Alternative titles; symbols
HGNC Approved Gene Symbol: GPR101
Cytogenetic location: Xq26.3 Genomic coordinates (GRCh38) : X:137,023,929-137,033,995 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq26.3 | Pituitary adenoma 2, GH-secreting | 300943 | X-linked | 3 |
G protein-coupled receptors (GPCRs, or GPRs), such as GPR101, contain 7 transmembrane domains and transduce extracellular signals through heterotrimeric G proteins (Lee et al., 2001).
Lee et al. (2001) identified GPR101 within a genomic database using sequences of the histamine receptor H1 (600167) as query. PCR primers were designed to amplify and clone GPR101 from a genomic library. Full-length GPR101 encodes a deduced 508-amino acid protein that shares approximately 30% sequence identity in the transmembrane regions with the G protein-coupled receptor RE2, the serotonin 5HT1A receptor (HTR1A; 109760), and the alpha-1A-adrenergic receptor (104221). Northern blot analysis of human brain tissues revealed expression of 9.5- and 4.2-kb transcripts in the caudate putamen and hypothalamus. No expression was detected in cortex, thalamus, hippocampus and pons.
Bates et al. (2006) cloned mouse Gpr101 from a brain cDNA library. The deduced 511-amino acid protein shares 71% identity with human GPR101. Northern blot analysis detected an approximately 5.5-kb transcript in brain, with little to no expression in 7 other mouse tissues examined. Gpr101 was variably expressed in all mouse brain regions examined, with highest expression in hypothalamus and lowest expression in cerebral cortex. In situ hybridization of mouse brain sections detected Gpr101 in numerous limbic, autonomic, and sensory areas and nuclei, with most prominent expression restricted to a few nuclei. In spinal cord, Gpr101 expression was detected in superficial layers of the dorsal horn and surrounding central canal in lamina X.
Using Hi-C to characterize the chromatin structure at the XLAG (300942) locus, Franke et al. (2022) showed that the GPR101 gene is located in a discrete topologically associated domain (TAD), which is separated from centromeric genes and regulatory sequences by a TAD border. Franke et al. (2022) determined that this structural organization was maintained in 21 different human tissues and in mice, showing that the organization is tissue invariant and evolutionarily conserved.
Using a reporter gene assay, Bates et al. (2006) determined that human GPR101 was coupled to Gs (see 139320). Expression of GPR101 in HEK293 cells resulted in a dose-dependent elevation in reporter activity and intracellular cAMP. In a yeast system, overexpression of GPR101 resulted in agonist-independent reporter activation in the presence of a yeast chimeric Gs.
Nilaweera et al. (2008) had previously found that expression of Gpcr101 increased in the posterior hypothalamus in mice deprived of food, and that it decreased with obesity. Nilaweera et al. (2008) found that, during pregnancy and lactation in rat, Gpcr101 expression did not significantly change in most hypothalamic nuclei. However, Gpcr101 expression increased significantly in supraoptic nucleus and in the rostral ventromedial parvocellular subdivision of the paraventricular nucleus at late stages of pregnancy and remained high during lactation.
Trivellin et al. (2014) showed that GPR101 encodes an orphan G protein-coupled receptor that is highly expressed in rodent hypothalamus and is predicted to couple to the stimulatory G protein (Gs), a potent activator of adenylyl cyclase.
Protein Structure
Trivellin et al. (2014) constructed a structural model of GPR101 in complex with a Gs heterotrimer. The E308D mutation (300393.0001) is on the cytosolic side of the receptor that interacts with heterotrimeric G proteins. Residue E308 is located in the long intracellular loop 3, which connects transmembrane domains 5 and 6.
Lee et al. (2001) mapped the GPR101 gene to the X chromosome based on sequence similarity between the GPR101 sequence and a genomic clone (GenBank AL390879) localized to the X chromosome.
Using FISH, Bates et al. (2006) mapped the human GPR101 gene to chromosome Xq26-q27.
Hartz (2014) mapped the GPR101 gene to chromosome Xq26.3 based on an alignment of the GPR101 sequence (GenBank BC069439) with the genomic sequence (GRCh38).
Bates et al. (2006) mapped the mouse Gpr101 gene to chromosome XA5, where it lies in a region of conserved synteny with human chromosome Xq26-q27.
Trivellin et al. (2014) identified a recurrent GPR101 mutation (E308D; 300393.0001) in 4.4% of DNA from tumor samples and in 1.8% of DNA from peripheral blood mononuclear cell (PBMC) samples obtained from patients with sporadic acromegaly (300943). Trivellin et al. (2014) did not find GPR101 mutations in families with isolated familial pituitary adenomas.
In a patient with sporadic acromegaly, Kamenicky et al. (2015) identified a novel germline mutation in the GPR101 gene (D366E; 300393.0002).
Iacovazzo et al. (2016) sequenced DNA from 579 acromegaly patients and identified 4 patients (0.69%) with a germline E308D mutation in the GPR101 gene. No other rare or novel coding variants were detected, and the authors suggested that GPR101 variants do not occur frequently and might not play a significant role in the pathogenesis of acromegaly.
Franke et al. (2022) compared differentially expressed genes between tumors from 4 individuals with XLAG and normal pituitary tissue from 3 control individuals and identified GPR101 as the most significantly dysregulated gene, with a greater than 12 log2-fold increase in expression in the tumors. Franke et al. (2022) then evaluated the organization of the topologically associated domain (TAD) that contains the GPR101 gene in PBMCs from patients with XLAG using 4C seq analysis. The Xq23.3 duplication in patients with XLAG was found to result in altered chromatin confirmation, which permits new interactions between the GPR101 promoter and centromeric regulatory enhancers.
