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Open Access

Mutations in G Protein–Coupled Receptors: Mechanisms, Pathophysiology and Potential Therapeutic Approaches

Torsten Schöneberg and Ines Liebscher
Paul Insel, ASSOCIATE EDITOR
Pharmacological Reviews January 2021, 73 (1) 89-119; DOI: https://doi.org/10.1124/pharmrev.120.000011
Torsten Schöneberg
Rudolf Schönheimer Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, Leipzig, Germany
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Ines Liebscher
Rudolf Schönheimer Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, Leipzig, Germany
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Paul Insel
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  • Fig. 1.
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    Fig. 1.

    Approaches to identify mutant GPCR as cause for inherited diseases in the course of time. After cloning and sequencing of the first GPCR genes in the mid-80s/90s, genomic loci information of large disease-affected families was matched with mutations in GPCR genes. In the 1990s, targeted GPCR gene disruption in animal models and subsequent phenotyping guided the identification of human phenotypes and diseases caused by mutations in orthologous human GPCR genes. Currently, large-scale exome and genome sequencing of disease and control cohorts allows for comparative analysis yielding rare GPCR variants that can be linked to human phenotypes. In the future, deep-sequenced transcriptomes of tissues and even defined cell populations will add information on the disease-relevant impact of mutations in the coding and noncoding regions with respect to promoter activity and splicing. Figure was created with BioRender.

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    Fig. 2.

    General mechanisms of disease-relevant LoF mutations in GPCRs. The LoF of GPCRs can be caused by alterations at different levels of the receptor protein biosynthesis (genomic, transcriptomic, and/or translational level), protein folding, processes of peri- and post-transcriptional modifications, and trafficking (lower panel). In most of these cases, there is no or insufficient receptor protein at the cell surface to mediate signal transduction. The LoF of mutant GPCRs that are transferred to the plasma membrane can be the results of receptor oligomerization effects, mutations that interfere with proper binding of the agonist or tethered agonist (upper left panel), or mutations that interfere with interaction of G proteins or other adapter proteins (upper right panel). Figure was created with BioRender. ER, endoplasmic reticulum; PTM, post-transcriptional modification.

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    Fig. 3.

    General mechanisms of disease-relevant GoF mutations in GPCRs. There are two general forms of GPCR alterations that cause a gain of receptor function—agonist-independent and agonist-dependent causes. Mutations in transmembrane helices or, more rarely, in the exctracellular loops promote an active conformation of this domain. Some GPCRs (see text) contain an internal agonist, and mutations within or surrounding the tethered sequence can shift this internal agonist into its active conformation, triggering the on-stage of the transmembrane domain. In rare cases, mutations can increase the potency of the physiologic agonist, which shifts the concentration-response significantly leftward and generates a quasi-constitutively active GPCR. Mutations can also change the agonist specificity, leading to a GPCR that now recognizes a related and more potent endogenous ligand. Decrease of receptor inactivation (e.g., due to lack of arrestin recruitment) or degradation and increased transport or recycling can also appear as an increased receptor activity. Figure was created with BioRender. uORF, upstream ORF.

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    Fig. 4.

    Other mechanisms of disease-relevant GPCR pathologies. As in the case of many other inherited diseases, more complex genomic alterations can cause a loss but also a gain of GPCR function. Chromosomal mutations can have an impact of gene dosage (deletions, large insertions, rearrangements, duplications, gene fusions), which results in reduced, increased, or ectopic GPCR expression. Mutations may also have an impact on proper mRNA transcription and processing when promoter, UTR, or intronic regions are affected. For most of the known genomic alterations, there are also examples for GPCR genes (see text). Figure was created with BioRender.

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    Fig. 5.

    Potential therapeutic strategies to influence altered GPCR functions. There are direct and indirect approaches to influence altered GPCR functions. Direct approaches target the affected receptor (ligands, pharmacoperones) or receptor gene or transcript (gene replacement, gene editing, premature stop-codon suppression) (for details see text). Indirect methods usually target the function of signaling pathway components downstream of the receptor (e.g., G proteins, adenylyl cyclases, PDE). It is also feasible to activate a different GPCR expressed in cells in which the disease-causing GPCR occurs, which should have a similar (in case of LoF) or an opposite (in case of GoF) signal transduction (for details, see text). AC, adenylyl cyclase; Cas9, CRISPR-associated protein 9; PKA, protein kinase A; TMAO, trimethylamine N-oxide; 4-PBA, 4-phenylbutyric acid.

