HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: GPR101, an orphan GPCR with roles in growth and pituitary tumorigenesis

in Endocrine-Related Cancer

Correspondence should be addressed to C A Stratakis: stratakc@mail.nih.gov

This paper is part of a thematic section on current knowledge and future research opportunities in hereditary endocrine tumours, as discussed at MEN2019: 16th International Workshop on Multiple Endocrine Neoplasia, 27–29 March 2019, Houston, TX, USA. This meeting was sponsored by Endocrine-Related Cancer

A Beckers, A F Daly and C A Stratakis are members of the editorial board of Endocrine-Related Cancer. They were not involved in the review or editorial process for this paper, on which they are listed as authors

We recently described X-linked acrogigantism (X-LAG) in sporadic cases of infantile gigantism and a few familial cases of pituitary gigantism in the context of the disorder known as familial isolated pituitary adenomas. X-LAG cases with early onset gigantism (in infants or toddlers) shared copy number gains (CNG) of the distal long arm of chromosome X (Xq26.3). In all patients described to date with Xq26.3 CNG and acro-gigantism, the only coding gene sequence shared by all chromosomal defects was that of GPR101. GPR101 is a class A, rhodopsin-like orphan guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR) with no known endogenous ligand. We review what is known about GPR101, specifically its expression profile in human and animal models, the evidence supporting causation of X-LAG and possibly other roles, including its function in growth, puberty and appetite regulation, as well as efforts to identify putative ligands.

Abstract

We recently described X-linked acrogigantism (X-LAG) in sporadic cases of infantile gigantism and a few familial cases of pituitary gigantism in the context of the disorder known as familial isolated pituitary adenomas. X-LAG cases with early onset gigantism (in infants or toddlers) shared copy number gains (CNG) of the distal long arm of chromosome X (Xq26.3). In all patients described to date with Xq26.3 CNG and acro-gigantism, the only coding gene sequence shared by all chromosomal defects was that of GPR101. GPR101 is a class A, rhodopsin-like orphan guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR) with no known endogenous ligand. We review what is known about GPR101, specifically its expression profile in human and animal models, the evidence supporting causation of X-LAG and possibly other roles, including its function in growth, puberty and appetite regulation, as well as efforts to identify putative ligands.

Introduction

In 2014 (Trivellin et al. 2014), we described X-linked acrogigantism (X-LAG, MIM #300942), a disorder that presents with infant-onset overgrowth and gigantism due to growth hormone (GH) over secretion (Beckers et al. 2015, Hannah-Shmouni et al. 2016, Trivellin et al. 2018a). The clinical characteristics of patients with X-LAG are described in the accompanying review by Vasilev et al. (2020).

In this review, we will focus on the identification of what strongly appears to be the causative gene in X-LAG, GPR101, a class A, rhodopsin-like orphan guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR) (https://www.guidetopharmacology.org/GRAC/GPCRListForward?class=A) with an as yet unknown endogenous ligand (Alexander et al. 2019), the delineation of its expression and ongoing work in animal models.

Identification of GPR101 in X-LAG

To date, 36 patients have been reported to have X-LAG due to Xq26.3 copy number gains (CNG) (Trivellin et al. 2018a, Trivellin & Stratakis 2019). In more than 30 of these cases, array comparative genomic hybridization (aCGH) has been performed and confirmed that the smallest region of overlap (SRO) by these non-recurrent genomic rearrangements contains a single fully coded gene within a 73-kb sequence that is known to harbor GPR101 (SRO2) (Trivellin et al. 2018a). Patients also share an 8-kb sequence that includes the last two exons of the VGLL1 gene and the miRNA miR-934 (SRO1). All CNG described so far are duplications that involve just the Xq26.3 locus with no other genomic regions consistently affected (e.g., no insertions of the Xq26.3 genes to distant loci were reported).

The originally reported SRO contained at least four protein-coding genes and a number of other sequences, but subsequent work narrowed the X-LAG-linked region down to SRO1 and SRO2. Two subsequent cases helped to confirm the importance of GPR101: one subject with X-LAG in whom the SRO contained only GPR101 (Iacovazzo et al. 2016) and another boy with various developmental defects, who carried a Xq26.3 CNG that stopped short of including GPR101 and did not have overgrowth or other X-LAG related abnormalities (Trivellin et al. 2018b).

The duplications are on average about 600-kb long and are generated by replication errors at regions of microhomology which, in all but one case analyzed so far, can be explained by the mitotic DNA replication-based mechanism of fork stalling and template switching/microhomology-mediated break-induced replication (FoSTeS/MMBIR) (Trivellin et al. 2014, Beckers et al. 2015, Iacovazzo et al. 2016). An Alu-Alu mediated rearrangement was reported in the remaining case (Iacovazzo et al. 2016). So far, the CNG were germline in females and somatic in sporadic males, with mosaicism levels varying from 15% to 60% (Daly et al. 2016a, Iacovazzo et al. 2016, Rodd et al. 2016). However, the clinical characteristics of X-LAG patients are similar in both sexes (Beckers et al. 2015, Daly et al. 2016a). This suggests that even a small percentage of cells harboring the duplication in specific tissues is sufficient to cause the phenotype, as we have reviewed elsewhere (Trivellin et al. 2018a).

Moreover, the contribution of X chromosome inactivation (XCI) in females should be taken into consideration, as this could alter the expression of the duplicated genes. To test this hypothesis, we conducted an XCI analysis in 12 X-LAG patients. We observed skewed XCI in just two patients (17%) (Trivellin et al. 2014, Trivellin & Stratakis 2019). However, no significant differences in clinical phenotypes were observed in these two patients compared with the rest. This observation resembles what happens in mosaic males, in whom just a small fraction of cells with the duplicated X-chromosome leads to acrogigantism. While we cannot completely rule out an effect of age on the rate of skewing (these two patients were tested for XCI using blood that was collected, on average, 26 years later than the others), these data suggest that X-LAG patients commonly undergo random XCI. Most recently, it was reported that patients with autoimmunity and CD40LG duplications preferentially inactivate their duplicated X-chromosome (Le Coz et al. 2018). Although CD40LG, located in the Xq26.3 region about 400 kb upstream of GPR101, is commonly duplicated alongside GPR101 in patients with X-LAG, no autoimmune phenotypes have been observed to date (Beckers et al. 2015, Iacovazzo et al. 2016). This likely suggests that Xq26.3 CNG associated with X-LAG have a different impact on local chromatin domains and consequently on gene regulation, therefore causing unrelated phenotypes.

There are several results that support a crucial role for GPR101 as being the causative gene in X-LAG. Besides being the only entire protein-coding gene that is always duplicated in all X-LAG patients analyzed so far, as stated previously, it is also strongly over-expressed in their pituitary tumors/hyperplasia (up to 1000 times the expression levels detected in non-duplicated somatotroph tumors or the normal pituitary gland) (Trivellin et al. 2014, 2016), and it activates the cyclic AMP (cAMP) signaling pathway (Bates et al. 2006, Trivellin et al. 2014), which is one of the major stimuli of proliferation and GH and prolactin secretion in pituitary cells (Hernandez-Ramirez et al. 2018). GPR101 seems thus to behave as a putative oncogene in X-LAG, but it remains to be fully elucidated how this GPCR is involved in the pathogenesis of this disease. To address this aspect, our groups are currently characterizing GPR101 transgenic and knockout mouse and zebrafish models.

Moreover, there is no published data as yet that explain how GPR101 expression is so massively enhanced in X-LAG lesions. Simplistically, by duplicating the genomic content of a DNA segment, one can expect to find double the expression of the affected genes. Clearly, what happens in X-LAG is more complicated than that. We hypothesize that Xq26.3 CNG affects local interactions of non-coding regulatory sequences; this, in turn, leads to the abnormal expression of GPR101 in specific tissues, such as the pituitary (Trivellin et al. 2014). Other tissues might be involved as well, but this will be difficult to prove since X-LAG patients develop gross lesions affecting only the pituitary gland; finer cellular and subcellular abnormalities in other tissues such as the brain are difficult to assess in humans. The animal models under study can also help to shed light on this still obscure aspect of X-LAG molecular pathogenesis.

Although GPR101 was identified as a GPCR linked to Gs and is constitutively active, as shown by increased cAMP production following transient over-expression in HEK293 and GH3 cells (Bates et al. 2006, Trivellin et al. 2014), one recent study reported conflicting results (Martin et al. 2015). In the experimental setting used by the authors (CHO-K1 cells), GPR101 did not meet their criteria for constitutive activity (200% elevation over baseline cAMP-dependent response element (CRE) reporter activity). Further studies will be needed to address these different observations about the pharmacology of GPR101 in different cellular settings.

The GPR101 gene and protein: structure and expression

Structure

The human GPR101 gene was identified and found to be located on the X chromosome in 2001 (Lee et al. 2001), while its murine orthologue was identified 5 years later (Bates et al. 2006). Until we reported in late 2014 that GPR101 was associated with a pathological condition, X-LAG, only a handful of studies had investigated this orphan receptor, mainly in rodents. In the following 5 years, more than 30 studies on GPR101 and/or X-LAG came out, greatly contributing to expand our understanding of this disease and the biology of this receptor (Fig. 1). Indeed, until recently, just the coding sequence (CDS) of GPR101 was reported in human genome databases (NM_054021.1). GPR101 encodes a 508 amino acid-long GPCR; its CDS is composed of a single protein-coding exon that is about 80% and 55% identical to the rodents and zebrafish orthologues, respectively (http://www.ncbi.nlm.nih.gov/homologene/). Interestingly, some domains seem to have diverged substantially more than others during evolution, especially the intracellular loop 3 (ICL3) (Trivellin et al. 2018a, Hou & Tao 2019).

Figure 1
Figure 1

Number of publications studying GPR101 and X-LAG from 2001 to 2019. The following parameters were used for the search: source, PubMed; search terms, ‘GPR101’, ‘GPCR101’, ‘Xq26.3 microduplication’, ‘X-LAG’, ‘XLAG’, ‘X-linked acrogigantism’. Only relevant publications encompassing original studies or correspondence letters were included, while literature and systematic reviews were excluded.

