Article Figures & Data
Figures
- 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.
- 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.
- 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.
- 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.
- 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.
Tables
- 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 Gene Disease/Syndrome Missense Nonsense In/del Splice Large Reference ADGRC1*° Neural tube defect, spina bifida 28 1 3 Robinson et al., 2012 ADGRE2° Vibratory urticaria 1 Boyden et al., 2016 ADGRG1° Bilateral frontoparietal polymicrogyria 14 6 7 2 1 Piao et al., 2004 ADGRG2*° Congenital bilateral aplasia of the vas deferens 3 Patat et al., 2016 ADGRG6° Arthrogryposis multiplex congenita, lethal congenital contracture syndrome-9 1 1 1 Ravenscroft et al., 2015 ADGRV1° Usher syndrome type IIC 69 21 41 7 4 Weston et al., 2004 AGTR1 Renal tubular dysgenesis 1 2 1 Gribouval et al., 2005, 2012 AVPR2 X-linked NDI 135 23 75 3 27 Rosenthal et al., 1992 AVPR2 X-linked nephrogenic syndrome of inappropriate antidiuresis 4 Feldman et al., 2005 CALCRL* Autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia 1 Mackie et al., 2018 CASR Hypocalciuric hypercalcemia, neonatal hyperparathyroidism 226 17 35 6 3 Pollak et al., 1993 CASR Dominant and sporadic hypoparathyroidism 62 1 Pollak et al., 1994 CHRM3* Prune belly syndrome, familial congenital bladder malformation, impaired pupillary constriction, dry mouth 1 Weber et al., 2011 CXCR4 WHIM syndrome 1 5 4 1 Hernandez et al., 2003 CXCR2 Autosomal recessive severe congenital neutropenia due to CXCR2 deficiency 3 1 Auer et al., 2014 CYSLTR2 Uveal melanoma, blue nevi 2 Moore et al., 2016; Möller et al., 2017 EDNRA* Mandibulofacial dysostosis with alopecia 2 Gordon et al., 2015 EDNRB Susceptibility to Hirschsprung disease 2, Waardenburg syndrome type 4A, ABCD syndrome 35 5 7 2 4 Puffenberger et al., 1994; Verheij et al., 2002 FPR1 Juvenile periodontitis 3 Gwinn et al., 1999 FSHR Hypergonadotropic ovarian dysgenesis 15 1 Aittomäki et al., 1995 FSHR Ovarian hyperstimulation syndrome 8 De Leener et al., 2008 FZD2 Autosomal dominant omodysplasia, Robinow syndrome 1 2 Saal et al., 2015 FZD4* Dominant familial exudative vitreoretinopathy 42 9 13 2 Robitaille et al., 2002 FZD5 Autosomal dominant coloboma 1 Liu et al., 2016 FZD6 Recessive isolated congenital nail dysplasia 4 2 Fröjmark et al., 2011 GCGR Mahvash disease 7 1 2 1 Zhou et al., 2009 GHRHR Growth hormone deficiency 21 2 6 10 1 Wajnrajch et al., 1996 GHSR Growth hormone deficiency and short stature 7 1 1 Pantel et al., 2006 GNRHR Hypogonadotropic hypogonadism 42 1 4 1 2 de Roux et al., 1997 GPR88° Childhood-onset chorea with psychomotor retardation 1 Alkufri et al., 2016 GPR101° X-linked acrogigantism 2 8 Kamenický et al., 2015 GPR143 Ocular albinism type I, congenital nystagmus, altered thickness of the iris 44 7 29 17 29 Bassi et al., 1995; Zhou et al., 2008b; Peng et al., 2009 GPR179 Congenital stationary night blindness 5 1 5 1 1 Audo et al., 2012 GRM1* Autosomal recessive spinocerebellar ataxia 3 1 Guergueltcheva et al., 2012 GRM1* Autosomal dominant spinocerebellar ataxia 2 Watson et al., 2017 GRM6# Congenital stationary night blindness 17 5 6 1 Dryja et al., 2005 KISS1R Hypogonadotropic hypogonadism 19 4 3 2 1 de Roux et al., 2003; Seminara et al., 2003 KISS1R Central precocious puberty 1 Teles et al., 2008 LHCGR Leydig cell hypoplasia, pseudohermaphroditism, primary amenorrhea 18 6 5 2 5 Kremer et al., 1995 LHCGR Male-limited precocious puberty, Leydig cell adenoma 18 Shenker et al., 1993 LPAR6 Hypotrichosis, wooly hair 11 2 10 2 Pasternack et al., 2008; Shimomura et al., 2008 MC1R Hypopigmentation 73 1 8 Valverde et al., 