HGNC Approved Gene Symbol: GCGR
SNOMEDCT: 1228875006;
Cytogenetic location: 17q25.3 Genomic coordinates (GRCh38): 17:81,804,150-81,814,008 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q25.3 | Mahvash disease | 619290 | Autosomal recessive | 3 |
The physiologic effects of glucagon (GCG; 138030) are mediated through the glucagon receptor (GCGR), a member of the superfamily of receptors characterized by a 7-transmembrane domain structure and by their coupling via GTP-binding proteins (G proteins) to adenyl cyclase (summary by Menzel et al., 1994).
Jelinek et al. (1993) cloned the rat glucagon receptor cDNA. Using the rat GCGR cDNA as template, Menzel et al. (1994) cloned a partial human GCGR cDNA encoding a deduced protein showing 91% sequence identity with the rat homolog.
Lok et al. (1994) isolated a cDNA encoding a complete functional human glucagon receptor from a liver cDNA library by a combination of polymerase chain reaction and colony hybridization. They found that the deduced 477-amino acid protein has 80% sequence identity with the rat glucagon receptor, binds (125-I)-labeled glucagon, and transduces a signal leading to increases in the concentration of intracellular cyclic AMP.
By fluorescence in situ hybridization, Menzel et al. (1994) localized the GCGR gene to 17q25. An Alu variable poly(A) DNA polymorphism was identified in the gene. Use of the polymorphism in a study of CEPH families showed linkage between the polymorphism and markers localized to distal 17q.
By in situ hybridization, Lok et al. (1994) mapped the GCGR locus to 17q25.
Lok et al. (1994) determined that the coding region of GCGR spans over 5.5 kb and is interrupted by 12 introns. Southern blot analysis of human DNA suggested the presence of a single GCGR locus.
Crystal Structure
To understand the molecular recognition of human GCGR for its native ligand, Siu et al. (2013) reported the crystal structure of the 7-transmembrane helical domain of human GCGR at 3.4-angstrom resolution, complemented by extensive site-specific mutagenesis, and a hybrid model of glucagon bound to GCGR. Beyond the shared 7-transmembrane fold, the GCGR transmembrane domain deviates from G protein-coupled receptors of class A with a large ligand-binding pocket and the first transmembrane helix having a stalk region that extends 3 alpha-helical turns above the plane of the membrane. The stalk positions the extracellular domain relative to the membrane to form the glucagon-binding site that captures the peptide and facilitates the insertion of glucagon's amino terminus into the 7-transmembrane domain.
Zhang et al. (2017) reported the 3.0-angstrom crystal structure of full-length GCGR containing both the extracellular domain and transmembrane domain in an inactive conformation. The 2 domains are connected by a 12-residue segment termed the stalk, which adopts a beta-strand conformation, instead of forming an alpha-helix as observed in the previously solved structure of the GCGR transmembrane domain. The first extracellular loop exhibits a beta-hairpin conformation and interacts with the stalk to form a compact beta-sheet structure. Hydrogen-deuterium exchange, disulfide crosslinking, and molecular dynamics studies suggested that the stalk and the first extracellular loop have critical roles in modulating peptide ligand binding and receptor activation.
Zhang et al. (2018) reported the 3.0-angstrom-resolution crystal structure of full-length GCGR in complex with a glucagon analog and partial agonist, NNC1702. This structure provided molecular details of the interactions between GCGR and the peptide ligand. It revealed a marked change in the relative orientation between the extracellular domain and transmembrane domain of the glucagon receptor compared to the previously solved structure of the inactive GCGR-NNC0640-mAb1 complex (Zhang et al., 2017). Notably, the stalk region and the first extracellular loop undergo major conformational changes in secondary structure during peptide binding, forming key interactions with the peptide. Zhang et al. (2018) further proposed a dual binding-site trigger model for glucagon receptor activation, which requires conformational changes of the stalk, first extracellular loop, and transmembrane domain, that extended understanding of the 2-domain peptide-binding model of class B G protein-coupled receptors.
