected individuals and obligate carriers in a large kindred with PHP Ib, Linglart et al. (2005) identified a 4.4-kb microdeletion overlapping with a region of the 3-kb deletion identified by Bastepe et al. (2003). Affected individuals exhibited loss of methylation only at GNAS exon A/B. Linglart et al. (2005) concluded that PHP Ib comprises at least 2 distinct conditions sharing the same clinical phenotype: one associated with the loss of exon A/B methylation alone and, in most cases, with a heterozygous microdeletion in the STX16 region, and the other associated with methylation abnormalities at all GNAS DMRs, including the DMR at exon A/B.
In affected members of 2 unrelated kindreds with PHP Ib, Bastepe et al. (2005) identified a 4.7-kb deletion (139320.0031) removing the entire NESP55 DMR and exons 3 and 4 of the antisense transcript of the GNAS gene (GNASAS; 610540.0001). Maternal inheritance of the deletion caused loss of imprinting in cis at the entire GNAS locus.
Liu et al. (2005) found that all of 20 PHP Ib probands studied had loss of GNAS exon 1A imprinting (a paternal epigenotype on both alleles). All 5 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. In contrast, the STX16 mutation was absent in all sporadic cases. The majority of these patients had abnormal imprinting of the more upstream regions in addition to the exon 1A imprinting defect, with 8 of 15 having a paternal epigenotype on both alleles throughout the GNAS locus. In virtually all cases, the imprinting status of the paternally methylated NESP55 and maternally methylated NESPAS/XL-alpha-s promoters was concordant, suggesting that their imprinting may be coregulated, whereas the imprinting of the NESPAS/XL-alpha-s promoter region and XL-alpha-s first exon was not always concordant, even though they are closely linked and lie within the same DMR. The authors concluded that familial and sporadic forms of PHP Ib have distinct GNAS imprinting patterns that occur through different defects in the imprinting mechanism.
Activating Mutations in the GNAS Gene
Activating gain-of-function mutations in the GNAS1 gene result in the McCune-Albright syndrome (MAS; 174800), polyostotic fibrous dysplasia (POFD; see 174800), and various endocrine tumors. These activating mutations are present in the mosaic state, resulting from a postzygotic somatic mutation appearing early in the course of development which yields a monoclonal population of mutated cells within variously affected tissues. The nonmosaic state for activating mutations is presumably lethal to the embryo (Aldred and Trembath, 2000; Lumbroso et al., 2004).
Weinstein et al. (1991) analyzed DNA from tissues of 4 patients with the McCune-Albright syndrome for the presence of activating mutations in the GNAS1 gene and identified 1 of 2 activating mutations, R201C (139320.0008) and R201H (139320.0009) in tissues from all 4 patients.
Among 113 patients with McCune-Albright syndrome, including 98 girls and 15 boys, Lumbroso et al. (2004) found that 43% had a GNAS1 mutation involving arg201, with a net preponderance of the R201H (34) compared to R201C (15). No difference in severity or manifestations of the disease was noted between the two mutations. In patients who had several tissue samples analyzed, the same mutation was always found, supporting the hypothesis of an early postzygotic somatic mutation.
Bianco et al. (2000) analyzed a series of 8 consecutive cases of polyostotic fibrous dysplasia without other features of McCune-Albright syndrome and identified arg201 mutations (see, e.g., 139320.0013) in the GNAS1 gene in all of them.
In a review, Aldred and Trembath (2000) noted that mutations leading to constitutive activation of the GNAS1 gene occur in 2 specific codons, 201 and 227.
Fragoso et al. (2003) identified somatic heterozygous mutations in the GNAS1 gene (R201H, 139320.0009 and R201S, 139320.0013) in adrenal tissue from 3 unrelated patients with ACTH-independent macronodular adrenal hyperplasia (AIMAH; 219080). The mutations resulted in constitutive activation of the G protein. The mutations were not present in peripheral blood, and none of the patients had signs of McCune-Albright syndrome. Fragoso et al. (2003) discussed whether the patients could be considered part of the spectrum of McCune-Albright syndrome or whether they represent isolated cases of AIMAH associated with somatic mutations.
Sato et al. (2014) identified 2 different somatic heterozygous mutations in the GNAS1 gene, both affecting the codon R201 (R201H and R201C), in adrenocortical tumor tissue derived from 11 (16.9%) of 65 cases of corticotropin-independent adrenal Cushing syndrome. The mutations were confirmed to be somatic in all 6 cases tested. GNAS-positive tumors were smaller (average diameter 31.9 mm) than tumors without GNAS mutations (average diameter 37.7 mm), but additional pathologic findings were not reported.
Somatic Mutations in Pituitary Adenomas
Growth hormone-releasing hormone (GHRH; 139190) uses cAMP as a second messenger to stimulate growth hormone (GH; 139250) secretion and proliferation of normal pituitary somatotrophs (Billestrup et al., 1986). Vallar et al. (1987) identified constitutive activation of Gs in tissue from a subset of GH-secreting pituitary tumors (102200).
In a series of 32 corticotroph adenomas of the pituitary (617686), Williamson et al. (1995) found 2 with somatic mutations in the GNAS1 gene at codon 227 (139320.0010; 139320.0012).