Citation: Endocrine-Related Cancer 27, 8; 10.1530/ERC-20-0025

We contributed to the characterization of the structure of GPR101 by investigating its repertoire of transcripts (Trivellin et al. 2016a). We identified four isoforms generated by alternative splicing involving the 5ʹUTR; RNA-Seq data from X-LAG tumors allowed to discover that the 3ʹUTR is 6.1-kb long (Fig. 2). Isoform-1 is expressed at levels much higher than what is seen for the other isoforms in the pituitary cells of X-LAG patients; this finding suggests that this represents the main transcript, at least in the pituitary gland (Trivellin et al. 2016a). Supporting our findings, in the most recent assembly of the human genome (hg38), a novel transcript (ENST00000651716.1, GPR101–202) has been manually annotated from the Havana project (https://www.sanger.ac.uk/science/groups/vertebrate-annotation). The structure of this transcript closely resembles that of isoform-2 (Fig. 2), and it may be that the two isoforms actually represent the same transcript species.

Figure 2
Figure 2

The five different GPR101 isoforms reported in the literature (isoform-1 to isoform-4, (Trivellin et al. 2016a)) and in the UCSC Genome Browser (GPR101-202, http://genome.ucsc.edu/) were drawn with the Gene Structure Display Server (GSDS 2.0, http://gsds.cbi.pku.edu.cn/) (Hu et al. 2015). The location of two CpG islands, the transcription start sites (TSS) and a H3K4me3 mark (promoter-specific histone modification) are also indicated.

Citation: Endocrine-Related Cancer 27, 8; 10.1530/ERC-20-0025

We also predicted using bioinformatics that the GPR101 promoter is TATA-less and overlaps with a CpG island located about 2 kb upstream of the CDS, thus including the first non-coding exon of isoform-2 (Trivellin et al. 2016a). Interestingly, another CpG island overlaps with the ATG, indicating that GPR101 transcription may be regulated by two promoter sequences, but this prediction requires further confirmation. Estradiol was recently described to stimulate Gpr101 expression in the arcuate nucleus (ARC) in rats, but no classical estrogen response elements (EREs) were detected in Gpr101 promoter (Bauman et al. 2017).

GPCRs are integral membrane proteins with a common architecture: an extracellular N-terminal domain, seven transmembrane domains (TM1-TM7) linked by three extracellular (ECL1-ECL3) and three intracellular loops (ICL1-ICL3) and an intracellular C-terminal domain. While the TM domains show great similarity in overall architecture and secondary structure across different GPCRs, there is considerable variation among ICL and ECL regions, in particular the ICL3 (Moreira 2014). According to most recent estimates, the human genome contains about 800 GPCRs (Lv et al. 2016, Sriram & Insel 2018, Alexander et al. 2019), phylogenetically categorized into five classes: class A (rhodopsin-like), class B1 (secretin-like), class B2 (adhesion-like), class C (glutamate-like) and the Frizzled/Taste2 family. About half of the GPCRs have sensory functions, the rest are non-sensory GPCRs that mediate signaling, usually following ligand binding. Class A comprises the majority of GPCRs, 719, of which around 300 are non-sensory; about 90 class A GPCRs are categorized as ‘orphan’ (no known endogenous ligand) (Alexander et al. 2019). GPCRs vary greatly in length, with some consisting of more than 1000 residues; most, however, are around 200–400 amino acid in length (Tao & Conn 2014, Lv et al. 2016, Alexander et al. 2019).

Phylogenetic analyses revealed that GPR101 belongs to class A (Kakarala & Jamil 2014, Alexander et al. 2019), which includes the prototypical rhodopsin and β2-adrenergic receptors. Within class A, GPR101 belongs to the family of aminergic receptors (adrenergic, serotonin (5-HT), dopamine and histamine receptors). In particular, the 5-HT2C receptor shows the highest identity with GPR101 in the transmembrane domains (24%), while the 5-HT2B shows the highest identity in the putative binding cavity (28%) (analysis performed through the structure-based alignment tool of GPCRdb) (Munk et al. 2019). GPR101 was also shown to be related to GPR161, another orphan GPCR that is associated with primary cilia (Mukhopadhyay et al. 2013, Bachmann et al. 2016). Interestingly, GPR161 defects were associated to a pituitary developmental disorder: a homozygous loss-of-function (LOF) missense variant was observed in a consanguineous family with pituitary stalk interruption syndrome (Karaca et al. 2015).

A transmembrane topology and signal peptide analysis of human GPR101 predicted the absence of a N-terminal signal peptide for endoplasmic reticulum targeting and insertion (analysis performed with Phobius, http://phobius.sbc.su.se/, (Kall et al. 2004) and further confirmed by SignalP 4.1, http://www.cbs.dtu.dk/services/SignalP-4.1/, (Petersen et al. 2011)). This is not surprising, since the vast majority of GPCRs (90–95%) rather contain signal anchor sequences that are not cleaved-off but are inherent parts of the mature GPCRs. This function is usually exerted by TM1 (Rutz et al. 2015). Moreover, out of three highly conserved structural motifs involved in G protein coupling/recognition and activation, GPR101 was found to harbor only an intact E/DRY motif at the ECL2-TM3 interface (DRY residues 128–130), while it lacks a complete BBXXB motif (B represents a basic residue and X a non-basic residue) at the ICL3-TM6 interface (CKAAK residues 395–399) and a complete D/NPXXY motif within TM7 (HPYVY residues 450–454). As in the majority of GPCRs, GPR101 contains also two conserved cysteines in TM3 and ECL2 that form a disulphide bond (residues 104 and 182) (Trivellin et al. 2018a). Different kinases usually phosphorylate GPCRs at serine/threonine residues located in the ICL3 and C-terminus after activation of the receptor. This event promotes β-arrestin binding, which, in turn, leads to receptor desensitization and internalization (Yang et al. 2017). Four phosphorylation sites at serine 15 (N-terminus), 27 (TM1) and 309–310 (ICL3) have been functionally annotated for GPR101 (Hornbeck et al. 2015). It is interesting to note that the p.E308D variant precedes the ICL3 phosphorylation site and might therefore interfere with this post-translational modification, an hypothesis that needs to be tested.

Out of the more than 800 diverse GPCRs, about 60 have been crystalized to date (https://zhanglab.ccmb.med.umich.edu/GPCR-EXP/); the vast majority belongs to class A (Munk et al. 2019). The modest number of crystalized 3D structures depends mainly by challenges in GPCRs expression, purification, stability and crystallization (Salon et al. 2011). Using the crystallized structure of the activated β2 adrenergic receptor (β2 AR) as a template, we have previously generated an in silico predicted structural model of GPR101 in complex with the Gs heterotrimer (Trivellin et al. 2014). Of note, the long ICL3 connecting TM5 and TM6 (163 amino acids, about 30% of the total protein length) could not be modeled because of the lack of a template. ICL3 is indeed one of the least conserved GPCR domains, being very heterogeneous in sequence and length. In particular, the difference in length (which can range from five to up to hundreds of residues) has been proposed to account for selectivity on G proteins coupling (Katritch et al. 2012, Bouvier 2013).

Tissue expression

Different labs have extensively studied GPR101 mRNA and protein expression in vertebrate tissues. Several studies revealed a strong expression in the CNS in different species (zebrafish, rodents and humans), suggesting its function has been conserved during evolution. In particular, GPR101 is highly expressed in the amygdala and hypothalamus, especially the ARC, and in the nucleus accumbens (NAc) (Bates et al. 2006, Nilaweera et al. 2007, 2008, Regard et al. 2008, GTEx Consortium 2013, Ronnekleiv et al. 2014, Trivellin et al. 2014, 2016a, Ehrlich et al. 2018, LaRese et al. 2019, Ieda et al. 2020). Other human tissues showing moderate mRNA expression are fat, optic nerve and lymphocytes (Trivellin et al. 2016a). The detection of GPR101 in the NAc is an interesting finding, especially in the context of X-LAG. The NAc is the main component of ventral striatum and is involved in food reward by coding for motivated appetite behavior (Uribe-Cerda et al. 2018). About one-third of X-LAG patients show increased food seeking, a behavior that we speculate might be controlled by GPR101 (Beckers et al. 2015). Supporting the findings in humans, Gpr101 expression in mouse brain regions was found to positively correlate with GPR101 expression in human brain. In mice, Gpr101 was found to be restricted in the shell of the NAc, enriched in the central amygdala and densely localized throughout several hypothalamic nuclei (Ehrlich et al. 2018). Moreover, Gpr101 was reported as a marker of γ-Aminobutyric acid (GABA) neurons and also expressed by a small subgroup of dopamine neurons within the ventral tegmental area (VTA) (Paul et al. 2019). Starvation was also found to increase Gpr101 expression in the posterior hypothalamus, while ob/ob obese mice showed decreased expression. Within the ARC, Gpr101 is expressed in about 50% of the neurons expressing the anorexigenic peptide proopiomelanocortin (POMC) (Nilaweera et al. 2007) and in glutamatergic neurons (Ieda et al. 2020), while thyrotropin-releasing hormone (TRH) positive neurons expressed Gpr101 in the lateral hypothalamus (Mickelsen et al. 2019). All these brain regions are implicated in various aspects of feeding and reward (Uribe-Cerda et al. 2018). Interestingly, several GPCRs endowed with constitutive activity play a crucial role in modulating dopamine signaling in the mesolimbic dopamine system, a neural network critical in processing rewards and their cues (Meye et al. 2014). GPR101 might well be one of these. Altogether, these findings suggest a possible role for GPR101 in the control of energy balance and showed that mice may represent a good model to test this hypothesis.

The expression of Gpr101 in the medial preoptic (mPOA) area in mice suggests also a possible role for this GPCR in reproduction. Gonadotrophin-releasing hormone (GnRH) is the master regulator of reproduction through its activity on the hypothalamus–pituitary–gonadal axis, and the mPOA is a major site for GnRH cell bodies. In the ARC, kisspeptin neurons control the pulsatile release of GnRH. Very few kisspeptin neurons express Gpr101, while Gpr101 is found in the glutamatergic neurons (Ieda et al. 2020). Since glutamate stimulates luteinizing hormone (LH) release from the pituitary by affecting kisspeptin neurons (Uenoyama et al. 2015), these findings raise the possibility that GPR101 signaling may facilitate LH release via indirect activation of kisspeptin neurons (Ieda et al. 2020). Further studies are therefore necessary to shed light on the precise role played by GPR101 in reproduction.