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    TABLE 1

    Monogenic diseases caused by mutations in GPCRs

    Currently known monogenic inherited human diseases caused by mutations in GPCRs [sources: MALAcards (https://www.malacards.org/)(Rappaport et al., 2017), Online Mendelian Inheritance in Man (https://omim.org/, Pubmed literature screen), and the TSHR mutation data base (https://www.tsh-receptor-mutation-database.org)] are listed together with the current number of causative missense, nonsense, splice-site, and large-deletion/rearrangement mutations (source: http://www.hgmd.cf.ac.uk/ac/index.php). Diseases written in bold are caused by activating mutations. Some GPCR genes were also identified in studies screening human genomes for LoF variants: *genes intolerant for LoF (Lek et al., 2016), #homozygous LoF genes in Pakistani adults (Saleheen et al., 2017), °orphan GPCR.

    GPCR GeneDisease/SyndromeMissenseNonsenseIn/delSpliceLargeReference
    ADGRC1*°Neural tube defect, spina bifida2813Robinson et al., 2012
    ADGRE2°Vibratory urticaria1Boyden et al., 2016
    ADGRG1°Bilateral frontoparietal polymicrogyria146721Piao et al., 2004
    ADGRG2*°Congenital bilateral aplasia of the vas deferens3Patat et al., 2016
    ADGRG6°Arthrogryposis multiplex congenita, lethal congenital contracture syndrome-9111Ravenscroft et al., 2015
    ADGRV1°Usher syndrome type IIC69214174Weston et al., 2004
    AGTR1Renal tubular dysgenesis121Gribouval et al., 2005, 2012
    AVPR2X-linked NDI1352375327Rosenthal et al., 1992
    AVPR2X-linked nephrogenic syndrome of inappropriate antidiuresis4Feldman et al., 2005
    CALCRL*Autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia1Mackie et al., 2018
    CASRHypocalciuric hypercalcemia, neonatal hyperparathyroidism226173563Pollak et al., 1993
    CASRDominant and sporadic hypoparathyroidism621Pollak et al., 1994
    CHRM3*Prune belly syndrome, familial congenital bladder malformation, impaired pupillary constriction, dry mouth1Weber et al., 2011
    CXCR4WHIM syndrome1541Hernandez et al., 2003
    CXCR2Autosomal recessive severe congenital neutropenia due to CXCR2 deficiency31Auer et al., 2014
    CYSLTR2Uveal melanoma, blue nevi2Moore et al., 2016; Möller et al., 2017
    EDNRA*Mandibulofacial dysostosis with alopecia2Gordon et al., 2015
    EDNRBSusceptibility to Hirschsprung disease 2, Waardenburg syndrome type 4A, ABCD syndrome355724Puffenberger et al., 1994; Verheij et al., 2002
    FPR1Juvenile periodontitis3Gwinn et al., 1999
    FSHRHypergonadotropic ovarian dysgenesis151Aittomäki et al., 1995
    FSHROvarian hyperstimulation syndrome8De Leener et al., 2008
    FZD2Autosomal dominant omodysplasia, Robinow syndrome12Saal et al., 2015
    FZD4*Dominant familial exudative vitreoretinopathy429132Robitaille et al., 2002
    FZD5Autosomal dominant coloboma1Liu et al., 2016
    FZD6Recessive isolated congenital nail dysplasia42Fröjmark et al., 2011
    GCGRMahvash disease7121Zhou et al., 2009
    GHRHRGrowth hormone deficiency2126101Wajnrajch et al., 1996
    GHSRGrowth hormone deficiency and short stature711Pantel et al., 2006
    GNRHRHypogonadotropic hypogonadism421412de Roux et al., 1997