Hayward et al. (2001) noted that approximately 40% of growth hormone-secreting pituitary adenomas contain somatic mutations in the GNAS1 gene. These mutations, which occur at arg201 or glu227 (see, e.g., 139320.0008 and 139320.0010, respectively), constitutively activate the alpha subunit of GNAS1. Although transcripts encoding Gs-alpha are biallelically derived in most human tissues, Hayward et al. (2001) showed that the mutation had occurred on the maternal allele in 21 of 22 GNAS1-positive somatotroph adenomas. They also showed that Gs-alpha is monoallelically expressed from the maternal allele in normal adult pituitary tissue. This monoallelic expression of Gs-alpha was frequently relaxed in somatotroph tumors regardless of GNAS1 mutation status. These findings implied a possible role for loss of Gs-alpha imprinting during pituitary somatotroph tumorigenesis.
Other Disease Associations
Jia et al. (1999) identified a common silent polymorphism in the GNAS1 gene involving a change of codon 131 from ATT (ile) to ATC (ile). The authors found a significant difference in the frequency of the alleles between 268 white patients with essential hypertension (145500) (51% +) and a matched group of 231 control subjects (58% +) (P = 0.02).
Genevieve et al. (2005) reported 2 unrelated girls who presented with severe pre- and postnatal growth retardation and had de novo interstitial deletions of chromosome 20q13.2-q13.3. Molecular studies showed that the deletions were of paternal origin in both girls and were approximately 4.5 Mb in size, encompassing the GNAS imprinted locus, including paternally imprinted Gnasxl, and the TFAP2C gene (601602). Both patients had intractable feeding difficulties, microcephaly, facial dysmorphism with high forehead, broad nasal bridge, small chin and malformed ears, mild psychomotor retardation, and hypotonia. Genevieve et al. (2005) noted that a mouse model with disruption of the Gnasxl gene had poor postnatal growth and survival (Plagge et al., 2004), and that a patient reported by Aldred et al. (2002) with a paternal deletion of the GNAS complex also showed pre- and postnatal growth retardation and feeding difficulties. Moreover, disruption of the Tfap2c gene in mice had been shown to affect embryonic development (Werling and Schorle, 2002).
Using metaanalysis combining data from case control and family studies in Gambia, Kenya, and Malawi and a case control study from Ghana, Auburn et al. (2008) detected associations between intronic or conservative SNPs of GNAS and severe malaria. SNPs with significant associations clustered in the 5-prime end of GNAS. Auburn et al. (2008) proposed that the impact of GNAS on malaria parasite invasion efficacy may alter susceptibility to disease.
Yu et al. (1998) generated mice with a mutation in exon 2 of the Gnas gene, resulting in a null allele. Homozygous Gs deficiency was embryonically lethal. Heterozygotes with maternal (m-/+) and paternal (+/p-) inheritance of the Gnas null allele had distinct phenotypes, suggesting that Gnas is an imprinted gene. Parathyroid hormone (PTH) resistance is present in m-/+ but not +/p- mice. Expression of the alpha subunit in the renal cortex (the site of PTH action) was markedly reduced in m-/+ but not in +/p- mice, demonstrating that the Gnas paternal allele is imprinted in this tissue. Gnas was also imprinted in brown and white adipose tissue. The maximal physiologic response to vasopressin (urinary concentrating ability) was normal in both m-/+ and +/p- mice and Gnas was not imprinted in the renal inner medulla, the site of vasopressin action. Tissue-specific imprinting of Gnas was likely the mechanism for variable and tissue-specific hormone resistance in the knockout mice and a similar mechanism might explain the variable phenotype in AHO.
Exon 2 m-/+ mice are obese and hypometabolic, whereas exon 2 +/p- mice are lean and hypermetabolic. To study the effect of Gs-alpha deficiency without disrupting other Gnas gene products, Chen et al. (2005) disrupted exon 1 of the Gnas gene in mice. They found that exon 1 +/p- mice lacked the exon 2 +/p- phenotype and developed obesity and insulin resistance. Exon 2 and exon 1 m-/+ mice both had subcutaneous edema at birth, presumably due to loss of maternal Gs-alpha expression; however, they differed in other respects, raising the possibility for the presence of other maternal-specific gene products. Exon 1 m-/+ mice had more severe obesity and insulin resistance and a lower metabolic rate relative to exon 1 +/p- mice. Chen et al. (2005) concluded that the lean, hypermetabolic, and insulin-sensitive exon 2 +/p- phenotype appeared to result from XL-alpha-s deficiency, whereas loss of paternal-specific Gs-alpha expression in exon 1 +/p- mice led to an opposite metabolic phenotype. Thus, alternative GNAS gene products have opposing effects on glucose and lipid metabolism. The differences between exon 1 m-/+ and +/p- mice presumably resulted from differential effects on Gs-alpha expression in tissues where Gs-alpha is normally imprinted.
A suspicion of the existence of one or more imprinted genes on distal mouse chromosome 2 had been raised by Cattanach and Kirk (1985) and Peters et al. (1994): paternal uniparental disomy (UPD)/maternal deletion and maternal UPD/paternal deletion of a region between breakpoints T2Wa and T28H on distal mouse chromosome 2 resulted in distinct phenotypes and early lethality. Neuronatin (NNAT; 603106) is an imprinted gene on distal mouse chromosome 2 that maps outside the T2Wa-T28H imprinted region (Kikyo et al., 1997). Given the large distance and the presence of multiple nonimprinted genes between Gnas and Nnat, it is likely that they lie within distinct imprinting domains. The tissue-specific imprinting of Gnas observed by Yu et al. (1998) had been demonstrated for other imprinted genes; e.g., DeChiara et al. (1991) had demonstrated tissue-specific parental imprinting in the case of the insulin-like growth factor II gene (147280) by study of targeted disruption of the gene in mice.