1995 MC2R Glucocorticoid deficiency 34 3 8 Clark et al., 1993; Tsigos et al., 1993 MC2R ACTH-independent Cushing syndrome 1 Swords et al., 2002 MC3R Obesity 25 1 Lee et al., 2002 MC4R Obesity 119 7 21 1 Vaisse et al., 1998; Yeo et al., 1998 MTNR1B Susceptibility to diabetes mellitus type 2 27 Bonnefond et al., 2012 OGR1 (GPR68) Amelogenesis imperfecta 1 2 Parry et al., 2016 OPN1SW# Tritanopia 6 Weitz et al., 1992 OPN1MW Deuteranomaly, cone dystrophy 5 1 1 6 Winderickx et al., 1992 OPN1LW* Blue cone monochromacy 12 3 1 35 Nathans et al., 1993 P2RY12 Bleeding disorder 9 2 Hollopeter et al., 2001 PROKR2 Kallmann syndrome 42 2 4 Dodé et al., 2006 PTH1R Blomstrand chondrodysplasia, Eiken syndrome, primary failure of tooth eruption 6 8 9 9 Jobert et al., 1998; Decker et al., 2008 PTH1R Murk Jansen type of metaphyseal chondrodysplasia 6 Schipani et al., 1995 RGR Retinitis pigmentosa 4 1 2 Morimura et al., 1999 RHO Congenital night blindness, autosomal dominant retinitis pigmentosa 141 9 20 6 3 Dryja et al., 1990 RHO Autosomal dominant retinitis pigmentosa 9 Rao et al., 1994; Park, 2014 S1PR2 Deafness 2 Santos-Cortez et al., 2016 SMO Basal cell carcinoma 3 Xie et al., 1998; Khamaysi et al., 2016 SMO Curry-Jones syndrome (Mosaizism) 1 Khamaysi et al., 2016 TACR3 Normosmic hypogonadotropic hypogonadism 19 6 2 2 Topaloglu et al., 2009 TBXA2R Bleeding disorder 4 1 Hirata et al., 1994 TRHR Hypothyroidism 1 2 1 Collu et al., 1997 TSHR Hypothyroidism 80 10 12 4 4 Sunthornthepvarakul et al., 1995 TSHR Congenital hyperthyroidism, hyperfunctioning thyroid adenoma, and carcinoma 105 3 Parma et al., 1993 - 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 Gene Human Phenotype/Main Symptoms Mouse Phenotype/Main Symptoms References ADGRV1 Usher syndrome type IIC; ciliopathy, sensorineural hearing deficiencies at birth and later development of progressive retinitis pigmentosa Cochlear defects, progressive hearing impairment, deafness, audiogenic seizure McGee et al., 2006; Yagi et al., 2007 CASR Neonatal hyperparathyroidism; hypocalciuric hypercalcemia elevated PTH, bone demineralization, failure to thrive, associated with parathyroid hyperplasia Hypocalciuric hypercalcemia, decreased phosphate serum level, elevated parathyroid hormone level, parathyroid hyperplasia, bone abnormalities, retarded growth, premature death Ho et al., 1995 EDNRB Hirschsprung disease, aganglionic megacolon; congenital absence of intrinsic ganglion cells in the myenteric (Auerbach) and submucosal (Meissner) plexuses of the gastrointestinal tract Required for neural crest–derived melanocyte and enteric neuron development, homozygous mice are predominantly white and die as juveniles from megacolon Shin et al., 1997 FZD4 Dominant 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 patients Homozygous animals develop cerebellar degeneration, severe ataxia, abnormal absence of a skeletal muscle sheath around the lower esophagus, progressive deafness, small kidney Wang et al., 2001; Xu et al., 2004 GNRHR Hypogonadotropic hypogonadism; absent or incomplete sexual maturation, low levels of circulating gonadotropins and testosterone Small sexual organs, low levels of FSH, LH, and steroid hormones, failure of sexual maturation, infertility, inability to respond to exogenous GnRH Wu et al., 2010 MC1R Hypopigmentation; defect in eumelanin production, fair skin, red hair, increased risk of melanoma Yellow coat color, reduced sensitivity to noxious stimuli, increased analgesic responsiveness Robbins et al., 1993; Mogil et al., 2005; Wada et al., 2005; D’Orazio et al., 2006 MC4R Early-onset childhood obesity, hyperphagia due to alteration of hypothalamic appetite regulation, metabolic syndrome Maturity-onset obesity