Cryoelectron Microscopy
Using cryoelectron microscopy, Qiao et al. (2020) determined the structures of human GCGR bound to glucagon and distinct classes of heterotrimeric G proteins, Gs (see 139320) or Gi1 (see 139310). These 2 structures adopt a similar open binding cavity to accommodate Gs and Gi1. The Gs binding selectivity of GCGR is explained by a larger interaction interface, but there are specific interactions that affect Gi more than Gs binding. Conformational differences in the receptor intracellular loops were found to be key selectivity determinants. These distinctions in transducer engagement were supported by mutagenesis and function studies.
Mahvash Disease
In a 65-year-old Persian woman with Mahvash disease, who was previously reported by Yu et al. (2008), Zhou et al. (2009) identified a homozygous mutation in the GCGR gene (P86S; 138033.0002). The mutation was identified by direct sequencing of the GCGR gene.
In 3 patients with Mahvash disease, Sipos et al. (2015) identified homozygous or compound heterozygous mutations in the GCGR gene (138033.0003-138033.0006). One patient (patient 3) had 2 homozygous mutations (see 138033.0006). The mutations were identified by Sanger sequencing and pyrosequencing of the GCGR gene.
Larger et al. (2016) identified a homozygous splice site mutation in the GCGR gene (138033.0007) in a 51-year-old man with Mahvash disease. Evaluation of liver membrane preparations derived from the patient as well as of COS-7 cells transiently transfected with the mutant cDNA showed that the mutation resulted in loss of both glucagon binding and cAMP production.
In a 47-year-old man with Mahvash disease, Gild et al. (2018) identified a homozygous missense mutation in the GCGR gene (D63N; 138033.0008). The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies were not performed.
Li et al. (2018) identified a homozygous 3-bp deletion in the GCGR gene (Phe320del; 138033.0009) in a 7-year-old girl with Mahvash disease. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. HEK293 cells transfected with mutant GCGR with the deletion of Phe320 did not generate cAMP in response to glucagon.
Associations Pending Confirmation
For discussion of a possible association between variation in the GCGR gene and diabetes mellitus type 2 (125853), see 138033.0001.
To examine the role of glucagon in glucose homeostasis, Gelling et al. (2003) generated Gcgr-null mice. These mice displayed lower blood glucose levels throughout the day and improved glucose tolerance but similar insulin levels compared with control animals. The homozygous null mice displayed supraphysiologic glucagon levels associated with postnatal enlargement of the pancreas and hyperplasia of islets due predominantly to alpha cell, and to a lesser extent, delta cell, proliferation. They also displayed reduced adiposity and leptin levels but normal body weight, food intake, and energy expenditure. The data indicated that glucagon is essential for maintenance of normoglycemia and normal postnatal regulation of islet and alpha and delta cell numbers. The lean phenotype of the null mice suggested that glucagon action may be involved in the regulation of whole body composition.
To determine the extent to which blocking glucagon action would reverse hyperglycemia, Sloop et al. (2004) administered glucagon receptor antisense oligonucleotide inhibitors to db/db and ob/ob mice and ZDF rats and found decreased glucagon receptor expression, normalized blood glucose, improved glucose tolerance, and preserved insulin secretion. They also noted increased serum concentrations of active glucagon-like peptide-1 (see 138030) and insulin levels in pancreatic islets. Sloop et al. (2004) concluded that glucagon receptor inhibitors reverse the diabetes phenotype by the dual action of decreasing hepatic glucose production and improving pancreatic beta-cell function.
Yu et al. (2011) studied the pancreata of Gcgr-null mice from the ages of 2 to 12 months. At 2 months of age, the pancreata had normal islet cell morphology, but the islets consisted mostly of alpha cells. At 5 to 7 months of age, dysplastic islets were seen in the pancreata. At 10 to 12 months of age, micro-PNETs were seen in all pancreata, gross PNETs were seen in some pancreata, and dysplastic islets were numerous in the nontumor areas. Most of the PNETs were glucagonomas but some were nonfunctioning. Metastasis to the liver was uncommon and seen only in miliary form. Yu et al. (2011) found that apoptosis was barely detectable in the pancreata endocrine cells, and neogenesis was the likely predominant mechanism for the observed alpha-cell hyperplasia. The Gcgr-null mice did not gain significant weight after 3 months of age and had little subcutaneous and visceral fat.