The elevated circulating growth hormone releasing hormone (GHRH) levels detected in some X-LAG patients (Daly et al. 2016b) pointed toward the possible regulation of hypothalamic GHRH secretion by GPR101. The high levels of GPR101 in the ARC, where GHRH neurons are localized, support this hypothesis. However, no studies have yet specifically addressed whether GPR101 indeed co-localizes with GHRH in the ARC. Whether GPR101 has a direct or indirect effect on GHRH secretion is still an answered question.

In the normal human anterior pituitary gland, GPR101 seems to show an age-dependent pattern of expression. GPR101 was indeed found to be strongly expressed during fetal development (starting at around the gestational age of 19 weeks), while it appears only moderately so during the so-called adolescent growth spurt; on the contrary, GPR101 is expressed at very low levels in adult life. This expression pattern points toward an important physiological role for GPR101 during pituitary maturation. Moreover, the strong expression restricted to the lateral wings of the fetal anterior lobe, where most GH- and prolactin-secreting cells are located, suggests that GPR101 might regulate, directly or indirectly, the differentiation of mammosomatotroph cells. In the adult pituitary gland of rat and rhesus macaque, GPR101 is expressed in different cell types: gonadotroph cells in monkey and somatotrophs in rat. These results imply that GPR101 might have different functions in the pituitary gland of different species (Trivellin et al. 2016a, 2018a).

As mentioned in the previous section, GPR101 was found to be strongly over-expressed both at the mRNA and protein level in the pituitary lesions of X-LAG patients (Trivellin et al. 2014, 2016a). However, GPR101 rarely co-localized with GH-expressing cells, as assessed by immunostaining (Trivellin et al. 2014). The tumors expressed relatively high levels of somatostatin receptor type 2 and GHRH receptor (Beckers et al. 2015), as well as stem cell/progenitor cell markers such as SOX2 and OCT4 and multiple lineage-specific transcription factors such as PIT1, suggesting that the tumors are multipotential (Wise-Oringer et al. 2019).

GnRH-(1–5) and RvD5n-3 DPA: putative ligands?

GPCRs can be activated by an extremely diverse repertoire of ligands (Alexander et al. 2019). In 2014, the same year we described X-LAG, GnRH-(1–5), a processed pentapeptide cleaved from GnRH, was reported as a putative GPR101 ligand (Cho-Clark et al. 2014). GnRH-(1–5) is involved in reproduction by regulating GnRH and LH levels (Wu et al. 2005, Ieda et al. 2020). In Ishikawa cells (endometrial cancer), following GPR101 binding, GnRH-(1–5) induced EGF release, followed by EGF receptor (EGFR) phosphorylation and activation of downstream signaling pathways; this ultimately led to increased proliferation, migration and invasion (Cho-Clark et al. 2014, 2015). However, this ligand does not seem to be effective in pituitary cells secreting GH and prolactin. Indeed, no significant effects on cAMP pathway activation and hormone secretion were observed in in vitro studies using GH3 cells (rat pituitary tumor cells) and primary X-LAG tumor cells with high GPR101 expression (Naves et al. 2016, Trivellin et al. 2018a). Since the treatment of Ishikawa cells with GnRH-(1–5) had no effect on cAMP accumulation (Baldwin et al. 2007), it is possible that this molecule activates a different signal transduction pathway in a cell type-dependent fashion. Further studies employing different and relevant cell types using the same experimental settings are needed to determine whether this is indeed the case.

Most recently, N-3 docosapentaenoic acid-derived resolvin D5 (RvD5n-3 DPA), an autacoid, pro-resolving mediator, regulating inflammatory responses like arachidonic acid was reported as a putative ligand of GPR101 in macrophages and other monocytes (Flak et al. 2020). Interestingly, knockdown of GPR101 reversed the protective actions of RvD5n-3 DPA in limiting inflammatory arthritis, suggesting a potential role for GPR101 in the regulation of inflammation in leucocytes (Flak et al. 2020). It remains unclear how these findings translate to the pituitary gland and hypothalamic GPR101 functions and require characterization in these tissues.

GPCRs are considered the largest family of targets for approved pharmaceutical drugs, with estimates of around 30–50% of them targeting these proteins (Fang et al. 2015). We are currently performing a high-throughput screening of small molecule libraries to identify additional GPR101-binding molecules. Clearly, the discovery of inhibitors, especially inverse agonists, can be very beneficial to illuminate the physiology of GPR101 and hopefully can lead to a specific treatment for X-LAG patients.

Is GPR101 involved in other diseases?

Like we and others have done elsewhere (Trivellin et al. 2018a, Hou & Tao 2019), we will discuss here several rare GPR101 single nucleotide variants (SNVs) with a global minor allele frequency (MAF) <1% as reported in the Genome Aggregation Database (gnomAD). These variants have been reported in patients with X-LAG and other pathologies, such as other types of pituitary tumors, GH deficiency and heterotaxy. With the exception of c.370G>T (p.V124L, MAF = 36.7%), more common SNVs such as c.878C>T (p.T293I, MAF = 2.2%) and c.1127T>C (p.L376P, MAF = 16.8%) will not be discussed. The location of all naturally occurring SNVs is shown in Fig. 3.

Figure 3
Figure 3

The 2D-predicted structure of GPR101 was retrieved from GPCRdb (https://gpcrdb.org/) and modified to accurately demarcate the transmembrane domains. The N-terminal domain is given in red, while the C-terminus is given in yellow; the seven TM domains are highlighted with a different saturation of blue and purple; ICL3 is in green; all other domains are in white; the naturally occurring SNVs are given in black.

Citation: Endocrine-Related Cancer 27, 8; 10.1530/ERC-20-0025

A heterozygous missense SNV affecting residue 308 (c.924G>C, p.E308D), located within ICL3, was identified in about 4% of patients with sporadic acromegaly, in one case occurring de novo in the pituitary tumor (Trivellin et al. 2014). This variant was described in controls with a MAF of 0.36%. A synonymous SNV affecting the same residue (c.924G>A, p.E308D) was also observed with a MAF of 0.18% (Lek et al. 2016). p.E308D moderately increased GH secretion and cell proliferation when transiently over-expressed in GH- and prolactin-secreting cells (Trivellin et al. 2014). However, subsequent studies in separate cohorts of acromegaly patients did not find an increased prevalence, suggesting that it probably does not contribute to the pathogenesis of this disease (Ferrau et al. 2016, Iacovazzo et al. 2016, Lecoq et al. 2016, Matsumoto et al. 2016). Interestingly, p.E308D was identified by whole exome sequencing (WES) as a secondary finding in two out of six patients with premature ovarian failure primarily caused by hemizygous deletions in genes essential for meiosis or folliculogenesis (Tsuiko et al. 2016). Another heterozygous missense, SNV located in ICL3, c.1098C>A (p.D366E), was also reported in a patient with sporadic acromegaly (Lecoq et al. 2016). This variant has been submitted to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) with accession number RCV000172847.6. p.D366E was not found in controls or in a series of almost 400 patients with sporadic acromegaly (Iacovazzo et al. 2016) but has not been functionally tested yet. A structural hypothesis on the effect of all SNVs located on ICL3 cannot be proposed at the moment giving the absence of a properly modeled domain. Solving the structure of GPR101 would constitute a great step toward a better understanding of the effects of its variants, especially since ICL3, where many of the variants are located, appears to be a hotspot for gain-of-function SNVs (Fukami et al. 2018).

Other nonsynonymous SNVs were also detected in other types of pituitary tumors, such as prolactinomas and corticotropinomas. Two heterozygous missense SNVs affecting highly conserved amino acids, c.974C>T (p.T325I) and c.1294C>T (p.P432S), were found in one prolactinoma patient each (cohort of 256 patients). p.T325I is a novel SNV located in ICL3, while p.P432S in ECL3 and is rarely seen in controls (MAF = 0.04%) (Lecoq et al. 2016). The impact of these SNVs on the structure/function of GPR101 is not known. Two heterozygous missense SNVs were also described in patients with Cushing disease (CD). A novel SNV in TM3, c.365T>C (p.I122T), was reported in a female patient (cohort of 68 patients) (Lecoq et al. 2016). This SNV affects a highly conserved residue and is predicted to be deleterious, but no in vitro studies have been done. A rare SNV located in TM1, c.91G>A (p.G31S, MAF = 0.11%), was also reported in a separate cohort (36 CD patients). This SNV was evaluated in vitro in a mouse corticotroph tumor cell line (AtT-20 cells) but did not affect ACTH secretion or cell proliferation (Trivellin et al. 2016b).

GPR101 has also been screened for LOF SNVs and deletions in patients with congenital isolated GH deficiency (GHD) of unknown genetic etiology (cohort of 41 patients). A novel heterozygous missense SNV in TM5, c.589G>T (p.V197L), was found in one female patient. Although predicted to be deleterious, when functionally tested in GH3 cells, it did not significantly decrease GH secretion or intracellular cAMP levels (Castinetti et al. 2016).

Heterotaxy syndrome is a condition arising from defects of the correct specification of left–right patterning established during embryonic development. Interestingly, GPR101 is located next to ZIC3, a gene causing X-linked heterotaxy (Paulussen et al. 2016). Moreover, GPR161, a GPCR related to GPR101 (Mukhopadhyay et al. 2013), was also shown to be required for left–right patterning (Leung et al. 2008). A rare (MAF = 0.07%) missense SNV in GPR101, c.1225G>A (p.V409M), was detected by WES in one family with X-linked heterotaxy. The pedigree consisted of four affected males. This SNV is located in TM6, was predicted to be damaging, and functional studies in animal models supported a causative role (Tariq et al. 2013). However, peer-reviewed studies are necessary to confirm these preliminary findings published as a conference proceeding.

Most recently, the common p.V124L GPR101 SNV was reported in a meta-analysis of up to 622,409 individuals as being associated with smoking behavior traits, specifically cigarettes per day and pack-years (Erzurumluoglu et al. 2019). This finding is intriguing in light of the expression of GPR101 in brain regions associated with addictive behaviors.

In addition to variants within the CDS, the promoter region of GPR101 was found to be hypermethylated in about 40% of patients with colorectal cancer (Kober et al. 2011); this epigenetic modification was found to be of prognostic value in stage-IV male patients, as it correlated with a longer time to disease progression.