    GPR88°Childhood-onset chorea with psychomotor retardation1Alkufri et al., 2016
    GPR101°X-linked acrogigantism28Kamenický et al., 2015
    GPR143Ocular albinism type I, congenital nystagmus, altered thickness of the iris447291729Bassi et al., 1995; Zhou et al., 2008b; Peng et al., 2009
    GPR179Congenital stationary night blindness51511Audo et al., 2012
    GRM1*Autosomal recessive spinocerebellar ataxia31Guergueltcheva et al., 2012
    GRM1*Autosomal dominant spinocerebellar ataxia2Watson et al., 2017
    GRM6#Congenital stationary night blindness17561Dryja et al., 2005
    KISS1RHypogonadotropic hypogonadism194321de Roux et al., 2003; Seminara et al., 2003
    KISS1RCentral precocious puberty1Teles et al., 2008
    LHCGRLeydig cell hypoplasia, pseudohermaphroditism, primary amenorrhea186525Kremer et al., 1995
    LHCGRMale-limited precocious puberty, Leydig cell adenoma18Shenker et al., 1993
    LPAR6Hypotrichosis, wooly hair112102Pasternack et al., 2008; Shimomura et al., 2008
    MC1RHypopigmentation7318Valverde et al., 1995
    MC2RGlucocorticoid deficiency3438Clark et al., 1993; Tsigos et al., 1993
    MC2RACTH-independent Cushing syndrome1Swords et al., 2002
    MC3RObesity251Lee et al., 2002
    MC4RObesity1197211Vaisse et al., 1998; Yeo et al., 1998
    MTNR1BSusceptibility to diabetes mellitus type 227Bonnefond et al., 2012
    OGR1 (GPR68)Amelogenesis imperfecta12Parry et al., 2016
    OPN1SW#Tritanopia6Weitz et al., 1992
    OPN1MWDeuteranomaly, cone dystrophy5116Winderickx et al., 1992
    OPN1LW*Blue cone monochromacy123135Nathans et al., 1993
    P2RY12Bleeding disorder92Hollopeter et al., 2001
    PROKR2Kallmann syndrome4224Dodé et al., 2006
    PTH1RBlomstrand chondrodysplasia, Eiken syndrome, primary failure of tooth eruption6899Jobert et al., 1998; Decker et al., 2008
    PTH1RMurk Jansen type of metaphyseal chondrodysplasia6Schipani et al., 1995
    RGRRetinitis pigmentosa412Morimura et al., 1999
    RHOCongenital night blindness, autosomal dominant retinitis pigmentosa14192063Dryja et al., 1990
    RHOAutosomal dominant retinitis pigmentosa9Rao et al., 1994; Park, 2014
    S1PR2Deafness2Santos-Cortez et al., 2016
    SMOBasal cell carcinoma3Xie et al., 1998; Khamaysi et al., 2016
    SMOCurry-Jones syndrome (Mosaizism)1Khamaysi et al., 2016
    TACR3Normosmic hypogonadotropic hypogonadism19622Topaloglu et al., 2009
    TBXA2RBleeding disorder41Hirata et al., 1994
    TRHRHypothyroidism121Collu et al., 1997
    TSHRHypothyroidism80101244Sunthornthepvarakul et al., 1995
    TSHRCongenital hyperthyroidism, hyperfunctioning thyroid adenoma, and carcinoma1053Parma et al., 1993
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    TABLE 2

    Monogenic diseases caused by mutations in GPCRs

    The top 10 autosomal diseases caused by mutations in GPCRs are listed together with the detailed human phenotype and the phenotype found in the respective gene-deficient mouse model (given reference). X-chromosomal diseases and their mouse phenotypes are listed in Supplemental Table 1. Mouse phenotypes are taken from the listed reference and the mouse phenotype data base (http://www.informatics.jax.org).