Bastepe et al. (2004) studied chimeric mice containing wildtype chondrocytes and chondrocytes with either homozygous or heterozygous disruption of Gnas exon 2. Haploinsufficiency of Gnas signaling resulted in chondrocytes that differentiated prematurely. The phenotype was similar to that observed in Pthr1 (168468)-deficient mice. Bastepe et al. (2004) determined that expression of Gnas in chondrocytes occurs from both parental alleles. They concluded that GNAS is the primary mediator of PTHR1 in chondrocytes and that haploinsufficiency of GNAS signaling contributes to the skeletal phenotypes of AHO.
In a mother and son with pseudohypoparathyroidism type Ia (103580), Patten et al. (1989, 1990) identified a heterozygous A-to-G transition in exon 1 of the GNAS1 gene, resulting in a met1-to-val (M1V) substitution at the initiator codon. Initiation at the next AUG was in-frame and predicted to result in deletion of 59 N-terminal amino acids. Laboratory studies showed that the GNAS protein was reactive with a C-terminal Gs-alpha antiserum, but not with 2 Gs-alpha peptide antisera to amino acid residues 28-42 or 47-61. This was the first molecular delineation of a mutation in a human G protein and a conclusive demonstration that mutation at the GNAS1 locus results in AHO.
In 4 sisters with PHP Ia (103580), Weinstein et al. (1990) identified a heterozygous G-to-C transversion in intron 10 of the GNAS1 gene, resulting in a splice site mutation. The authors used PCR to amplify genomic fragments with an attached high-melting G+C-rich region ('GC clamp') and DGGE to analyze the fragments. All 4 daughters had decreased Gs-alpha mRNA and functional Gs-alpha deficiency. The mother, who had PPHP (612463), also carried the heterozygous mutation. She had minor stigmata of Albright hereditary osteodystrophy, such as unilateral brachyphalangy I, x-ray evidence of subcutaneous calcifications, and short stature relative to other members of her family, but no hormonal abnormalities. The kindred had previously been reported by Kinard et al. (1979)l.
In a mother with PPHP (612463) and her daughter with PHP1A (103580), Weinstein et al. (1990) identified a heterozygous 1-bp deletion (G) in exon 10 of the GNAS gene, resulting in a frameshift.
Adegbite et al. (2008) identified the same deletion (725delC) in an unaffected carrier father and in 3 of his 5 children with progressive osseous heteroplasia (POH; 166350). The 3 children exhibited varying degrees of severity based on the extent of the heterotropic ossification lesions and resultant functional impairment.
Levine and Deily (1990) identified a family in which members affected with PHP1A (103580) had an A-to-G transition 12 bases from the 3-prime terminus of intron 3 of the GNAS gene. The mutation was predicted to result in a frameshift and a premature stop codon.
In affected members of a family with PHP Ia (103580), Levine and Deily (1990) identified a heterozygous T-to-C transition in the GNAS gene, resulting in a leu99-to-pro (L99P) substitution.
In affected members of a family with PHP1A (103580), Levine and Vechio (1990) identified a heterozygous C-to-T transition in exon 6 of the GNAS gene, resulting in a cys165-to-arg (C165R) substitution.
In various tissues from 4 patients with McCune-Albright syndrome (174800), Weinstein et al. (1991) found 1 of 2 activating mutations within codon 201 in exon 8 of the GNAS gene. Two patients carried an arg201-to-cys substitution (R201C); the other 2 carried an R201H substitution (139320.0009). Tissues analyzed included affected endocrine organs, such as gonads, adrenal glands, thyroid, and pituitary, as well as tissues not classically involved in the McCune-Albright syndrome. In each patient the proportion of cells affected varied from tissue to tissue. In 2 endocrine organs, the highest proportion of mutant alleles was found in regions of abnormal cell proliferation. Weinstein et al. (1991) concluded that somatic mutation of the GNAS gene early in embryogenesis resulted in the mosaic population of normal and mutant-bearing tissues that underlie the clinical manifestations of McCune-Albright syndrome.
Candeliere et al. (1995) found the R201C mutation in a 14-year-old boy who had previously been reported as a case of panostotic fibrous dysplasia (see 174800).
Landis et al. (1989) identified somatic gain-of-function mutations in the GNAS1 gene in 4 of 8 growth hormone-secreting pituitary tumors (PITA3; 617686) surgically removed from patients with acromegaly. Two tumors contained a C-to-T transition resulting in an R201C substitution. The other 2 tumors had an R201H substitution (139320.0009) and a Q227R substitution (139320.0010), respectively. All the mutations resulted in constitutive activation of Gs by inhibiting its GTPase activity and behaved like dominantly acting oncogenes.
Yang et al. (1996) identified somatic mutations at GNAS codon 201 in 9 of 21 pituitary adenomas derived from Korean patients with acromegaly. Eight tumors had the R201C mutation and 1 had an R201S substitution (139320.0013). Clinically, patients with the GNAS mutations were older and responded better to octreotide-induced growth hormone suppression than those without mutations.
Collins et al. (2003) identified an R201C mutation in thyroid carcinoma derived from a patient with McCune-Albright syndrome.
Fragoso et al. (1998) identified a somatic R201C mutation in 4 (66.6%) of 14 human sex cord stromal tumors, including ovarian and testicular Leydig cell tumors. In contrast, no GIP2 (139360) mutations were found in any of the sex cord stromal tumors studied.