Conclusions and future perspectives

Since the discovery of GPR101 almost 20 years ago, some progress, mainly concentrated during the last 6 years, has been made. This was mainly due to a strong boost in research that took place after the characterization of X-LAG and was aided by the rapid progress in the development of new high-throughput screening technologies. We have now started to shed light on the expression pattern of this orphan GPCR in different vertebrates, its regulatory regions and isoforms and the intracellular signaling pathways engaged when active; new putative ligands have been reported, as well as naturally occurring SNVs.

Clearly, much more needs to be done. Concerning physiological functions, we need to dissect the potential roles played by GPR101 in regulating appetite, energy homeostatis, reproduction and human growth. How GPR101 affects GH release and pituitary function in physiological and pathological states needs also to be investigated. Many questions concerning the biology of GPR101 remain still unanswered. For example, the role of the two reported putative ligands needs to be further investigated in physiologically representative models as well as the constitutive activity and activation of G proteins in different cell types. Finding new ligands, especially inhibitors, would also aid in the treatment of X-LAG. From a genetic perspective, functional studies for many SNVs are still lacking. How GPR101 expression is regulated and what are the pituitary cell types expressing this receptor in the context of X-LAG are also two important translational aspects that have to be addressed. Clarifying these and many other gaps in knowledge using the most recent technological tools at our disposal as well as novel animal models will ultimately benefit not only our basic understanding of GPR101 but also, more importantly, the patients that harbor defects in this orphan GPCR.

Declaration of interest

Dr Trivellin, Dr Faucz, Dr Stratakis, Dr Daly and Dr Beckers hold patents on technologies involving GPR101 causing pituitary tumors. Both laboratories have received research funding support by Pfizer Inc. for investigations on growth hormone-producing pituitary adenomas.

Funding

This study was funded by the NICHD Intramural Research Program, Bethesda, MD, USA (Dr Trivellin, Dr Faucz and Dr Stratakis), and supported by grants from the FIRS-CHU de Liège 2018–2019 and from the JABBS Foundation, UK (Dr Daly and Dr Beckers).

References

  • AlexanderSPHChristopoulosADavenportAPKellyEMathieAPetersJAVealeELArmstrongJFFaccendaEHardingSDet al. 2019 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein-coupled receptors. British Journal of Pharmacology 176 (Supplement 1) S21S141. (https://doi.org/10.1111/bph.14748)

    • Search Google Scholar
    • Export Citation
  • BachmannVAMayrhoferJEIlouzRTschaiknerPRaffeinerPRockRCourcellesMApeltFLuTWBaillieGSet al. 2016 Gpr161 anchoring of PKA consolidates GPCR and cAMP signaling. PNAS 113 77867791. (https://doi.org/10.1073/pnas.1608061113)

    • Search Google Scholar
    • Export Citation
  • BaldwinELWegorzewskaINFloraMWuTJ 2007 Regulation of type II luteinizing hormone-releasing hormone (LHRH-II) gene expression by the processed peptide of LHRH-I, LHRH-(1–5) in endometrial cells. Experimental Biology and Medicine 232 146155. (https://doi.org/10.3181/00379727-207-2320146)

    • Search Google Scholar
    • Export Citation
  • BatesBZhangLNawoschikSKodangattilSTsengEKopscoDKramerAShanQTaylorNJohnsonJet al. 2006 Characterization of Gpr101 expression and G-protein coupling selectivity. Brain Research 1087 114. (https://doi.org/10.1016/j.brainres.2006.02.123)

    • Search Google Scholar
    • Export Citation
  • BaumanBMYinWGoreACWuTJ 2017 Regulation of gonadotropin-releasing hormone-(1–5) signaling genes by estradiol is age dependent. Frontiers in Endocrinology 8 282. (https://doi.org/10.3389/fendo.2017.00282)

    • Search Google Scholar
    • Export Citation
  • BeckersALodishMBTrivellinGRostomyanLLeeMFauczFRYuanBChoongCSCabergJHVerruaEet al. 2015 X-linked acrogigantism syndrome: clinical profile and therapeutic responses. Endocrine-Related Cancer 22 353367. (https://doi.org/10.1530/ERC-15-0038)

    • Search Google Scholar
    • Export Citation
  • BouvierM 2013 Unraveling the structural basis of GPCR activation and inactivation. Nature Structural and Molecular Biology 20 539541. (https://doi.org/10.1038/nsmb.2584)

    • Search Google Scholar
    • Export Citation
  • CastinettiFDalyAFStratakisCACabergJHCastermansETrivellinGRostomyanLSaveanuAJullienNReynaudRet al. 2016 GPR101 mutations are not a frequent cause of congenital isolated growth hormone deficiency. Hormone and Metabolic Research 48 389393. (https://doi.org/10.1055/s-0042-100733)

    • Search Google Scholar
    • Export Citation
  • Cho-ClarkMLarcoDOSemsarzadehNNVastaFManiSKWuTJ 2014 GnRH-(1–5) transactivates EGFR in Ishikawa human endometrial cells via an orphan G protein-coupled receptor. Molecular Endocrinology 28 8098. (https://doi.org/10.1210/me.2013-1203)

    • Search Google Scholar
    • Export Citation
  • Cho-ClarkMLarcoDOZahnBRManiSKWuTJ 2015 GnRH-(1–5) activates matrix metallopeptidase-9 to release epidermal growth factor and promote cellular invasion. Molecular and Cellular Endocrinology 415 114125. (https://doi.org/10.1016/j.mce.2015.08.010)

    • Search Google Scholar
    • Export Citation
  • DalyAFYuanBFinaFCabergJHTrivellinGRostomyanLde HerderWWNavesLAMetzgerDCunyTet al. 2016a Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects. Endocrine-Related Cancer 23 221233. (https://doi.org/10.1530/ERC-16-0082)

    • Search Google Scholar
    • Export Citation
  • DalyAFLysyPADesfillesCRostomyanLMohamedACabergJHRaverotVCastermansEMarbaixEMaiterDet al. 2016b GHRH excess and blockade in X-LAG syndrome. Endocrine-Related Cancer 23 161-170. (https://doi.org/10.1530/ERC-15-0478)

    • Search Google Scholar
    • Export Citation
  • EhrlichATMaroteauxGRobeAVenteoLNasseefMTvan KempenLCMechawarNTureckiGDarcqEKiefferBL 2018 Expression map of 78 brain-expressed mouse orphan GPCRs provides a translational resource for neuropsychiatric research. Communications Biology 1 102. (https://doi.org/10.1038/s42003-018-0106-7)

    • Search Google Scholar
    • Export Citation
  • ErzurumluogluAMLiuMJacksonVEBarnesDRDattaGMelbourneCAYoungRBatiniCSurendranPJiangTet al. 2019 Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci. Molecular Psychiatry [epub]. (https://doi.org/10.1038/s41380-018-0313-0)

    • Search Google Scholar
    • Export Citation
  • FangYKenakinTLiuC 2015 Editorial: Orphan GPCRs as emerging drug targets. Frontiers in Pharmacology 6 295. (https://doi.org/10.3389/fphar.2015.00295)

    • Search Google Scholar
    • Export Citation
  • FerrauFRomeoPDPuglisiSRagoneseMTorreMLScaroniCOcchiGDe MenisEArnaldiGTrimarchiFet al. 2016 Analysis of GPR101 and AIP genes mutations in acromegaly: a multicentric study. Endocrine 54 762767. (https://doi.org/10.1007/s12020-016-0862-4)

    • Search Google Scholar
    • Export Citation
  • FlakMBKoenisDSSobrinoASmithJPistoriusKPalmasFDalliJ 2020 GPR101 mediates the pro-resolving actions of RvD5n-3 DPA in arthritis and infections. Journal of Clinical Investigation 130 359373. (https://doi.org/10.1172/JCI131609)

    • Search Google Scholar
    • Export Citation
  • FukamiMSuzukiEIgarashiMMiyadoMOgataT 2018 Gain-of-function mutations in G-protein-coupled receptor genes associated with human endocrine disorders. Clinical Endocrinology 88 351359. (https://doi.org/10.1111/cen.13496)

    • Search Google Scholar
    • Export Citation
  • GTEx Consortium 2013 The genotype-tissue expression (GTEx) project. Nature Genetics 45 580585. (https://doi.org/10.1038/ng.2653)

  • Hannah-ShmouniFTrivellinGStratakisCA 2016 Genetics of gigantism and acromegaly. Growth Hormone and IGF Research 30–31 3741. (https://doi.org/10.1016/j.ghir.2016.08.002)

    • Search Google Scholar
    • Export Citation
  • Hernandez-RamirezLCTrivellinGStratakisCA 2018 Cyclic 3′,5′-adenosine monophosphate (cAMP) signaling in the anterior pituitary gland in health and disease. Molecular and Cellular Endocrinology 463 7286. (https://doi.org/10.1016/j.mce.2017.08.006)

    • Search Google Scholar
    • Export Citation
  • HornbeckPVZhangBMurrayBKornhauserJMLathamVSkrzypekE 2015 PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Research 43 D512D520. (https://doi.org/10.1093/nar/gku1267)

    • Search Google Scholar
    • Export Citation
  • HouZSTaoYX 2019 Mutations in GPR101 as a potential cause of X-linked acrogigantism and acromegaly. Progress in Molecular Biology and Translational Science 161 4767. (https://doi.org/10.1016/bs.pmbts.2018.10.003)

    • Search Google Scholar
    • Export Citation
  • HuBJinJGuoAYZhangHLuoJGaoG 2015 GSDS 2.0: an upgraded gene feature visualization server. Bioinformatics 31 12961297. (https://doi.org/10.1093/bioinformatics/btu817)

    • Search Google Scholar
    • Export Citation
  • IacovazzoDCaswellRBunceBJoseSYuanBHernandez-RamirezLCKapurSCaimariFEvansonJFerrauFet al. 2016 Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study. Acta Neuropathologica Communications 4 56. (https://doi.org/10.1186/s40478-016-0328-1)

