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 (

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