To understand why GLP1 (see 138030) analogs result in pancreas proliferation and dysplasia, Yu et al. (2014) examined pancreas exocrine proliferation in Gcgr-null mice. Exocrine pancreas proliferation was 2-fold higher in Gcgr-null mice compared to wildtype and heterozygous mice at 2 to 3 months of age. The proliferation decreased to similar levels in all 3 mouse genotypes at 12 months of age. Apoptosis was rare regardless of genotype or age. Exocrine pancreas hyperplasia, but not dysplasia, was seen in old Gcgr-null mice (average of 18.7 months), leading Yu et al. (2014) to conclude that exocrine pancreas hyperplasia and dysplasia seen with GLP1 administration may be partially, but not completely, due to suppression of glucagon secretion.
Lin et al. (2020) used CRISPR/Cas9 gene editing to generate a mouse with a homozygous V369M mutation in the Gcgr gene, which is equivalent to the human V368M mutation (138033.0006). The mutant mice had hyperglucagonemia, alpha-cell hyperplasia, enlargement of the pancreas, and increased liver weight compared to wildtype mice. Liver cell membranes from the mutant mice had decreased glucagon binding and reduced cAMP production compared to controls. The mutant mice also had lower fasting blood glucose levels, improved glucose tolerance, and reduction in adiposity compared to wildtype. Yu (2020) commented that this mutant mouse is an appropriate model to study mild Mahvash disease, and that further characterization of pancreas morphology and histology at advanced ages is important to understand the progression of the disease.
This variant, formerly titled DIABETES MELLITUS, TYPE 2, has been reclassified as a polymorphism based on a review of the gnomAD database by Hamosh (2020).
Hager et al. (1995) reported the association of a single heterozygous gly40-to-ser (G40S) mutation in the glucagon receptor gene with late-onset noninsulin-dependent diabetes mellitus (NIDDM; T2D; 125853). In a pooled set of French and Sardinian patients, the gly40-to-ser mutation showed association with NIDDM (chi square = 14.4, P = 0.0001). In 18 sibships from 9 French pedigrees, some evidence for linkage to diabetes was found. Receptor binding studies using cultured cells expressing the G40S mutation demonstrated that this mutation results in a receptor that binds glucagon with a 3-fold lower affinity compared to the wildtype receptor.
Chambers and Morris (1996) found the G40S mutation in 5% of patients with hypertension and in only 1% of controls, suggesting that in a subset of hypertension patients it or a mutation in a closely linked gene in linkage disequilibrium is an etiologic factor.
Hamosh (2020) found that the G40S variant was present in 1,170 of 173,128 heterozygotes and in 5 homozygotes, with a frequency of 0.006758, in the gnomAD database (June 4, 2020).
In a 65-year-old Persian woman with Mahvash disease (MVSH; 619290), who was previously reported by Yu et al. (2008), Zhou et al. (2009) identified a homozygous c.256C-T transition in exon 4 of the GCGR gene, resulting in a pro86-to-ser (P86S) substitution in the extracellular domain. The mutation was identified by direct sequencing of the GCGR gene. Functional studies in HEK293 cells transfected with a plasmid containing GCGR with the P86S mutation showed that the mutant GCGR properly localized to the plasma membrane but had a lower affinity for glucagon compared to wildtype.
In a 25-year-old man (patient 1) with Mahvash disease (MVSH; 619290), Sipos et al. (2015) identified a homozygous 1-bp insertion in exon 4 of the GCGR gene, resulting in a frameshift and premature termination (Trp83LeufsTer35). The mutation was by Sanger sequencing and pyrosequencing of the GCGR gene in pancreatic tissue and blood from the patient, and his parents were found to be mutation carriers. The mutation was not present in 2,560 individuals from southern and northern regions of Germany or in the dbSNP and Exome Variant Server databases.