Kalfa et al. (2006) detected the R201C mutation in 8 of 30 cases of juvenile ovarian granulosa cell tumor, the most common sex cord stromal tumor. Laser microdissection confirmed that the mutation was exclusively localized in the tumoral granulosa cells and was absent in the ovarian stroma. Patients with a hyperactivated G-alpha-s exhibited a significantly more advanced tumor (p less than 0.05) because 7 of them (77.7%) were staged as Ic or had had a recurrence.
In tumor tissue derived from 6 unrelated patients with ACTH-independent adrenocortical hyperplasia (AIMAH; 219080) Sato et al. (2014) identified a somatic heterozygous c.556C-T transition in the GNAS gene, resulting in an R201C substitution in the switch I domain. Tumor tissue from 4 additional patients carried a somatic GNAS mutation affecting the same codon (R201H; 139320.0009). GNAS-positive tumors were smaller (average diameter 31.9 mm) than tumors without GNAS mutations (average diameter 37.7 mm), but additional pathologic findings were not reported.
In 2 patients with McCune-Albright syndrome (174800), Weinstein et al. (1991) identified an arg201-to-his (R201H) mutation in exon 8 of the GNAS gene in endocrine organs affected in this disorder, such as gonads, adrenal glands, thyroid, and pituitary, as well as tissues not classically involved. In 2 endocrine organs, ovary and adrenal, the highest proportion of mutant alleles was found in regions of abnormal cell proliferation. Weinstein et al. (1991) concluded that somatic mutation of the GNAS gene early in embryogenesis resulted in the mosaic population of normal and mutant-bearing tissues that underlie the clinical manifestations of McCune-Albright syndrome. It remained an open question whether GNAS1 mutations were causally related to the nonendocrine abnormalities in 3 of the patients: chronic liver disease in 1, thymic hyperplasia in 2, gastrointestinal adenomatous polyps in 1, cardiopulmonary disease in 1, and sudden death in 2.
Schwindinger et al. (1992) found a G-to-A transition resulting in the R201H substitution in a patient with McCune-Albright syndrome who had severe bony involvement, characteristic skin lesions, and a history of hyperthyroidism. The mutation was found in a higher proportion of skin cells from affected areas than from unaffected areas. The findings confirmed the Happle (1986) hypothesis that this disorder is due to mosaicism for a postzygotic GNAS1 mutation. The authors noted that arg201 is also the site of ADP-ribosylation by the cholera toxin.
Collins et al. (2003) identified the R201H mutation in thyroid carcinoma from a patient with McCune-Albright syndrome.
In 2 growth hormone (GH; 139250)-secreting pituitary tumors (102200) surgically removed from patients with acromegaly, Landis et al. (1989) identified a somatic mutation in the GNAS1 gene, resulting in an R201H substitution. The mutation resulted in constitutive activation of Gs by inhibiting its GTPase activity and behaved like a dominantly acting oncogene.
Fragoso et al. (2003) identified a heterozygous R201H mutation in adrenal tissue from 2 unrelated patients with ACTH-independent macronodular adrenal hyperplasia (219080). Sato et al. (2014) identified a heterozygous somatic R201H mutation in adrenocortical tumors derived from 4 unrelated patients with ACTH-independent Cushing syndrome. GNAS-positive tumors were smaller (average diameter 31.9 mm) than tumors without GNAS mutations (average diameter 37.7 mm), but additional pathologic findings were not reported.
In 1 of 30 cases of juvenile ovarian granulosa cell tumor, the most common sex cord stromal tumor, Kalfa et al. (2006) detected the R201H mutation of the GNAS gene. Laser microdissection confirmed that the mutation was exclusively localized in the tumoral granulosa cells and was absent in the ovarian stroma.
In a growth hormone-secreting pituitary adenoma (PITA3; 617686) surgically removed from a patient with acromegaly, Landis et al. (1989) identified a somatic mutation in the GNAS1 gene, resulting in a gln227-to-arg (Q227R) substitution. The mutation resulted in constitutive activation of Gs by inhibiting its GTPase activity and behaved like a dominantly acting oncogene.
In a series of 32 corticotroph adenomas of the pituitary, Williamson et al. (1995) found 2 with somatic mutations in the GNAS1 gene at codon 227. One had the Q227R mutation and the second had a Q227H mutation (139320.0012).
In a patient with PHP1A (103580), Weinstein et al. (1992) identified a heterozygous 4-bp deletion (565delCTGA) in exon 7 of the GNAS1 gene, resulting in a frameshift and premature stop codon. Analysis of lymphocyte RNA by reverse transcription-PCR and direct sequencing showed that the GNAS1 allele bearing the mutation was not expressed as mRNA. Consistent with this, Northern blot analysis revealed an approximately 50% deficiency in steady-state levels of GNAS1 mRNA.
Ahmed et al. (1998) identified this deletion mutation in 2 unrelated families with PHP Ia.
Shore et al. (2002) provided direct evidence that the 4-bp deletion can cause either progressive osseous heteroplasia (POH; 166350) or Albright hereditary osteodystrophy without hormone resistance (PPHP; 612463) in the same family. Five sisters with POH had inherited this mutation from the father in whom the mutation was nonpenetrant. Three offspring of these sisters had AHO, including traces of subcutaneous ossification. Shore et al. (2002) suggested that POH requires paternal inheritance of a GNAS1 mutation, whereas hormone resistance is more likely to occur when the genetic defect is maternally inherited.
