Characterization of Gpr101 expression and G-protein coupling selectivity

Bates, Brian; Zhang, Lynn; Nawoschik, Stanley; Kodangattil, Sreekumar; Tseng, Eugene; Kopsco, David C.; Krämer, Angela; Qin, Shan; Taylor, Noël; Johnson, Jeremy W.; Sun, Ying; Chen, Hui Min; Blatcher, Maria; Paulsen, Janet; Pausch, Mark H.

doi:10.1016/j.brainres.2006.02.123

Cited by 57 publications

(44 citation statements)

References 40 publications

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“…S11 and S12 in the Supplementary Appendix) and is predicted to couple to the stimulatory G protein (G s ), a potent activator of adenylyl cyclase. 13,14 A model of human GPR101 in complex with a G s heterotrimer shows the physical relationship between the p.E308D amino acid change and the activating p.A397K change, a mutation that has been described previously. 15 The two amino acids, which are predicted to be affected by the mutations, are on the cytosolic side of the receptor (Fig.…”

Section: Resultsmentioning

confidence: 76%

Gigantism and Acromegaly Due to Xq26 Microduplications and GPR101 Mutation

Trivellin¹,

Daly²,

Faucz³

et al. 2014

N Engl J Med

302

378

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BACKGROUND Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood. METHODS We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly. RESULTS We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. All the patients had disease onset during early childhood. Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years. Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein–coupled receptor, was overexpressed in patients’ pituitary lesions. We identified a recurrent GPR101 mutation (p.E308D) in 11 of 248 patients with acromegaly, with the mutation found mostly in tumors. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone–producing cells. CONCLUSIONS We describe a pediatric disorder (which we have termed X-linked acrogigantism [X-LAG]) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone. Duplication of GPR101 probably causes X-LAG. We also found a recurrent mutation in GPR101 in some adults with acromegaly. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.)

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Section: Resultsmentioning

confidence: 76%

Gigantism and Acromegaly Due to Xq26 Microduplications and GPR101 Mutation

Trivellin¹,

Daly²,

Faucz³

et al. 2014

N Engl J Med

302

378

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“…Deorphanization is the process of identifying ligands that are highly selective for orphan GPCRs. In general, the standard assays are radio-ligand binding, calcium flux, GTPγ binding, and modulation of cAMP levels [92][93][94][95][96][97][98] . With the development of molecular technology, several lines of approaches have been used for deorphanization.…”

Section: Deorphanization Strategymentioning

confidence: 99%

Orphan G protein-coupled receptors (GPCRs): biological functions and potential drug targets

et al. 2012

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The superfamily of G protein-coupled receptors (GPCRs) includes at least 800 seven-transmembrane receptors that participate in diverse physiological and pathological functions. GPCRs are the most successful targets of modern medicine, and approximately 36% of marketed pharmaceuticals target human GPCRs. However, the endogenous ligands of more than 140 GPCRs remain unidentified, leaving the natural functions of those GPCRs in doubt. These are the so-called orphan GPCRs, a great source of drug targets. This review focuses on the signaling transduction pathways of the Adhesion GPCR family, the LGR subfamily, and the PSGR subfamily, and their potential functions in immunology, development, and cancers. In this review, we present the current approaches and difficulties of orphan GPCR deorphanization and characterization.

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“…GHRH is a very potent physiological stimulator of GH, and GHRH secretion by a discreet population of hypothalamic neurons is tightly regulated by integrated central and peripheral signals (Gahete, et al 2009; Veldhuis, et al 2012). GPR101 is specifically expressed in regions of the hypothalamus and brain that are involved in integrating such signals, the dysregulation of GHRH secretion and pituitary pathology in XLAG syndrome (Bates, et al 2006; Trivellin, et al 2016; Trivellin et al 2014). Taken together these findings suggest a mechanism by which even modestly increased copy number of GPR101 could lead to the severe pituitary gigantism observed in XLAG syndrome patients with an Xq26.3 duplication; some of these mosaicism levels may be beyond that which can currently be detected by our techniques.…”

Section: Discussionmentioning

confidence: 99%

Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects

Daly¹,

Yuan²,

Fina³

et al. 2016

Endocrine-Related Cancer

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Somatic mosaicism has been implicated as a causative mechanism in a number of genetic and genomic disorders. X-linked acrogigantism (XLAG) syndrome is a recently characterized genomic form of pediatric gigantism due to aggressive pituitary tumors that is caused by submicroscopic chromosome Xq26.3 duplications that include GPR101. We studied XLAG syndrome patients (N=18) to determine if somatic mosaicism contributed to the genomic pathophysiology. Eighteen subjects with XLAG syndrome were identified with Xq26.3 duplications using high definition array comparative genome hybridization (HD-aCGH). We noted males with XLAG had a decreased log2 ratio compared with expected values, suggesting potential mosaicism, while females showed no such decrease. As compared with familial male XLAG cases, sporadic males had more marked evidence for mosaicism, with levels of Xq26.3 duplication between 16.1-53.8%. These characteristics were replicated using a novel, personalized breakpoint-junction specific quantification droplet digital PCR (ddPCR) technique. Using a separate ddPCR technique we studied the feasibility of identifying XLAG syndrome cases in a distinct patient population of 64 unrelated subjects with acromegaly/gigantism and identified one female gigantism patient that had increased copy number variation (CNV) threshold for GPR101 that was subsequently diagnosed as having XLAG syndrome on HD-aCGH. Employing a combination of HD-aCGH and novel ddPCR approaches, we have demonstrated, for the first time, that XLAG syndrome can be caused by variable degrees of somatic mosaicism for duplications at chromosome Xq26.3. Somatic mosaicism was shown to occur in sporadic males but not in females with XLAG syndrome, although the clinical characteristics of the disease were similarly severe in both sexes.

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Characterization of Gpr101 expression and G-protein coupling selectivity

Cited by 57 publications

References 40 publications

Gigantism and Acromegaly Due to Xq26 Microduplications and GPR101 Mutation

Gigantism and Acromegaly Due to Xq26 Microduplications and GPR101 Mutation

Orphan G protein-coupled receptors (GPCRs): biological functions and potential drug targets

Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects

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