syndrome, hyperphagia, hyperinsulinemia, hyperglycemia, nonalcoholic steatohepatitis, reduction in corpora lutea number Huszar et al., 1997; Sandrock et al., 2009; Lede et al., 2017 PROKR2 Kallmann syndrome; anosmia related to defective olfactory bulb morphogenesis, absent or incomplete sexual maturation, low levels of circulating gonadotropins and testosterone Hypoplasia in the olfactory bulb, small sexual organs, failure of sexual maturation, infertility Matsumoto et al., 2006 RHO Autosomal dominant early-onset retinitis pigmentosa; progressive retinal rod cells degeneration, night blindness, peripheral visual field loss Slow degeneration of the retina, decrease of light-evoked electroretinogram responses Naash et al., 1993 TSHR Congenital hypothyroidism, thyroid hypoplasia, bradycardia, oligophrenia, hypothermia, elevated TSH, reduced thyroid hormones Very low to undetectable serum thyroxine, elevation of TSH, retarded growth, infertility, mild anemia, elevated serum cholesterol, delayed ossification, reduced cortical bone Beamer et al., 1981; Abe et al., 2003; Bassett et al., 2008 - 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 Gene Disease DI Genes ADGRV1 (GPR98) Usher syndrome MYO7A, DFNB37, PDZD7 EDNRB Hirschsprung disease RET FZD4 Exudative vitreoretinopathy LRP5, F5 GNRHR Hypogonadotropic hypogonadism PROKR2, FGFR1 KISS1R Pituitary stalk interruption syndrome, Kallmann syndrome PROKR2, FGFR1, IL17RD OPN1LW Blue cone monochromacy (Nathans et al., 1993; Katagiri et al., 2018) OPN1MW PROKR2 Pituitary stalk interruption syndrome, Kallmann syndrome FGFR1, GNRHR, KAL1, KISSR1 TACR3 Hypogonadotropic hypogonadism NSMF TSHR Mild congenital hypothyroidism (Satoh et al., 2015; Fu et al., 2016; Abe et al., 2018) DUOX2, TG - 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 Gene Human Phenotype Reference ADGRB2* Progressive spastic paraparesis Purcell et al., 2017 ADGRC2 Idiopathic scoliosis Einarsdottir et al., 2017 ADGRG6 Adolescent idiopathic scoliosis Kou et al., 2013 ADGRL2 Microcephaly with severely reduced sulcation and rhombencephalosynapsis Vezain et al., 2018 ADORA1 Early-onset parkinsonism and cognitive dysfunction Jaberi et al., 2016 ADRB2 Nocturnal asthma Turki et al., 1995; Contopoulos-Ioannidis et al., 2005 ADRA2A Atypical familial partial lipodystrophy Garg et al., 2016 ADRA2B Familial adult myoclonic epilepsy/autosomal dominant cortical myoclonus and epilepsy Guerrini et al., 2001; De Fusco et al., 2014 CCKAR Cholesterol gallstone disease and obesity Miller et al., 1995 CHRH2 Bipolar disorder Cruceanu et al., 2018 CX3CR1 Impaired human monocyte survival, developmental dysplasia of the hip Feldman et al., 2013; Collar et al., 2018 GABBR2 Early infantile epileptic encephalopathy EuroEPINOMICS-RES Consortium; Epilepsy Phenome/Genome Project; Epi4K Consortium, 2014; Hamdan et al., 2017 GPR35 Albright hereditary osteodystrophy/pseudohypoparathyroidism, and mild-to-moderate mental retardation Shrimpton et al., 2004; Shim et al., 2014 GPR180 Congenital microcoria Fares-Taie et al., 2015 GPR161 Spina bifida, pituitary stalk interruption syndrome, childhood medulloblastoma Karaca et al., 2015; Kim et al., 2019; Begemann et al., 2020 HTR2B Severe impulsivity Bevilacqua et al., 2010 HTR7 Autism spectrum disorder Helsmoortel 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) Cryptorchidism Gorlov et al., 2002 TAS2R38 Chronic rhinosinusitis Lee et al., 2012 ADRB2, β2 adrenergic receptor.
•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
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
- Supplemental Data -
In this issue
Inherited GPCR-Related Diseases
Jump to section
- 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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