Ahmed et al. (2002) cautioned against a premature conclusion that POH may require paternal inheritance. In a family reported by Ahmed et al. (1998), the 4-bp deletion was found in a brother and sister and in their mother but not in their father. Aside from brachymetacarpia and short stature, the mother did not have features of AHO. The daughter had typical features of AHO and hormone resistant PHP1A; in contrast, her brother presented in the first year of life with ossification of subcutaneous tissue that was followed by progressive, generalized heterotopic ossification of skeletal muscle, without any clear evidence of hormone resistance. These cases exemplified the wide phenotypic heterogeneity in persons with mutations in GNAS1, even within 1 family.
Bastepe and Juppner (2002) suggested that, like some patients who have either PHP type Ia or PHP type Ib, the son described by Ahmed et al. (1998) may have developed resistance to parathyroid hormone later in life or not at all. Given that the patient's sister and mother had PHP type Ia and PPHP, respectively, POH resulting from maternally inherited GNAS1 mutations may actually represent an incomplete form of PHP type Ia. Bastepe and Juppner (2002) suggested that the underlying mechanism for this form of POH may be distinct from that described by Shore et al. (2002), which appears to result only from paternally inherited GNAS1 mutations.
Adegbite et al. (2008) identified heterozygosity for the 565delCTGA mutation in the GNAS gene in 13 POH cases (10 familial cases among 3 different families, and 3 individual spontaneous cases). The mutation resulted in variable severity and pleiotropy, both in family members and in unrelated sporadic cases.
In a series of 32 corticotroph adenomas of the pituitary (PITA3; 617686), Williamson et al. (1995) found 2 with somatic mutations in the GNAS1 gene at codon 227. One had a Q227R (139320.0010) substitution, and the other had a mutation resulting in a gln227-to-his (Q227H) substitution. The latter patient was a 35-year-old male who presented with severe Cushing syndrome complicated by psychosis.
In a series of growth hormone-secreting pituitary tumors (PITA3; 617686) derived from 21 Korean acromegalic patients, Yang et al. (1996) found that 1 tumor had a somatic C-to-A transversion in the GNAS1 gene, resulting in an arg201-to-ser (R201S) substitution.
Candeliere et al. (1997) reported a patient with polyostotic fibrous dysplasia (see 174800) in whom the R201S mutation was identified in the somatic mosaic state.
Fragoso et al. (2003) identified a heterozygous somatic R201S mutation in adrenal tissue from a patient with ACTH-independent macronodular adrenal hyperplasia (219080).
In a patient with PHP Ia (103580), Warner et al. (1997) identified a ser250-to-arg (S250R) mutation in the GNAS1 gene. Both GNAS1 activity and expression were decreased by approximately 50% in erythrocyte membranes from the affected patient. In vitro functional expression studies suggested that substitution or deletion of residue 250 may alter guanine nucleotide binding, which could lead to thermolability and impaired function.
In affected members of a large kindred in which 2 mothers had pseudopseudohypoparathyroidism (PPHP; 612463) and their 6 offspring had PHP Ia (103580), Fischer et al. (1998) identified a 38-bp deletion at the exon 1/intron 1 boundary of the GNAS gene. The deletion was predicted to eliminate the splice donor site of exon 1. Some of the patients had increased basal serum levels of thyroid-stimulating hormone (TSH; see 188540) and/or excessive TSH responses to thyrotropin-releasing hormone (TRH; 613879). The pseudo-PHP patients had decreased Gs activity, but normal urinary cAMP responses to PTH, normal TSH levels and responses to TRH, and normal serum levels of calcium and PTH.
In a 24-year-old man with PPHP (612463), Warner et al. (1998) identified a de novo arg258-to-trp (R258W) mutation in the GNAS1 gene. Arg258 is a nonconserved residue adjacent to a highly conserved glutamic acid residue, glu259, that is important for contact between switch 2 and 3 in the activated state. Warner et al. (1998) presented evidence that substitution of arg258 led to defective GDP binding, resulting in increased thermolability and decreased activation. Developmental delay, brachycephaly, and decreased muscle tone were noted by age 10 months. Throughout childhood he was small for his age and stocky in appearance. By 6 years, he developed learning disabilities as well as impulsive and aggressive behavior. Brachydactyly involved the distal phalanx of the thumb and the fourth metacarpals bilaterally. He also had intracranial calcifications in the globus pallidus. There was no evidence of resistance to parathyroid hormone or thyrotropin.
Warner et al. (1998) identified a heterozygous arg258-to-ala (R258A) substitution in the GNAS gene as a cause of PPHP (612463). The substitution led to increased GDP release and impaired receptor-mediated activation. Based on the crystal structure of GNAS1, arg258 interacts with residue gln170 within the helical domain. Loss of this interaction was predicted to open the cleft between the GTPase and helical domain, resulting in more rapid GDP release, as observed in the arg258 variants. Warner et al. (1998) suggested that interactions between arg258 and the helical domain are important for receptor-mediated activation. This same codon was affected in another patient with AHO (R258W; 139320.0016).
Warner and Weinstein (1999) showed that a gln170-to-ala substitution (Q170A; 139320.0018) also leads to increased GDP release but does not affect receptor-mediated activation. Therefore, interactions between arg258 and gln170 are important for maintaining guanine nucleotide binding but are not important for activation by receptor. Warner and Weinstein (1999) also showed that the R258A mutation, but not Q170A, was associated with a markedly elevated intrinsic GTPase rate, resulting in more rapid inactivation. Arg258, through mutual interactions with glu50, may constrain arg201, a residue critical for catalyzing GTP hydrolysis. Disruption of the interaction between arg258 and glu50 may relieve this constraint and allow arg201 to interact more efficiently with the gamma-phosphate of GTP in the transition state. This is an example of a mutation in a heterotrimeric G protein that increases the intrinsic GTPase activity and provides another mechanism by which receptor signaling can be impaired by G protein mutations.