    GPCR GeneHuman Phenotype/Main SymptomsMouse Phenotype/Main SymptomsReferences
    ADGRV1Usher syndrome type IIC; ciliopathy, sensorineural hearing deficiencies at birth and later development of progressive retinitis pigmentosaCochlear defects, progressive hearing impairment, deafness, audiogenic seizureMcGee et al., 2006; Yagi et al., 2007
    CASRNeonatal hyperparathyroidism; hypocalciuric hypercalcemia elevated PTH, bone demineralization, failure to thrive, associated with parathyroid hyperplasiaHypocalciuric hypercalcemia, decreased phosphate serum level, elevated parathyroid hormone level, parathyroid hyperplasia, bone abnormalities, retarded growth, premature deathHo et al., 1995
    EDNRBHirschsprung disease, aganglionic megacolon; congenital absence of intrinsic ganglion cells in the myenteric (Auerbach) and submucosal (Meissner) plexuses of the gastrointestinal tractRequired for neural crest–derived melanocyte and enteric neuron development, homozygous mice are predominantly white and die as juveniles from megacolonShin et al., 1997
    FZD4Dominant familial exudative vitreoretinopathy due to heterozygous inactivation of FZD4; incomplete development of the retinal vasculature, clinical appearance varies from blindness during infancy to mildly affected patientsHomozygous animals develop cerebellar degeneration, severe ataxia, abnormal absence of a skeletal muscle sheath around the lower esophagus, progressive deafness, small kidneyWang et al., 2001; Xu et al., 2004
    GNRHRHypogonadotropic hypogonadism; absent or incomplete sexual maturation, low levels of circulating gonadotropins and testosteroneSmall sexual organs, low levels of FSH, LH, and steroid hormones, failure of sexual maturation, infertility, inability to respond to exogenous GnRHWu et al., 2010
    MC1RHypopigmentation; defect in eumelanin production, fair skin, red hair, increased risk of melanomaYellow coat color, reduced sensitivity to noxious stimuli, increased analgesic responsivenessRobbins et al., 1993; Mogil et al., 2005; Wada et al., 2005; D’Orazio et al., 2006
    MC4REarly-onset childhood obesity, hyperphagia due to alteration of hypothalamic appetite regulation, metabolic syndromeMaturity-onset obesity syndrome, hyperphagia, hyperinsulinemia, hyperglycemia, nonalcoholic steatohepatitis, reduction in corpora lutea numberHuszar et al., 1997; Sandrock et al., 2009; Lede et al., 2017
    PROKR2Kallmann syndrome; anosmia related to defective olfactory bulb morphogenesis, absent or incomplete sexual maturation, low levels of circulating gonadotropins and testosteroneHypoplasia in the olfactory bulb, small sexual organs, failure of sexual maturation, infertilityMatsumoto et al., 2006
    RHOAutosomal dominant early-onset retinitis pigmentosa; progressive retinal rod cells degeneration, night blindness, peripheral visual field lossSlow degeneration of the retina, decrease of light-evoked electroretinogram responsesNaash et al., 1993
    TSHRCongenital hypothyroidism, thyroid hypoplasia, bradycardia, oligophrenia, hypothermia, elevated TSH, reduced thyroid hormonesVery low to undetectable serum thyroxine, elevation of TSH, retarded growth, infertility, mild anemia, elevated serum cholesterol, delayed ossification, reduced cortical boneBeamer et al., 1981; Abe et al., 2003; Bassett et al., 2008
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    TABLE 3

    Digenic inheritance of GPCR-caused diseases

    GPCRs involved in currently known digenic inherited human diseases are listed together with the comutated gene. Data were taken from the digenic diseases data base DIDA (http://dida.ibsquare.be) and the indicated literature.

    GPCR GeneDiseaseDI Genes
    ADGRV1 (GPR98)Usher syndromeMYO7A, DFNB37, PDZD7
    EDNRBHirschsprung diseaseRET
    FZD4Exudative vitreoretinopathyLRP5, F5
    GNRHRHypogonadotropic hypogonadismPROKR2, FGFR1
    KISS1RPituitary stalk interruption syndrome, Kallmann syndromePROKR2, FGFR1, IL17RD
    OPN1LWBlue cone monochromacy (Nathans et al., 1993; Katagiri et al., 2018)OPN1MW
    PROKR2Pituitary stalk interruption syndrome, Kallmann syndromeFGFR1, GNRHR, KAL1, KISSR1
    TACR3Hypogonadotropic hypogonadismNSMF
    TSHRMild congenital hypothyroidism (Satoh et al., 2015; Fu et al., 2016; Abe et al., 2018)DUOX2, TG
    • View popup
    TABLE 4

    Human phenotypes and diseases associated with GPCR dysfunction

    A selection of GPCR genes in which variants show a significant association with human phenotypes is given. Some GPCR genes were also identified in studies screening human genomes for LoF variants: *genes intolerant for LoF (Lek et al., 2016).

