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 |