See 139320.0017 and Warner and Weinstein (1999).
Iiri et al. (1994) studied 2 unrelated boys who had a paradoxical combination of PHP Ia (103580) and testotoxicosis (176410). Both boys were found to have an ala366-to-ser (A366S) mutation in the GNAS1 gene. PHP Ia is marked by resistance to hormones acting through cyclic AMP (parathyroid hormone and thyroid-stimulating hormone) as well as a 50% decrease in erythrocyte Gs activity in this heterozygous disorder. In contrast, testotoxicosis is a form of precocious puberty in which the Leydig cells secrete testosterone in the absence of luteinizing hormone, often due to constitutive activation of the luteinizing hormone receptor and (indirectly) of Gs. Iiri et al. (1994) demonstrated that this A366S mutation constitutively activated adenylyl cyclase in vitro, causing hormone-independent cAMP accumulation when expressed in cultured cells, and accounting for the testotoxicosis phenotype. Although the mutant form was quite stable at testis temperature, it was rapidly degraded at 37 degrees centigrade, explaining the PHP Ia phenotype caused by loss of Gs activity. In vitro experiments indicated that accelerated release of GDP caused both the constitutive activity and the thermolability of the A366S mutant form.
In patients with pseudohypoparathyroidism type Ia (103580), Farfel et al. (1996) identified an arg231-to-his (R231H) mutation in the GNAS1 gene which impaired the ability of the mutant protein to mediate hormonal stimulation of cAMP accumulation in transiently transfected cells.
Iiri et al. (1997) reported biochemical analyses showing that an activation defect caused by the R231H mutation was paradoxically intensified by hormonal and other stimuli. By substituting histidine for a conserved arginine residue, the mutation removed an internal salt bridge (to a conserved glutamate) that normally acts as an intramolecular hasp to maintain tight binding of the gamma-phosphate of GTP. The activation defect became prominent only under conditions that destabilized binding of guanine nucleotide (receptor stimulation) or impaired the ability of alpha-s to bind the gamma-phosphate of GTP (e.g., cholera toxin). Although GDP release is usually the rate-limiting step in nucleotide exchange, the biochemical phenotype of this mutant GNAS indicated that efficient G protein activation by receptors and other stimuli depends on the ability of the protein to clasp tightly the GTP molecule that enters the binding site. The 3 affected patients in the family carrying the R231H mutation of the GNAS1 gene showed classic clinical features of PHP Ia, including Albright hereditary osteodystrophy, but Gs activities in their erythrocytes were nearly normal (ranging between 60% and 90% of normal). Erythrocyte membranes of most PHP I patients contain only 50% of the normal complement of Gs activity and these patients are classified as PHP Ia, indicating that the affected patients carry inactivating mutations in the GNAS1 gene. In contrast, the PHP Ib phenotype is found in a smaller number of PHP I patients whose erythrocytes contain normal (or nearly normal) Gs activity. The R231H patients showed that results of the erythrocyte Gs assay can lead to an incorrect inference with respect to the genetic basis of the disease. PHP I patients with apparently normal or nearly normal erythrocyte Gs activities merit careful investigation, especially when they display the classic clinical phenotype, including Albright hereditary osteodystrophy. Although such patients may inherit mutations in genes other than GNAS1, their GNAS1 gene may encode mutant proteins with instructive qualitative defects, including impairment of conformational change, subcellular localization, or interaction with other proteins, including receptors, effectors, and regulators of G protein signaling proteins.
Ishikawa et al. (2001) found the R231H mutation in exon 9 of the GNAS1 gene in a Japanese patient with pseudohypoparathyroidism type Ia.
Riminucci et al. (1999) studied a patient who had been diagnosed with McCune-Albright syndrome (174800) at the age of 8 years. In an affected parietal bone sample, the authors identified a heterozygous C-to-G transversion in the GNAS1 gene, resulting in an arg201-to-gly (R201G) amino acid substitution. The boy presented with precocious puberty, facial deformities, and typical cafe-au-lait spots with a 'coast of Maine' profile. Extensive involvement of the cranial vault was apparent on x-ray. At the age of 13, acromegalic bone changes and growth hormone oversecretion were detected. With the exception of a single case of polyostotic fibrous dysplasia in which an R201S mutation was found (139320.0013), R201C (139320.0008) and R201H (139320.0009) had been the mutations consistently found in McCune-Albright syndrome patients and in non-MAS cases of fibrous dysplasia of bone. Thus, of the predicted missense mutations of codon 201, only R201P and R201L remained undetected (although R201L had been observed by Gorelov et al. (1995) in isolated, non-MAS endocrine tumors).
In affected members of a kindred with either PHP1A (103580) or PPHP (612463), Yu et al. (1999) identified a 2-bp deletion in exon 8 of the GNAS gene, resulting in premature termination of the protein. Serial measurements of thyroid function in members of kindred 1 indicated that thyroid-stimulating hormone (TSH; see 188540) resistance progressed with age and became more evident after the first year of life in those with PHP1A.
In affected members of a kindred with either PHP1A (103580) or PPHP (612463), Yu et al. (1999) identified a heterozygous 2-bp deletion (CT) in exon 4 of the GNAS gene, resulting in a frameshift and premature termination codon.