In a 43-year-old woman (patient 2) with Mahvash disease (MVSH; 619290), Sipos et al. (2015) identified compound heterozygous mutations in the GCGR gene: arg8-to-ter (R8X) in exon 2 and gln327-to-ter (Q327X; 138033.0005) in exon 11. The mutations were identified by Sanger sequencing and pyrosequencing of the GCGR gene in hyperplastic glucagon cells and nontumorous pancreatic tissue from the patient. The mutations were not present in 2,560 individuals from southern and northern regions of Germany or in the dbSNP and Exome Variant Server databases.
For discussion of the gln327-to-ter (Q327X) mutation in the GCGR gene that was identified in compound heterozygous state in a patient with Mahvash disease (MVSH; 619290) by Sipos et al. (2015), see 138033.0004.
In a 58-year-old man (patient 3) with Mahvash disease (MAVH; 619290), Sipos et al. (2015) identified 2 homozygous mutations in the GCGR gene: a val368-to-met (V368M) substitution in exon 12, and an arg225-to-his (R225H) substitution in exon 8. The mutations were identified by Sanger sequencing and pyrosequencing of the GCGR gene. The mutations were not present in 2,560 individuals from southern and northern regions of Germany. The V368M mutation was not present in the dbSNP and Exome Variant Server databases, and the R225H mutation was present in these databases at a low frequency.
Li et al. (2018) stated that the V368M mutation resulted from a c.1102G-A transition and the R225H mutation resulted from a c.674G-A transition in the GCGR gene. They noted that the V368M mutation was found in 1 homozygote in the gnomAD database (minor allele frequency of 0.026 in South Asians) and the R225H mutation was found in 2 homozygotes (minor allele frequency of 0.175 in South Asians).
Lin et al. (2020) showed that mice with a homozygous V369M mutation in the Gcgr gene, which is equivalent to the human V368M mutation, displayed a phenotype similar to Mahvash disease; see ANIMAL MODEL.
Variant Function
Lin et al. (2020) performed in vitro analysis of the R225H and V368M variants. Both variants displayed significantly impaired glucagon-elicited cAMP production. Binding of glucagon of each variant, which was assessed in CHO cells by competitive binding assay, showed marked reductions in affinity and span of both variants. R225H also exhibited abnormal membrane location, and its surface expression level was only 52.58% of wildtype, whereas V368M had a much higher (82.05%) surface expression level. In addition, V368M had no significant effect on either expression level or cellular location of the receptor.
In a 51-year-old man with Mahvash disease (MVSH; 619290), Larger et al. (2016) identified a homozygous G-A transition in the -1 position of intron 8 (IVS8-1G-A) of the GCGR gene, predicted to result in a frameshift and premature termination. The mutation was found by sequencing of the GCGR gene. Sequencing of GCGR cDNA derived from the patient's liver showed a transcript that was approximately 70 bp shorter than wildtype. Evaluation of liver membrane preparations derived from the patient as well as of COS-7 cells transiently transfected with the mutant cDNA showed that the mutation resulted in loss of both glucagon binding and cAMP production.
In a 47-year-old man with Mahvash disease (MVSH; 619290), Gild et al. (2018) identified a homozygous c.187G-A transition in exon 4 of the GCGR gene, resulting in an asp63-to-asn (D63N) substitution. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies were not performed. The clinical features in this patient included hypercalcemia, alpha-cell hyperplasia, and neoplasia with metastatic disease.
In a 7-year-old Indian girl, born to consanguineous parents, with Mahvash disease (MVSH; 619290), Li et al. (2018) identified a homozygous 3-bp deletion (c.958_960del, NM_000160.3) in the GCGR gene, resulting in deletion of Phe320 (Phe320del). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The parents were shown to be mutation carriers. The mutation was present as a single allele in the gnomAD database. HEK293 cells transfected with mutant Phe310del GCGR did not generate cAMP in response to glucagon.
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