    • Search Google Scholar
    • Export Citation
  • IedaNAssadullahMSIkegamiKWatanabeYSugimotoYSugimotoAKawaiNIshiiHInoueNet al. 2020 GnRH(1-5), a metabolite of gonadotropin-releasing hormone, enhances luteinizing hormone release via activation of kisspeptin neurons in female rats. Endocrine Journal 67 409–418. (https://doi.org/10.1507/endocrj.EJ19-0444)

    • Search Google Scholar
    • Export Citation
  • KakaralaKKJamilK 2014 Sequence-structure based phylogeny of GPCR class A rhodopsin receptors. Molecular Phylogenetics and Evolution 74 6696. (https://doi.org/10.1016/j.ympev.2014.01.022)

    • Search Google Scholar
    • Export Citation
  • KallLKroghASonnhammerEL 2004 A combined transmembrane topology and signal peptide prediction method. Journal of Molecular Biology 338 10271036. (https://doi.org/10.1016/j.jmb.2004.03.016)

    • Search Google Scholar
    • Export Citation
  • KaracaEBuyukkayaRPehlivanDCharngWLYaykasliKOBayramYGambinTWithersMAtikMMArslanogluIet al. 2015 Whole-exome sequencing identifies homozygous GPR161 mutation in a family with pituitary stalk interruption syndrome. Journal of Clinical Endocrinology and Metabolism 100 E140E147. (https://doi.org/10.1210/jc.2014-1984)

    • Search Google Scholar
    • Export Citation
  • KatritchVCherezovVStevensRC 2012 Diversity and modularity of G protein-coupled receptor structures. Trends in Pharmacological Sciences 33 1727. (https://doi.org/10.1016/j.tips.2011.09.003)

    • Search Google Scholar
    • Export Citation
  • KoberPBujkoMOledzkiJTysarowskiASiedleckiJA 2011 Methyl-CpG binding column-based identification of nine genes hypermethylated in colorectal cancer. Molecular Carcinogenesis 50 846856. (https://doi.org/10.1002/mc.20763)

    • Search Google Scholar
    • Export Citation
  • LaReseTPRheaumeBAAbrahamREipperBAMainsRE 2019 Sex-specific gene expression in the mouse nucleus accumbens before and after cocaine exposure. Journal of the Endocrine Society 3 468487. (https://doi.org/10.1210/js.2018-00313)

    • Search Google Scholar
    • Export Citation
  • Le CozCTrofaMSyrettCMMartinAJyonouchiHJyonouchiSAngueraMCRombergN 2018 CD40LG duplication-associated autoimmune disease is silenced by nonrandom X-chromosome inactivation. Journal of Allergy and Clinical Immunology 141 2308.e72311.e7. (https://doi.org/10.1016/j.jaci.2018.02.010)

    • Search Google Scholar
    • Export Citation
  • LecoqALBouligandJHageMCazabatLSalenaveSLinglartAYoungJGuiochon-MantelAChansonPKamenickyP 2016 Very low frequency of germline GPR101 genetic variation and no biallelic defects with AIP in a large cohort of patients with sporadic pituitary adenomas. European Journal of Endocrinology 174 523530. (https://doi.org/10.1530/EJE-15-1044)

    • Search Google Scholar
    • Export Citation
  • LeeDKNguyenTLynchKRChengRVantiWBArkhitkoOLewisTEvansJFGeorgeSRO’DowdBF 2001 Discovery and mapping of ten novel G protein-coupled receptor genes. Gene 275 8391. (https://doi.org/10.1016/s0378-1119(01)00651-5)

    • Search Google Scholar
    • Export Citation
  • LekMKarczewskiKJMinikelEVSamochaKEBanksEFennellTO’Donnell-LuriaAHWareJSHillAJCummingsBBet al. 2016 Analysis of protein-coding genetic variation in 60,706 humans. Nature 536 285291. (https://doi.org/10.1038/nature19057)

    • Search Google Scholar
    • Export Citation
  • LeungTHumbertJEStaufferAMGigerKEChenHTsaiHJWangCMirshahiTRobishawJD 2008 The orphan G protein-coupled receptor 161 is required for left-right patterning. Developmental Biology 323 3140. (https://doi.org/10.1016/j.ydbio.2008.08.001)

    • Search Google Scholar
    • Export Citation
  • LvXLiuJShiQTanQWuDSkinnerJJWalkerALZhaoLGuXChenNet al. 2016 In vitro expression and analysis of the 826 human G protein-coupled receptors. Protein and Cell 7 325337. (https://doi.org/10.1007/s13238-016-0263-8)

    • Search Google Scholar
    • Export Citation
  • MartinALSteurerMAAronstamRS 2015 Constitutive activity among orphan class-A G protein coupled receptors. PLoS ONE 10 e0138463. (https://doi.org/10.1371/journal.pone.0138463)

    • Search Google Scholar
    • Export Citation
  • MatsumotoRIzawaMFukuokaHIguchiGOdakeYYoshidaKBandoHSudaKNishizawaHTakahashiMet al. 2016 Genetic and clinical characteristics of Japanese patients with sporadic somatotropinoma. Endocrine Journal 63 953963. (https://doi.org/10.1507/endocrj.EJ16-0075)

    • Search Google Scholar
    • Export Citation
  • MeyeFJRamakersGMAdanRA 2014 The vital role of constitutive GPCR activity in the mesolimbic dopamine system. Translational Psychiatry 4 e361. (https://doi.org/10.1038/tp.2013.130)

    • Search Google Scholar
    • Export Citation
  • MickelsenLEBolisettyMChimileskiBRFujitaABeltramiEJCostanzoJTNaparstekJRRobsonPJacksonAC 2019 Single-cell transcriptomic analysis of the lateral hypothalamic area reveals molecularly distinct populations of inhibitory and excitatory neurons. Nature Neuroscience 22 642656. (https://doi.org/10.1038/s41593-019-0349-8)

    • Search Google Scholar
    • Export Citation
  • MoreiraIS 2014 Structural features of the G-protein/GPCR interactions. Biochimica and Biophysica Acta 1840 1633. (https://doi.org/10.1016/j.bbagen.2013.08.027)

    • Search Google Scholar
    • Export Citation
  • MukhopadhyaySWenXRattiNLoktevARangellLScalesSJJacksonPK 2013 The ciliary G-protein-coupled receptor Gpr161 negatively regulates the Sonic hedgehog pathway via cAMP signaling. Cell 152 210223. (https://doi.org/10.1016/j.cell.2012.12.026)

    • Search Google Scholar
    • Export Citation
  • MunkCMuttEIsbergVNikolajsenLFBibbeJMFlockTHansonMAStevensRCDeupiXGloriamDE 2019 An online resource for GPCR structure determination and analysis. Nature Methods 16 151162. (https://doi.org/10.1038/s41592-018-0302-x)

    • Search Google Scholar
    • Export Citation
  • NavesLADalyAFDiasLAYuanBZakirJCBarraGBPalmeiraLVillaCTrivellinGJuniorAJet al. 2016 Aggressive tumor growth and clinical evolution in a patient with X-linked acro-gigantism syndrome. Endocrine 51 236244. (https://doi.org/10.1007/s12020-015-0804-6)

    • Search Google Scholar
    • Export Citation
  • NilaweeraKNOzanneDWilsonDMercerJGMorganPJBarrettP 2007 G protein-coupled receptor 101 mRNA expression in the mouse brain: altered expression in the posterior hypothalamus and amygdala by energetic challenges. Journal of Neuroendocrinology 19 3445. (https://doi.org/10.1111/j.1365-2826.2006.01502.x)

    • Search Google Scholar
    • Export Citation
  • NilaweeraKNWilsonDBellLMercerJGMorganPJBarrettP 2008 G protein-coupled receptor 101 mRNA expression in supraoptic and paraventricular nuclei in rat hypothalamus is altered by pregnancy and lactation. Brain Research 1193 7683. (https://doi.org/10.1016/j.brainres.2007.11.048)

    • Search Google Scholar
    • Export Citation
  • PaulEJTossellKUnglessMA 2019 Transcriptional profiling aligned with in situ expression image analysis reveals mosaically expressed molecular markers for GABA neuron sub-groups in the ventral tegmental area. European Journal of Neuroscience 50 37323749. (https://doi.org/10.1111/ejn.14534)

    • Search Google Scholar
    • Export Citation
  • PaulussenADSteylsAVanoevelenJvan TienenFHKrapelsIPClaesGRChocronSVelterCTan-SindhunataGMLundinCet al. 2016 Rare novel variants in the ZIC3 gene cause X-linked heterotaxy. European Journal of Human Genetics 24 17831791. (https://doi.org/10.1038/ejhg.2016.91)

    • Search Google Scholar
    • Export Citation
  • PetersenTNBrunakSvon HeijneGNielsenH 2011 SignalP 4.0: discriminating signal peptides from transmembrane regions. Nature Methods 8 785786. (https://doi.org/10.1038/nmeth.1701)

    • Search Google Scholar
    • Export Citation
  • RegardJBSatoITCoughlinSR 2008 Anatomical profiling of G protein-coupled receptor expression. Cell 135 561571. (https://doi.org/10.1016/j.cell.2008.08.040)

    • Search Google Scholar
    • Export Citation
  • RoddCMilletteMIacovazzoDStilesCEBarrySEvansonJAlbrechtSCaswellRBunceBJoseSet al. 2016 Somatic GPR101 duplication causing X-linked acrogigantism (XLAG)-diagnosis and management. Journal of Clinical Endocrinology and Metabolism 101 19271930. (https://doi.org/10.1210/jc.2015-4366)

    • Search Google Scholar
    • Export Citation
  • RonnekleivOKFangYZhangCNestorCCMaoPKellyMJ 2014 Research resource: gene profiling of G protein-coupled receptors in the arcuate nucleus of the female. Molecular Endocrinology 28 13621380. (https://doi.org/10.1210/me.2014-1103)

    • Search Google Scholar
    • Export Citation
  • RutzCKleinWSchuleinR 2015 N-terminal signal peptides of G protein-coupled receptors: significance for receptor biosynthesis, trafficking, and signal transduction. Progress in Molecular Biology and Translational Science 132 267287. (https://doi.org/10.1016/bs.pmbts.2015.03.003)

    • Search Google Scholar
    • Export Citation
  • SalonJALodowskiDTPalczewskiK 2011 The significance of G protein-coupled receptor crystallography for drug discovery. Pharmacological Reviews 63 901937. (https://doi.org/10.1124/pr.110.003350)

    • Search Google Scholar
    • Export Citation
  • SriramKInselPA 2018 G Protein-coupled receptors as targets for approved drugs: how many targets and how many drugs? Molecular Pharmacology 93 251258. (https://doi.org/10.1124/mol.117.111062)

    • Search Google Scholar
    • Export Citation
  • TaoYXConnPM 2014 Chaperoning G protein-coupled receptors: from cell biology to therapeutics. Endocrine Reviews 35 602647. (https://doi.org/10.1210/er.2013-1121)

    • Search Google Scholar
    • Export Citation
  • TariqMCastABelmontJWareS 2013 Identification of a novel cause of X-linked heterotaxy. In ASHG 2013. Conference abstract.