In 2 patients with progressive osseous heteroplasia (166350) from different families, Shore et al. (2002) identified a 1-bp deletion (348delC) in exon 5 of the GNAS1 gene.
Shapira et al. (1995) had described the same mutation in a patient with pseudohypoparathyroidism type Ia (103580).
In an Italian patient with pseudohypoparathyroidism type Ia (103580), Mantovani et al. (2000) detected a heterozygous 1-bp deletion (C) within codon 38 in exon 1 of the GNAS1 gene, resulting in a premature stop codon at position 57. This mutation was also found in the patient's mother, who had pseudopseudohypoparathyroidism (612463).
In an Italian patient with pseudohypoparathyroidism type Ia (103580), Mantovani et al. (2000) detected a heterozygous 2-bp deletion (TG) within codon 287 in exon 11 of the GNAS1 gene, resulting in a premature stop codon at position 298. The mutation was also found in the patient's mother, who presented the same clinical and biologic features.
In an unusual case of progressive osseous heteroplasia (166350) involving the face in an 8-year-old Albanian girl, Faust et al. (2003) identified a heterozygous 2-bp deletion in the GNAS1 gene, 860-861delTG, resulting in a frameshift of 11 amino acids followed by a premature stop codon.
In a woman with PPHP (612463), Ahrens et al. (2001) identified a C-to-T transition in exon 5 of the GNAS gene, resulting in a pro115-to-leu (P115L) substitution. Her son, who had the same mutation, had PHP Ia (103580).
In 2 unrelated kindreds with pseudohypoparathyroidism type Ib (603233), Bastepe et al. (2005) identified a 4.7-kb deletion in the GNAS locus that removed the differentially methylated region (DMR) of the GNAS gene encompassing the NESP55 region and exons 3 and 4 of the GNAS antisense transcript (GNASAS; 610540.0001). When inherited from a female, the deletion abolished all maternal GNAS imprints and derepressed maternally silenced transcripts, suggesting that the deleted region contains a cis-acting element that controls imprinting of the maternal GNAS allele.
This variant, formerly titled PROLONGED BLEEDING TIME, BRACHYDACTYLY, AND MENTAL RETARDATION, has been reclassified because delineation of the phenotype and the contribution of the variant to the phenotype are unclear.
In 3 patients from 2 families with markedly prolonged bleeding time accompanied by neurologic problems, brachydactyly, and a variable degree of mental retardation, Freson et al. (2001) identified a paternally inherited functional polymorphism in XL exon 1, consisting of a 36-bp duplication and 2 nucleotide substitutions, resulting in changes of codon 138 from alanine to aspartic acid (A138D) and of codon 161 from proline to arginine (P161R), that was associated with Gs hyperfunction in platelets, leading to an increased trauma-related bleeding tendency.
Freson et al. (2003) described 8 additional patients who inherited the same XLAS polymorphism paternally and who showed Gs hyperfunction in their platelets and fibroblasts. The clinical features were variable: 3 patients resembled those reported by Freson et al. (2001) and had psychomotor retardation, disturbed behavior, facial dysmorphism, feeding or gastrointestinal motility problems, and abnormal bleeding following trauma, whereas 5 patients had growth deficiency and no clinical bleeding abnormalities. All carriers also had an elongated ALEX protein as a consequence of the paternally inherited insertion. The paternally inherited double XLAS/ALEX functional polymorphism was also associated with elevated platelet membrane Gs-alpha protein levels. The in vitro interaction between the 2 elongated XLAS and ALEX proteins was markedly reduced. Freson et al. (2003) suggested that in contrast to the strong interaction between the 2 wildtype proteins, the defective association may result in unimpeded receptor-stimulated activation of XLAS.
In 3 brothers with a clinical diagnosis of pseudohypoparathyroidism type Ib (603233) and their clinically unaffected mother and maternal grandfather, Wu et al. (2001) identified heterozygosity for a 3-bp deletion (CAT) in exon 13 of the GNAS gene, resulting in the deletion of ile382. Biochemical studies showed normal erythrocyte Gs activity, but decreased cAMP response to PTH infusion. When expressed in vitro, mutant Gs-alpha was unable to interact with PTHR1 (168468) but showed normal coupling to other coexpressed heptahelical receptors. The mutation was not found in the unaffected father and sister or in 30 unrelated controls. Wu et al. (2001) noted that the absence of PTH resistance in the mother and maternal grandfather who carried the same mutation was consistent with models of paternal imprinting of the GNAS gene.
In a 10-year-old girl with brachymetacarpia, mental retardation, normocalcemic pseudohypoparathyroidism, and hypothyroidism (103580), Thiele et al. (2007) identified a heterozygous insertion of an adenosine in exon 3 of the GNAS gene, altering codon 85 and leading to a frameshift and a stop at codon 87 in exon 4. Molecular studies of cDNA from blood RNA demonstrated normal, biallelic expression of Gs-alpha-S transcripts, whereas expression of Gs-alpha-L transcripts from the maternal allele was reduced. Both the reduced activity and the mutation were also found in the mother and the affected younger brother. Thiele et al. (2007) noted that this was the first reported pathogenic mutation in exon 3 of the GNAS gene. The mutation is associated with pseudohypoparathyroidism type Ia due to selective deficiency of Gs-alpha-L and a partial reduction of Gs-alpha activity.