In 11 of 248 patients with acromegaly and growth hormone-producing adenomas (PITA2; 300943), Trivellin et al. (2014) identified a c.924G-C transversion in the GPR101 gene, resulting in a glu308-to-asp (E308D) substitution. In 3 mutation carriers, the mutation appeared to be a germline event, as the mutation was detected in peripheral blood. In 8 patients, the mutation was only seen in tumor DNA, and in 1 patient, it was confirmed as a de novo somatic mutation, as it was not found in peripheral blood. This mutation was not found in 7,600 control samples from public databases. Transfection of a construct expressing GPR101 containing the E308D mutation increased proliferation and growth hormone secretion in a rat pituitary cell line.
Roohi (2015) reported that the E308D mutation in GPR101 shows an allele frequency of 0.55% among Europeans in the ExAC database and 0.36% among the total cohort of 61,500 unrelated individuals. Given the frequency of the variant, Roohi (2015) urged caution in interpreting it as a disease-associated variant. Daly et al. (2015) responded that the SNP rs73637412 describes both E308D (c.924G-C) and its synonymous counterpart, c.924G-A. The synonymous variant is reported at a lower frequency in the ExAC database than in other databases, suggesting discrepancies in variant calling. Daly et al. (2015) pointed out that the presence of the E308D variant in pituitary tumors, as well as constitutively, supports a gain of function.
Iacovazzo et al. (2016) sequenced DNA from 579 acromegaly patients and identified 4 patients with a germline E308D mutation in the GPR101 gene, none of whom had a family history of pituitary adenoma. The authors noted that the allele frequency of the E308D variant in this series, 0.45%, was similar to that reported in the ExAC database (0.37%).
In a patient with adult-onset sporadic acromegaly and invasive macroadenoma (PITA2; 300943), Kamenicky et al. (2015) identified a germline asp366-to-glu (D366E) mutation in the GPR101 gene. The mutation was not reported in the Exome Aggregation Consortium, 1000 Genomes Project, dbSNP, or Exome Variant Server databases. The D366E mutation is located in intracellular loop 3 of the GPR101 protein. No functional studies were performed.
Bates, B., Zhang, L., Nawoschik, S., Kodangattil, S., Tseng, E., Kopsco, D., Kramer, A., Shan, Q., Taylor, N., Johnson, J., Sun, Y., Chen, H. M., Blatcher, M., Paulsen, J. E., Pausch, M. H. Characterization of Gpr101 expression and G-protein coupling selectivity. Brain Res. 1087: 1-14, 2006. [PubMed: 16647048] [Full Text: https://doi.org/10.1016/j.brainres.2006.02.123]
Daly, A. F., Trivellin, G., Stratakis, C. A. Gigantism, acromegaly, and GPR101 mutations. (Letter) New Eng. J. Med. 372: 1265 only, 2015. [PubMed: 25806919] [Full Text: https://doi.org/10.1056/NEJMc1500340]
Franke, M., Daly, A. F., Palmeira, L., Tirosh, A., Stigliano, A., Trifan, E., Faucz, F. R., Abboud, D., Petrossians, P., Tena, J. J., Vitali, E., Lania, A. G., Gomez-Skarmeta, J. L., Beckers, A., Stratakis, C. A., Trivellin, G. Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism. Am. J. Hum. Genet. 109: 553-570, 2022. [PubMed: 35202564] [Full Text: https://doi.org/10.1016/j.ajhg.2022.02.002]
Hartz, P. A. Personal Communication. Baltimore, Md. 12/30/2014.
Iacovazzo, D., Caswell, R., Bunce, B., Jose, S., Yuan, B., Hernandez-Ramirez, L. C., Kapur, S., Caimari, F., Evanson, J., Ferrau, F., Dang, M. N., Gabrovska, P., and 23 others. Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study. Acta Neuropath. Commun. 4: 56, 2016. Note: Electronic Article. [PubMed: 27245663] [Full Text: https://doi.org/10.1186/s40478-016-0328-1]
Kamenicky, P., Bouligand, J., Chanson, P. Gigantism, acromegaly, and GPR101 mutations. (Letter) New Eng. J. Med. 372: 1264 only, 2015. [PubMed: 25806920] [Full Text: https://doi.org/10.1056/NEJMc1500340]
Lee, D. K., Nguyen, T., Lynch, K. R., Cheng, R., Vanti, W. B., Arkhitko, O., Lewis, T., Evans, J. F., George, S. R., O'Dowd, B. F. Discovery and mapping of ten novel G protein-coupled receptor genes. Gene 275: 83-91, 2001. [PubMed: 11574155] [Full Text: https://doi.org/10.1016/s0378-1119(01)00651-5]
Nilaweera, K. N., Wilson, D., Bell, L., Mercer, J. G., Morgan, P. J., Barrett, P. G protein-coupled receptor 101 mRNA expression in supraoptic and paraventricular nuclei in rat hypothalamus is altered by pregnancy and lactation. Brain Res. 1193: 76-83, 2008. [PubMed: 18187126] [Full Text: https://doi.org/10.1016/j.brainres.2007.11.048]
Roohi, J. Gigantism, acromegaly, and GPR101 mutations. (Letter) New Eng. J. Med. 372: 1264-1265, 2015. [PubMed: 25806921] [Full Text: https://doi.org/10.1056/NEJMc1500340]
Trivellin, G., Daly, A. F., Faucz, F. R., Yuan, B., Rostomyan, L., Larco, D. O., Schernthaner-Reiter, M. H., Szarek, E., Leal, L. F., Caberg, J.-H., Castermans, E., Villa, C., and 39 others. Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. New Eng. J. Med. 371: 2363-2374, 2014. [PubMed: 25470569] [Full Text: https://doi.org/10.1056/NEJMoa1408028]