  • TrivellinGStratakisCA 2019 CD40LG duplications in patients with X-LAG syndrome commonly undergo random X-chromosome inactivation. Journal of Allergy and Clinical Immunology 143 1659. (https://doi.org/10.1016/j.jaci.2018.12.1017)

    • Search Google Scholar
    • Export Citation
  • TrivellinGDalyAFFauczFRYuanBRostomyanLLarcoDOSchernthaner-ReiterMHSzarekELealLFCabergJHet al. 2014 Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. New England Journal of Medicine 371 23632374. (https://doi.org/10.1056/NEJMoa1408028)

    • Search Google Scholar
    • Export Citation
  • TrivellinGBjelobabaIDalyAFLarcoDOPalmeiraLFauczFRThiryALealLFRostomyanLQuezadoMet al. 2016a Characterization of GPR101 transcript structure and expression patterns. Journal of Molecular Endocrinology 57 97111. (https://doi.org/10.1530/JME-16-0045)

    • Search Google Scholar
    • Export Citation
  • TrivellinGCorreaRRBatsisMFauczFRChittiboinaPBjelobabaILarcoDOQuezadoMDalyAFStojilkovicSSet al. 2016b Screening for GPR101 defects in pediatric pituitary corticotropinomas. Endocrine-Related Cancer 23 357365. (https://doi.org/10.1530/ERC-16-0091)

    • Search Google Scholar
    • Export Citation
  • TrivellinGHernandez-RamirezLCSwanJStratakisCA 2018a An orphan G-protein-coupled receptor causes human gigantism and/or acromegaly: molecular biology and clinical correlations. Best Practice and Research. Clinical Endocrinology and Metabolism 32 125140. (https://doi.org/10.1016/j.beem.2018.02.004)

    • Search Google Scholar
    • Export Citation
  • TrivellinGSharwoodEHijaziHCarvalhoCMBYuanBTatton-BrownKComanDLupskiJRCotterillAMLodishMBet al. 2018b Xq26.3 duplication in a boy with motor delay and low muscle tone refines the X-linked Acrogigantism genetic locus. Journal of the Endocrine Society 2 11001108. (https://doi.org/10.1210/js.2018-00156)

    • Search Google Scholar
    • Export Citation
  • TsuikoONoukasMZilinaOHensenKTapanainenJSMagiRKalsMKivistikPAHaller-KikkataloKSalumetsAet al. 2016 Copy number variation analysis detects novel candidate genes involved in follicular growth and oocyte maturation in a cohort of premature ovarian failure cases. Human Reproduction 31 19131925. (https://doi.org/10.1093/humrep/dew142)

    • Search Google Scholar
    • Export Citation
  • UenoyamaYNakamuraSHayakawaYIkegamiKWatanabeYDeuraCMinabeSTomikawaJGotoTIedaNet al. 2015 Lack of pulse and surge modes and glutamatergic stimulation of luteinising hormone release in Kiss1 knockout rats. Journal of Neuroendocrinology 27 187197. (https://doi.org/10.1111/jne.12257)

    • Search Google Scholar
    • Export Citation
  • Uribe-CerdaSMorselliEPerez-LeightonC 2018 Updates on the neurobiology of food reward and their relation to the obesogenic environment. Current Opinion in Endocrinology Diabetes and Obesity 25 292297. (https://doi.org/10.1097/MED.0000000000000427)

    • Search Google Scholar
    • Export Citation
  • VasilevVDalyAFTrivellinGStratakisCAZacharievaSBeckersA 2020 HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: The roles of AIP and GPR101 in familial isolated pituitary adenomas (FIPA). Endocrine-Related Cancer 27 7786. (https://doi.org/10.1530/ERC-20-0015)

    • Search Google Scholar
    • Export Citation
  • Wise-OringerBKZanazziGJGordonRJWardlawSLWilliamCAnyane-YeboaKChungWKKohnBWisoffJHDavidRet al. 2019 Familial X-linked Acrogigantism: postnatal outcomes and tumor pathology in a prenatally diagnosed infant and his mother. Journal of Clinical Endocrinology and Metabolism 104 46674675. (https://doi.org/10.1210/jc.2019-00817)

    • Search Google Scholar
    • Export Citation
  • WuTJManiSKGlucksmanMJRobertsJL 2005 Stimulation of luteinizing hormone-releasing hormone (LHRH) gene expression in GT1-7 cells by its metabolite, LHRH-(1-5). Endocrinology 146 280286. (https://doi.org/10.1210/en.2004-0560)

    • Search Google Scholar
    • Export Citation
  • YangZYangFZhangDLiuZLinALiuCXiaoPYuXSunJP 2017 Phosphorylation of G protein-coupled receptors: from the barcode hypothesis to the flute model. Molecular Pharmacology 92 201210. (https://doi.org/10.1124/mol.116.107839)

    • Search Google Scholar
    • Export Citation

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  • View in gallery

    Number of publications studying GPR101 and X-LAG from 2001 to 2019. The following parameters were used for the search: source, PubMed; search terms, ‘GPR101’, ‘GPCR101’, ‘Xq26.3 microduplication’, ‘X-LAG’, ‘XLAG’, ‘X-linked acrogigantism’. Only relevant publications encompassing original studies or correspondence letters were included, while literature and systematic reviews were excluded.

  • View in gallery

    The five different GPR101 isoforms reported in the literature (isoform-1 to isoform-4, (Trivellin et al. 2016a)) and in the UCSC Genome Browser (GPR101-202, http://genome.ucsc.edu/) were drawn with the Gene Structure Display Server (GSDS 2.0, http://gsds.cbi.pku.edu.cn/) (Hu et al. 2015). The location of two CpG islands, the transcription start sites (TSS) and a H3K4me3 mark (promoter-specific histone modification) are also indicated.

  • View in gallery

    The 2D-predicted structure of GPR101 was retrieved from GPCRdb (https://gpcrdb.org/) and modified to accurately demarcate the transmembrane domains. The N-terminal domain is given in red, while the C-terminus is given in yellow; the seven TM domains are highlighted with a different saturation of blue and purple; ICL3 is in green; all other domains are in white; the naturally occurring SNVs are given in black.

  • AlexanderSPHChristopoulosADavenportAPKellyEMathieAPetersJAVealeELArmstrongJFFaccendaEHardingSDet al. 2019 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein-coupled receptors. British Journal of Pharmacology 176 (Supplement 1) S21S141. (https://doi.org/10.1111/bph.14748)

    • Search Google Scholar
    • Export Citation
  • BachmannVAMayrhoferJEIlouzRTschaiknerPRaffeinerPRockRCourcellesMApeltFLuTWBaillieGSet al. 2016 Gpr161 anchoring of PKA consolidates GPCR and cAMP signaling. PNAS 113 77867791. (https://doi.org/10.1073/pnas.1608061113)

    • Search Google Scholar
    • Export Citation
  • BaldwinELWegorzewskaINFloraMWuTJ 2007 Regulation of type II luteinizing hormone-releasing hormone (LHRH-II) gene expression by the processed peptide of LHRH-I, LHRH-(1–5) in endometrial cells. Experimental Biology and Medicine 232 146155. (https://doi.org/10.3181/00379727-207-2320146)

    • Search Google Scholar
    • Export Citation
  • BatesBZhangLNawoschikSKodangattilSTsengEKopscoDKramerAShanQTaylorNJohnsonJet al. 2006 Characterization of Gpr101 expression and G-protein coupling selectivity. Brain Research 1087 114. (https://doi.org/10.1016/j.brainres.2006.02.123)

    • Search Google Scholar
    • Export Citation
  • BaumanBMYinWGoreACWuTJ 2017 Regulation of gonadotropin-releasing hormone-(1–5) signaling genes by estradiol is age dependent. Frontiers in Endocrinology 8 282. (https://doi.org/10.3389/fendo.2017.00282)

    • Search Google Scholar
    • Export Citation
  • BeckersALodishMBTrivellinGRostomyanLLeeMFauczFRYuanBChoongCSCabergJHVerruaEet al. 2015 X-linked acrogigantism syndrome: clinical profile and therapeutic responses. Endocrine-Related Cancer 22 353367. (https://doi.org/10.1530/ERC-15-0038)

    • Search Google Scholar
    • Export Citation
  • BouvierM 2013 Unraveling the structural basis of GPCR activation and inactivation. Nature Structural and Molecular Biology 20 539541. (https://doi.org/10.1038/nsmb.2584)

    • Search Google Scholar
    • Export Citation
  • CastinettiFDalyAFStratakisCACabergJHCastermansETrivellinGRostomyanLSaveanuAJullienNReynaudRet al. 2016 GPR101 mutations are not a frequent cause of congenital isolated growth hormone deficiency. Hormone and Metabolic Research 48 389393. (https://doi.org/10.1055/s-0042-100733)

    • Search Google Scholar
    • Export Citation
  • Cho-ClarkMLarcoDOSemsarzadehNNVastaFManiSKWuTJ 2014 GnRH-(1–5) transactivates EGFR in Ishikawa human endometrial cells via an orphan G protein-coupled receptor. Molecular Endocrinology 28 8098. (https://doi.org/10.1210/me.2013-1203)

    • Search Google Scholar
    • Export Citation
  • Cho-ClarkMLarcoDOZahnBRManiSKWuTJ 2015 GnRH-(1–5) activates matrix metallopeptidase-9 to release epidermal growth factor and promote cellular invasion. Molecular and Cellular Endocrinology 415 114125. (https://doi.org/10.1016/j.mce.2015.08.010)

