Alternative titles; symbols
HGNC Approved Gene Symbol: KISS1R
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:917,333-921,005 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.3 | ?Precocious puberty, central, 1 | 176400 | Autosomal dominant | 3 |
| Hypogonadotropic hypogonadism 8 with or without anosmia | 614837 | Autosomal recessive | 3 |
Lee et al. (1999) isolated rat brain cDNAs encoding a novel GPCR, which they designated Gpr54. The predicted protein shares 44 to 45% and 37% sequence identity in the transmembrane regions with the rat galanin receptors (see 600377) and delta-1 opioid receptor (165195), respectively. Northern blot analysis and in situ hybridization indicated that rat Gpr54 has a complex and abundant central nervous system and peripheral tissue expression pattern. Lee et al. (1999) also identified the human GPR54 gene. The predicted 398-amino acid human protein is 81% identical to rat Gpr54. GPR54 is expressed in the human brain, pituitary gland, and placenta, as assessed by RT-PCR (Muir et al., 2001; Kotani et al., 2001).
Koemeter-Cox et al. (2014) found that Kiss1r was expressed on primary cilia of gonadotropin-releasing hormone (GNRH; see 152760)-expressing neurons in mouse medial hypothalamus and basal forebrain. The number of neurons with multiple Kiss1r-positive cilia increased with sexual maturity in both male and female mice.
Lee et al. (1999) showed that the human GPR54 gene contains 5 exons.
By searching a sequence database, Lee et al. (1999) identified a human GPR54 ortholog within a contig (GenBank AC005379) from chromosome 19p13.3.
Ohtaki et al. (2001) isolated a carboxy-terminally amidated peptide of KISS1 (603286) from human placenta as the endogenous ligand of GPR54. They named the truncated form of KISS1 'metastin.' Metastin inhibits chemotaxis and invasion of GPR54-transfected CHO cells in vitro and attenuates pulmonary metastasis of GPR54-transfected B16-BL6 melanomas in vivo.
KISS1 is a human metastasis suppressor gene whose product, metastin, had been identified as the endogenous agonist for GPR54, a Gq/11-coupled receptor (metastin receptor). Ringel et al. (2002) measured metastin and metastin receptor mRNA levels in 10 follicular carcinomas and 13 papillary carcinomas, 2 benign nonfunctioning follicular adenomas, and 11 normal thyroid samples, and evaluated the signaling pathways activated by metastin in ARO thyroid cancer cells that express the metastin receptor endogenously. Metastin receptor was not expressed in any normal thyroid or benign follicular adenoma samples, and was expressed in only a minority (2 of 10) of follicular carcinoma samples. However, the receptor was expressed in the majority (10 of 13) of papillary carcinomas. Increased levels of metastin receptor were detected in all 4 papillary carcinomas compared to adjacent normal tissue. Incubation of metastin receptor expressing ARO thyroid cancer cells with metastin resulted in activation of ERK, but not Akt. The authors concluded that metastin and/or metastin receptors have a potential role in modulating the biologic behavior of thyroid cancers.
Using real-time PCR, Shahab et al. (2005) found that the expression of Kiss1 mRNA increased with puberty in both male and female rhesus monkeys. Administration of kisspeptin-10 (112-121), a decapeptide derived from KISS1, to agonadal juvenile monkeys induced a GnRH response, as measured by a surge in plasma luteinizing hormone (LH; see 152780). In intact females, but not in agonadal males, the level of Gpr54 mRNA in the hypothalamus increased about 3-fold from the juvenile to midpubertal stage. In situ hybridization detected robust Kiss1 and Gpr54 expression in the arcuate nucleus. Shahab et al. (2005) concluded that KISS1 signaling through GPR54 in the primate hypothalamus at the end of the juvenile phase of development may contribute to the pubertal resurgence of pulsatile GnRH release.