In a brother and sister with a PHP Ia phenotype (103580), who also had neonatal diarrhea and pancreatic insufficiency, Aldred et al. (2000) identified heterozygosity for a 12-bp insertion in exon 13 of the GNAS1 gene, resulting in an in-frame ala-val-asp-thr (AVDT) repeat at codon 366 within the beta-6/alpha-5 loop. The mutation was not found in 2 unaffected sibs and was also not detected in the lymphocyte DNA of either of the clinically unaffected parents. Haplotype analysis confirmed germline mosaicism and indicated that the mutation was maternal in origin.
By biochemical and intact cell analysis of the mutant Gs-alpha containing the AVDT repeat within its GDP/GTP binding site, Makita et al. (2007) demonstrated that the mutant protein was unstable but constitutively active as a result of rapid GDP release and reduced GTP hydrolysis, suggesting that instability and paradoxical inactivation by receptor stimulation results in a loss of function. Gs-alpha-AVDT was located primarily in the cytosol except in rat and mouse small intestine epithelial cells, where it was found predominantly in the membrane, with adenylyl cyclase present and constitutive increases in cAMP accumulation occurring in parallel. Makita et al. (2007) suggested that the PHP Ia phenotype results from the instability of the Gs-alpha-AVDT mutant and that the accompanying neonatal diarrhea may result from its enhanced constitutive activity in the intestine.
In a girl with PHP type Ic (612462), Linglart et al. (2002) identified a heterozygous mutation in exon 13 of the GNAS gene, resulting in a tyr319-to-ter (Y391X) substitution only 4 amino acids before the wildtype stop codon. She had hormone resistance with features of Albright hereditary osteodystrophy and decreased cAMP response to PTH infusion, but normal erythrocyte Gs activity. The findings suggested that the mutation interfered somehow with receptor-mediated activation. Linglart et al. (2002) noted that the C terminus is required for receptor coupling, and postulated that the Y391X mutation in this patient interrupted receptor coupling, leading to hormone resistance. The findings showed the limits of the erythrocyte Gs bioassay used in the study.
Mariot et al. (2008) studied a girl with obvious Albright osteodystrophy features, PTH resistance, and normal G-alpha-s bioactivity in red blood cells (PHP Ib, 603233), yet no loss-of-function mutation in the GNAS coding sequence. Methylation analysis of the 4 GNAS differentially methylated regions, i.e., NESP, AS, XL, and A/B, revealed broad methylation changes at all of these regions, leading to a paternal epigenotype on both alleles. There was a dramatic decrease of methylation at exon A/B, XL, and AS promoter regions and therefore likely biallelic expression of A/B, XL, and AS transcripts. The NESP region appeared fully methylated in the patient, which was predicted to result in a dramatic decrease in NESP-specific transcripts. The cause of the imprinting defect was unknown. Mariot et al. (2008) concluded that: (1) the decreased expression of G-alpha-s due to GNAS epimutations is not restricted to the renal tubule but may affect nonimprinted tissues like bone; and (2) PHP-1b is a heterogeneous disorder that should lead to the study of GNAS epigenotype in patients with PHP and no mutation in GNAS exons 1 through 13, regardless of their physical features. They suggested that Albright osteodystrophy, or at least brachymetacarpia and obesity, are not specific symptoms of PHP-1a (103580).
In a 12-year-old boy with PHP IC (612462), Thiele et al. (2011) identified a heterozygous 1163T-G transversion in exon 13 of the GNAS gene, resulting in a leu388-to-arg (L388R) substitution in a conserved residue in the alpha-5-helix in the C-terminal part of the protein directly involved in the contact of Gs-alpha to the G protein-coupled receptor. The patient had characteristic features of AHO, including round face, brachymetacarpia, short stature, obesity, and mental retardation. Serum PTH and TSH were increased and calcium was low. His mother, who also carried the mutation, had short stature and brachymetacarpia, but no evidence of hormone resistance. In vitro functional expression studies showed that the L388R mutant protein caused complete absence of receptor-mediated cAMP production, with normal receptor-independent cAMP production. The findings indicated normal Gs-alpha activity, but a selective defect in Gs-alpha-receptor coupling functions.
In 13-year-old dizygotic twins and an unrelated 5-year-old girl with PHP IC (612462), Thiele et al. (2011) identified a heterozygous 1174G-T transversion in exon 13 of the GNAS gene, resulting in a glu392-to-ter (E392X) substitution in the alpha-5-helix in the C terminus. The patients had characteristic features of AHO, including round face, brachymetacarpia, short stature, and obesity. Serum PTH and TSH were increased and calcium was low. Both mothers, who also carried the mutation, had short stature, round face, and/or brachymetacarpia, but no evidence of hormone resistance. In vitro functional expression studies showed that the mutant protein caused complete absence of receptor-mediated cAMP production, with normal receptor-independent cAMP production. The findings indicated normal Gs-alpha activity, but a selective defect in Gs-alpha-receptor coupling functions.
In an 11-month-old girl with PHP IC (612462), Thiele et al. (2011) identified a heterozygous 1174G-A transition in exon 13 of the GNAS gene, resulting in a glu392-to-lys (E392K) substitution in the alpha-5-helix in the C terminus. The patient had characteristic features of AHO, including round face, brachymetacarpia, and short stature. Serum PTH and TSH were increased, but calcium was normal. Her mother, who also carried the mutation, had short stature and brachymetacarpia, but no evidence of hormone resistance. In vitro functional expression studies showed that the mutant protein caused a decrease in receptor-mediated cAMP production, with normal receptor-independent cAMP production. The findings indicated normal Gs-alpha activity, but a selective defect in Gs-alpha-receptor coupling functions.
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