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 |