    GPCR GeneHuman PhenotypeReference
    ADGRB2*Progressive spastic paraparesisPurcell et al., 2017
    ADGRC2Idiopathic scoliosisEinarsdottir et al., 2017
    ADGRG6Adolescent idiopathic scoliosisKou et al., 2013
    ADGRL2Microcephaly with severely reduced sulcation and rhombencephalosynapsisVezain et al., 2018
    ADORA1Early-onset parkinsonism and cognitive dysfunctionJaberi et al., 2016
    ADRB2Nocturnal asthmaTurki et al., 1995; Contopoulos-Ioannidis et al., 2005
    ADRA2AAtypical familial partial lipodystrophyGarg et al., 2016
    ADRA2BFamilial adult myoclonic epilepsy/autosomal dominant cortical myoclonus and epilepsyGuerrini et al., 2001; De Fusco et al., 2014
    CCKARCholesterol gallstone disease and obesityMiller et al., 1995
    CHRH2Bipolar disorderCruceanu et al., 2018
    CX3CR1Impaired human monocyte survival, developmental dysplasia of the hipFeldman et al., 2013; Collar et al., 2018
    GABBR2Early infantile epileptic encephalopathyEuroEPINOMICS-RES Consortium; Epilepsy Phenome/Genome Project; Epi4K Consortium, 2014; Hamdan et al., 2017
    GPR35Albright hereditary osteodystrophy/pseudohypoparathyroidism, and mild-to-moderate mental retardationShrimpton et al., 2004; Shim et al., 2014
    GPR180Congenital microcoriaFares-Taie et al., 2015
    GPR161Spina bifida, pituitary stalk interruption syndrome, childhood medulloblastomaKaraca et al., 2015; Kim et al., 2019; Begemann et al., 2020
    HTR2BSevere impulsivityBevilacqua et al., 2010
    HTR7Autism spectrum disorderHelsmoortel et al., 2016
    LGR4 (GPR48)Low bone mineral density and osteoporotic fractures, aniridia-genitourinary anomalies-mental retardation syndrome (AGR syndrome)Styrkarsdottir et al., 2013; Yi et al., 2014
    RXFP2 (LGR8)CryptorchidismGorlov et al., 2002
    TAS2R38Chronic rhinosinusitisLee et al., 2012
    • ADRB2, β2 adrenergic receptor.

    • View popup
    TABLE 5

    Main Points

    •Extended data base mining to identify LoF-intolerant GPCRs
    •Explore pathologic potential of variations in noncoding genic components of GPCR genes (promoter, introns, UTR)
    •Explore pathologic potential of neglected GPCRs (e.g., ecnomotopic odorant and taste receptors)
    •Improve structural and evolutional approaches to predict the functional relevance of GPCR variations
    •Extended use of genome editing methods in research and therapy

Additional Files

  • Figures
  • Tables
  • Data Supplement

    • Supplemental Data -

      Supplemental Table S1. X-chromosomal GPCRs containing obvious loss-of-function (LoF) mutations.

      Supplemental Table S2. GPCR genes containing homozygous LoF variants in humans

      Supplemental Table S3. Mutation rate in GPCR genes.

      Supplemental References

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Review ArticleReview Article

Inherited GPCR-Related Diseases

Torsten Schöneberg and Ines Liebscher
Pharmacological Reviews January 1, 2021, 73 (1) 89-119; DOI: https://doi.org/10.1124/pharmrev.120.000011

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Review ArticleReview Article

Inherited GPCR-Related Diseases

Torsten Schöneberg and Ines Liebscher
Pharmacological Reviews January 1, 2021, 73 (1) 89-119; DOI: https://doi.org/10.1124/pharmrev.120.000011
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  • Article
    • Abstract
    • I. Introduction
    • II. History
    • III. General Mechanisms of GPCR Pathologies
    • IV. Inactivating Mutations of GPCRs
    • V. Activating Mutations in GPCRs—GoF
    • VI. Other Causes of GPCR Dysfunctions
    • VII. Therapeutic Options and Approaches
    • VIII. Identification of Disease-Relevant GPCR Using Population Genetic Data
    • IX. Future Perspectives
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
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