    • Search Google Scholar
    • Export Citation
  • DalyAFYuanBFinaFCabergJHTrivellinGRostomyanLde HerderWWNavesLAMetzgerDCunyTet al. 2016a Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects. Endocrine-Related Cancer 23 221233. (https://doi.org/10.1530/ERC-16-0082)

    • Search Google Scholar
    • Export Citation
  • DalyAFLysyPADesfillesCRostomyanLMohamedACabergJHRaverotVCastermansEMarbaixEMaiterDet al. 2016b GHRH excess and blockade in X-LAG syndrome. Endocrine-Related Cancer 23 161-170. (https://doi.org/10.1530/ERC-15-0478)

    • Search Google Scholar
    • Export Citation
  • EhrlichATMaroteauxGRobeAVenteoLNasseefMTvan KempenLCMechawarNTureckiGDarcqEKiefferBL 2018 Expression map of 78 brain-expressed mouse orphan GPCRs provides a translational resource for neuropsychiatric research. Communications Biology 1 102. (https://doi.org/10.1038/s42003-018-0106-7)

    • Search Google Scholar
    • Export Citation
  • ErzurumluogluAMLiuMJacksonVEBarnesDRDattaGMelbourneCAYoungRBatiniCSurendranPJiangTet al. 2019 Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci. Molecular Psychiatry [epub]. (https://doi.org/10.1038/s41380-018-0313-0)

    • Search Google Scholar
    • Export Citation
  • FangYKenakinTLiuC 2015 Editorial: Orphan GPCRs as emerging drug targets. Frontiers in Pharmacology 6 295. (https://doi.org/10.3389/fphar.2015.00295)

    • Search Google Scholar
    • Export Citation
  • FerrauFRomeoPDPuglisiSRagoneseMTorreMLScaroniCOcchiGDe MenisEArnaldiGTrimarchiFet al. 2016 Analysis of GPR101 and AIP genes mutations in acromegaly: a multicentric study. Endocrine 54 762767. (https://doi.org/10.1007/s12020-016-0862-4)

    • Search Google Scholar
    • Export Citation
  • FlakMBKoenisDSSobrinoASmithJPistoriusKPalmasFDalliJ 2020 GPR101 mediates the pro-resolving actions of RvD5n-3 DPA in arthritis and infections. Journal of Clinical Investigation 130 359373. (https://doi.org/10.1172/JCI131609)

    • Search Google Scholar
    • Export Citation
  • FukamiMSuzukiEIgarashiMMiyadoMOgataT 2018 Gain-of-function mutations in G-protein-coupled receptor genes associated with human endocrine disorders. Clinical Endocrinology 88 351359. (https://doi.org/10.1111/cen.13496)

    • Search Google Scholar
    • Export Citation
  • GTEx Consortium 2013 The genotype-tissue expression (GTEx) project. Nature Genetics 45 580585. (https://doi.org/10.1038/ng.2653)

  • Hannah-ShmouniFTrivellinGStratakisCA 2016 Genetics of gigantism and acromegaly. Growth Hormone and IGF Research 30–31 3741. (https://doi.org/10.1016/j.ghir.2016.08.002)

    • Search Google Scholar
    • Export Citation
  • Hernandez-RamirezLCTrivellinGStratakisCA 2018 Cyclic 3′,5′-adenosine monophosphate (cAMP) signaling in the anterior pituitary gland in health and disease. Molecular and Cellular Endocrinology 463 7286. (https://doi.org/10.1016/j.mce.2017.08.006)

    • Search Google Scholar
    • Export Citation
  • HornbeckPVZhangBMurrayBKornhauserJMLathamVSkrzypekE 2015 PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Research 43 D512D520. (https://doi.org/10.1093/nar/gku1267)

    • Search Google Scholar
    • Export Citation
  • HouZSTaoYX 2019 Mutations in GPR101 as a potential cause of X-linked acrogigantism and acromegaly. Progress in Molecular Biology and Translational Science 161 4767. (https://doi.org/10.1016/bs.pmbts.2018.10.003)

    • Search Google Scholar
    • Export Citation
  • HuBJinJGuoAYZhangHLuoJGaoG 2015 GSDS 2.0: an upgraded gene feature visualization server. Bioinformatics 31 12961297. (https://doi.org/10.1093/bioinformatics/btu817)

    • Search Google Scholar
    • Export Citation
  • IacovazzoDCaswellRBunceBJoseSYuanBHernandez-RamirezLCKapurSCaimariFEvansonJFerrauFet al. 2016 Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study. Acta Neuropathologica Communications 4 56. (https://doi.org/10.1186/s40478-016-0328-1)

    • Search Google Scholar
    • Export Citation
  • IedaNAssadullahMSIkegamiKWatanabeYSugimotoYSugimotoAKawaiNIshiiHInoueNet al. 2020 GnRH(1-5), a metabolite of gonadotropin-releasing hormone, enhances luteinizing hormone release via activation of kisspeptin neurons in female rats. Endocrine Journal 67 409–418. (https://doi.org/10.1507/endocrj.EJ19-0444)

    • Search Google Scholar
    • Export Citation
  • KakaralaKKJamilK 2014 Sequence-structure based phylogeny of GPCR class A rhodopsin receptors. Molecular Phylogenetics and Evolution 74 6696. (https://doi.org/10.1016/j.ympev.2014.01.022)

    • Search Google Scholar
    • Export Citation
  • KallLKroghASonnhammerEL 2004 A combined transmembrane topology and signal peptide prediction method. Journal of Molecular Biology 338 10271036. (https://doi.org/10.1016/j.jmb.2004.03.016)

    • Search Google Scholar
    • Export Citation
  • KaracaEBuyukkayaRPehlivanDCharngWLYaykasliKOBayramYGambinTWithersMAtikMMArslanogluIet al. 2015 Whole-exome sequencing identifies homozygous GPR161 mutation in a family with pituitary stalk interruption syndrome. Journal of Clinical Endocrinology and Metabolism 100 E140E147. (https://doi.org/10.1210/jc.2014-1984)

    • Search Google Scholar
    • Export Citation
  • KatritchVCherezovVStevensRC 2012 Diversity and modularity of G protein-coupled receptor structures. Trends in Pharmacological Sciences 33 1727. (https://doi.org/10.1016/j.tips.2011.09.003)

    • Search Google Scholar
    • Export Citation
  • KoberPBujkoMOledzkiJTysarowskiASiedleckiJA 2011 Methyl-CpG binding column-based identification of nine genes hypermethylated in colorectal cancer. Molecular Carcinogenesis 50 846856. (https://doi.org/10.1002/mc.20763)

    • Search Google Scholar
    • Export Citation
  • LaReseTPRheaumeBAAbrahamREipperBAMainsRE 2019 Sex-specific gene expression in the mouse nucleus accumbens before and after cocaine exposure. Journal of the Endocrine Society 3 468487. (https://doi.org/10.1210/js.2018-00313)

    • Search Google Scholar
    • Export Citation
  • Le CozCTrofaMSyrettCMMartinAJyonouchiHJyonouchiSAngueraMCRombergN 2018 CD40LG duplication-associated autoimmune disease is silenced by nonrandom X-chromosome inactivation. Journal of Allergy and Clinical Immunology 141 2308.e72311.e7. (https://doi.org/10.1016/j.jaci.2018.02.010)

    • Search Google Scholar
    • Export Citation
  • LecoqALBouligandJHageMCazabatLSalenaveSLinglartAYoungJGuiochon-MantelAChansonPKamenickyP 2016 Very low frequency of germline GPR101 genetic variation and no biallelic defects with AIP in a large cohort of patients with sporadic pituitary adenomas. European Journal of Endocrinology 174 523530. (https://doi.org/10.1530/EJE-15-1044)

    • Search Google Scholar
    • Export Citation
  • LeeDKNguyenTLynchKRChengRVantiWBArkhitkoOLewisTEvansJFGeorgeSRO’DowdBF 2001 Discovery and mapping of ten novel G protein-coupled receptor genes. Gene 275 8391. (https://doi.org/10.1016/s0378-1119(01)00651-5)

    • Search Google Scholar
    • Export Citation
  • LekMKarczewskiKJMinikelEVSamochaKEBanksEFennellTO’Donnell-LuriaAHWareJSHillAJCummingsBBet al. 2016 Analysis of protein-coding genetic variation in 60,706 humans. Nature 536 285291. (https://doi.org/10.1038/nature19057)

    • Search Google Scholar
    • Export Citation
  • LeungTHumbertJEStaufferAMGigerKEChenHTsaiHJWangCMirshahiTRobishawJD 2008 The orphan G protein-coupled receptor 161 is required for left-right patterning. Developmental Biology 323 3140. (https://doi.org/10.1016/j.ydbio.2008.08.001)

    • Search Google Scholar
    • Export Citation
  • LvXLiuJShiQTanQWuDSkinnerJJWalkerALZhaoLGuXChenNet al. 2016 In vitro expression and analysis of the 826 human G protein-coupled receptors. Protein and Cell 7 325337. (https://doi.org/10.1007/s13238-016-0263-8)

    • Search Google Scholar
    • Export Citation
  • MartinALSteurerMAAronstamRS 2015 Constitutive activity among orphan class-A G protein coupled receptors. PLoS ONE 10 e0138463. (https://doi.org/10.1371/journal.pone.0138463)

    • Search Google Scholar
    • Export Citation
  • MatsumotoRIzawaMFukuokaHIguchiGOdakeYYoshidaKBandoHSudaKNishizawaHTakahashiMet al. 2016 Genetic and clinical characteristics of Japanese patients with sporadic somatotropinoma. Endocrine Journal 63 953963. (https://doi.org/10.1507/endocrj.EJ16-0075)

    • Search Google Scholar
    • Export Citation
  • MeyeFJRamakersGMAdanRA 2014 The vital role of constitutive GPCR activity in the mesolimbic dopamine system. Translational Psychiatry 4 e361. (https://doi.org/10.1038/tp.2013.130)

    • Search Google Scholar
    • Export Citation
  • MickelsenLEBolisettyMChimileskiBRFujitaABeltramiEJCostanzoJTNaparstekJRRobsonPJacksonAC 2019 Single-cell transcriptomic analysis of the lateral hypothalamic area reveals molecularly distinct populations of inhibitory and excitatory neurons. Nature Neuroscience 22 642656. (https://doi.org/10.1038/s41593-019-0349-8)

    • Search Google Scholar
    • Export Citation
  • MoreiraIS 2014 Structural features of the G-protein/GPCR interactions. Biochimica and Biophysica Acta 1840 1633. (https://doi.org/10.1016/j.bbagen.2013.08.027)

    • Search Google Scholar
    • Export Citation
  • MukhopadhyaySWenXRattiNLoktevARangellLScalesSJJacksonPK 2013 The ciliary G-protein-coupled receptor Gpr161 negatively regulates the Sonic hedgehog pathway via cAMP signaling. Cell 152 210223. (https://doi.org/10.1016/j.cell.2012.12.026)

    • Search Google Scholar
    • Export Citation
  • MunkCMuttEIsbergVNikolajsenLFBibbeJMFlockTHansonMAStevensRCDeupiXGloriamDE 2019 An online resource for GPCR structure determination and analysis. Nature Methods 16 151162. (https://doi.org/10.1038/s41592-018-0302-x)

    • Search Google Scholar
    • Export Citation
  • NavesLADalyAFDiasLAYuanBZakirJCBarraGBPalmeiraLVillaCTrivellinGJuniorAJet al. 2016 Aggressive tumor growth and clinical evolution in a patient with X-linked acro-gigantism syndrome. Endocrine 51 236244. (https://doi.org/10.1007/s12020-015-0804-6)

    • Search Google Scholar
    • Export Citation
  • NilaweeraKNOzanneDWilsonDMercerJGMorganPJBarrettP 2007 G protein-coupled receptor 101 mRNA expression in the mouse brain: altered expression in the posterior hypothalamus and amygdala by energetic challenges. Journal of Neuroendocrinology 19 3445. (https://doi.org/10.1111/j.1365-2826.2006.01502.x)

    • Search Google Scholar
    • Export Citation
  • NilaweeraKNWilsonDBellLMercerJGMorganPJBarrettP 2008 G protein-coupled receptor 101 mRNA expression in supraoptic and paraventricular nuclei in rat hypothalamus is altered by pregnancy and lactation. Brain Research 1193 7683. (https://doi.org/10.1016/j.brainres.2007.11.048)

    • Search Google Scholar
    • Export Citation
  • PaulEJTossellKUnglessMA 2019 Transcriptional profiling aligned with in situ expression image analysis reveals mosaically expressed molecular markers for GABA neuron sub-groups in the ventral tegmental area. European Journal of Neuroscience 50 37323749. (https://doi.org/10.1111/ejn.14534)

    • Search Google Scholar
    • Export Citation
  • PaulussenADSteylsAVanoevelenJvan TienenFHKrapelsIPClaesGRChocronSVelterCTan-SindhunataGMLundinCet al. 2016 Rare novel variants in the ZIC3 gene cause X-linked heterotaxy. European Journal of Human Genetics 24 17831791. (https://doi.org/10.1038/ejhg.2016.91)

    • Search Google Scholar
    • Export Citation
  • PetersenTNBrunakSvon HeijneGNielsenH 2011 SignalP 4.0: discriminating signal peptides from transmembrane regions. Nature Methods 8 785786. (https://doi.org/10.1038/nmeth.1701)

    • Search Google Scholar
    • Export Citation
  • RegardJBSatoITCoughlinSR 2008 Anatomical profiling of G protein-coupled receptor expression. Cell 135 561571. (https://doi.org/10.1016/j.cell.2008.08.040)

    • Search Google Scholar
    • Export Citation
  • RoddCMilletteMIacovazzoDStilesCEBarrySEvansonJAlbrechtSCaswellRBunceBJoseSet al. 2016 Somatic GPR101 duplication causing X-linked acrogigantism (XLAG)-diagnosis and management. Journal of Clinical Endocrinology and Metabolism 101 19271930. (https://doi.org/10.1210/jc.2015-4366)

    • Search Google Scholar
    • Export Citation
  • RonnekleivOKFangYZhangCNestorCCMaoPKellyMJ 2014 Research resource: gene profiling of G protein-coupled receptors in the arcuate nucleus of the female. Molecular Endocrinology 28 13621380. (https://doi.org/10.1210/me.2014-1103)

    • Search Google Scholar
    • Export Citation
  • RutzCKleinWSchuleinR 2015 N-terminal signal peptides of G protein-coupled receptors: significance for receptor biosynthesis, trafficking, and signal transduction. Progress in Molecular Biology and Translational Science 132 267287. (https://doi.org/10.1016/bs.pmbts.2015.03.003)

    • Search Google Scholar
    • Export Citation
  • SalonJALodowskiDTPalczewskiK 2011 The significance of G protein-coupled receptor crystallography for drug discovery. Pharmacological Reviews 63 901937. (https://doi.org/10.1124/pr.110.003350)

    • Search Google Scholar
    • Export Citation
  • SriramKInselPA 2018 G Protein-coupled receptors as targets for approved drugs: how many targets and how many drugs? Molecular Pharmacology 93 251258. (https://doi.org/10.1124/mol.117.111062)

    • Search Google Scholar
    • Export Citation
  • TaoYXConnPM 2014 Chaperoning G protein-coupled receptors: from cell biology to therapeutics. Endocrine Reviews 35 602647. (https://doi.org/10.1210/er.2013-1121)

    • Search Google Scholar
    • Export Citation
  • TariqMCastABelmontJWareS 2013 Identification of a novel cause of X-linked heterotaxy. In ASHG 2013. Conference abstract.

  • TrivellinGStratakisCA 2019 CD40LG duplications in patients with X-LAG syndrome commonly undergo random X-chromosome inactivation. Journal of Allergy and Clinical Immunology 143 1659. (https://doi.org/10.1016/j.jaci.2018.12.1017)

    • Search Google Scholar
    • Export Citation
  • TrivellinGDalyAFFauczFRYuanBRostomyanLLarcoDOSchernthaner-ReiterMHSzarekELealLFCabergJHet al. 2014 Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. New England Journal of Medicine 371 23632374. (https://doi.org/10.1056/NEJMoa1408028)

    • Search Google Scholar
    • Export Citation
  • TrivellinGBjelobabaIDalyAFLarcoDOPalmeiraLFauczFRThiryALealLFRostomyanLQuezadoMet al. 2016a Characterization of GPR101 transcript structure and expression patterns. Journal of Molecular Endocrinology 57 97111. (https://doi.org/10.1530/JME-16-0045)

    • Search Google Scholar
    • Export Citation
  • TrivellinGCorreaRRBatsisMFauczFRChittiboinaPBjelobabaILarcoDOQuezadoMDalyAFStojilkovicSSet al. 2016b Screening for GPR101 defects in pediatric pituitary corticotropinomas. Endocrine-Related Cancer 23 357365. (https://doi.org/10.1530/ERC-16-0091)

    • Search Google Scholar
    • Export Citation
  • TrivellinGHernandez-RamirezLCSwanJStratakisCA 2018a An orphan G-protein-coupled receptor causes human gigantism and/or acromegaly: molecular biology and clinical correlations. Best Practice and Research. Clinical Endocrinology and Metabolism 32 125140. (https://doi.org/10.1016/j.beem.2018.02.004)

    • Search Google Scholar
    • Export Citation
  • TrivellinGSharwoodEHijaziHCarvalhoCMBYuanBTatton-BrownKComanDLupskiJRCotterillAMLodishMBet al. 2018b Xq26.3 duplication in a boy with motor delay and low muscle tone refines the X-linked Acrogigantism genetic locus. Journal of the Endocrine Society 2 11001108. (https://doi.org/10.1210/js.2018-00156)

    • Search Google Scholar
    • Export Citation
  • TsuikoONoukasMZilinaOHensenKTapanainenJSMagiRKalsMKivistikPAHaller-KikkataloKSalumetsAet al. 2016 Copy number variation analysis detects novel candidate genes involved in follicular growth and oocyte maturation in a cohort of premature ovarian failure cases. Human Reproduction 31 19131925. (https://doi.org/10.1093/humrep/dew142)

    • Search Google Scholar
    • Export Citation
  • UenoyamaYNakamuraSHayakawaYIkegamiKWatanabeYDeuraCMinabeSTomikawaJGotoTIedaNet al. 2015 Lack of pulse and surge modes and glutamatergic stimulation of luteinising hormone release in Kiss1 knockout rats. Journal of Neuroendocrinology 27 187197. (https://doi.org/10.1111/jne.12257)

    • Search Google Scholar
    • Export Citation
  • Uribe-CerdaSMorselliEPerez-LeightonC 2018 Updates on the neurobiology of food reward and their relation to the obesogenic environment. Current Opinion in Endocrinology Diabetes and Obesity 25 292297. (https://doi.org/10.1097/MED.0000000000000427)

    • Search Google Scholar
    • Export Citation
  • VasilevVDalyAFTrivellinGStratakisCAZacharievaSBeckersA 2020 HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: The roles of AIP and GPR101 in familial isolated pituitary adenomas (FIPA). Endocrine-Related Cancer 27 7786. (https://doi.org/10.1530/ERC-20-0015)

    • Search Google Scholar
    • Export Citation
  • Wise-OringerBKZanazziGJGordonRJWardlawSLWilliamCAnyane-YeboaKChungWKKohnBWisoffJHDavidRet al. 2019 Familial X-linked Acrogigantism: postnatal outcomes and tumor pathology in a prenatally diagnosed infant and his mother. Journal of Clinical Endocrinology and Metabolism 104 46674675. (https://doi.org/10.1210/jc.2019-00817)

    • Search Google Scholar
    • Export Citation
  • WuTJManiSKGlucksmanMJRobertsJL 2005 Stimulation of luteinizing hormone-releasing hormone (LHRH) gene expression in GT1-7 cells by its metabolite, LHRH-(1-5). Endocrinology 146 280286. (https://doi.org/10.1210/en.2004-0560)

    • Search Google Scholar
    • Export Citation
  • YangZYangFZhangDLiuZLinALiuCXiaoPYuXSunJP 2017 Phosphorylation of G protein-coupled receptors: from the barcode hypothesis to the flute model. Molecular Pharmacology 92 201210. (https://doi.org/10.1124/mol.116.107839)

    • Search Google Scholar
    • Export Citation