Navarro et al. (2005) studied the effect of KISS1 peptide on LH secretion using in vitro and in vivo settings under different experimental conditions. Central intracerebroventricular administration of KISS1 peptide potently elicited LH secretion in vivo over a range of doses from 10 pmol to 1 nmol. The effect of centrally injected KISS1 appeared to be mediated via the hypothalamic LHRH (GNRH). However, no effect of central administration of KISS1 was detected on relative LHRH mRNA levels. Likewise, systemic (either intraperitoneal or intravascular) injection of KISS1 markedly stimulated LH secretion. Navarro et al. (2005) found that LH-releasing activity of KISS1 was persistently observed after blockade of endogenous excitatory amino acid and nitric oxide pathways, i.e., relevant neurotransmitters in the neuroendocrine control of LH secretion. Navarro et al. (2005) concluded that their results provided solid evidence for a potent stimulatory effect of KISS1 on LH release, acting at central levels (likely the hypothalamus) and eventually at the pituitary, and further documented a novel role of the KISS1/GPR54 system as a relevant downstream element in the neuroendocrine network governing LH secretion.
In a study of 6 healthy male volunteers, Dhillo et al. (2005) found that elevation of plasma concentrations of kisspeptin significantly increased circulating LH, FSH (see 136530), and testosterone levels. Dhillo et al. (2005) suggested that kisspeptin infusion may provide a novel mechanism for hypothalamic-pituitary-gonadal axis manipulation in disorders of the reproductive system.
By patch-clamp recording of brain slices from adult mice, Koemeter-Cox et al. (2014) found that kisspeptin increased the firing rate of Gnrh neurons. Inhibition of ciliary outgrowth in Gnrh neurons attenuated kisspeptin-dependent firing of these neurons in male mice, but not in female mice. No other defects in sexual maturity or fertility were observed in the absence of Kiss1r-positive cilia on Gnrh neurons.
Hypogonadotropic Hypogonadism 8 with or without Anosmia
Puberty, a complex biologic process involving sexual development, accelerated linear growth, and adrenal maturation, is initiated when gonadotropin-releasing hormone (see 152760 and 602352) begins to be secreted by the hypothalamus. Seminara et al. (2003) used complementary genetic approaches in studies in humans and mice to identify the genetic factors that determine the onset of puberty. In a consanguineous family with members who lacked pubertal development (idiopathic hypogonadotropic hypogonadism; see HH8, 614837), they searched for mutations in the GPR54 gene. Functional differences between wildtype and mutant GPR54 were examined in vitro. In parallel, a Gpr54-deficient mouse model was created and phenotyped. Seminara et al. (2003) found that affected patients in the index pedigree were homozygous for a leu148-to-ser mutation in the GPR54 gene (L148S; 604161.0001) and that an unrelated proband with idiopathic hypogonadotropic hypogonadism was a compound heterozygote for 2 mutations in the GPR54 gene (see 604161.0002). Gpr54-deficient mice had isolated hypogonadotropic hypogonadism (small testes in males and a delay in vaginal opening and an absence of follicular maturation in females), but they showed responsiveness to both exogenous gonadotropins and gonadotropin-releasing hormone and had normal levels of gonadotropin-releasing hormone in the hypothalamus. Seminara et al. (2003) discussed possible mechanisms that would allow abnormalities of GPR54 to cause pubertal delay. They concluded that GPR54 is a key regulator of the biology of puberty.
De Roux et al. (2003) studied a large consanguineous family in which 5 sibs had hypogonadotropic hypogonadism and a normal coding sequence of the gonadotropin-releasing hormone receptor gene (GNRHR; 138850). By homozygosity whole-genome mapping, they identified a novel locus for hypogonadotropic hypogonadism on 19p13. Sequencing of several genes located within this region showed that all affected sibs in the family carried a homozygous 155-bp deletion in the GPR54 gene (604161.0004). This deletion encompassed the splice acceptor site of the intron 4/exon 5 junction and part of exon 5. The deletion was absent or present on only 1 allele in unaffected family members. The study showed that loss of function of GPR54 is a cause of isolated hypogonadotropic hypogonadism and also identified GPR54, and possibly its ligand KISS1 (603286), as playing a major and previously unsuspected role in the physiology of the gonadotropic axis.
In a male patient with anosmic hypogonadotropic hypogonadism, Miraoui et al. (2013) identified 2 heterozygous missense mutations, 1 in the KISS1R gene (A194D; 604161.0007) and 1 in the IL17RD gene (A735P; 606807.0003).
In affected members of 2 unrelated families with normosmic hypogonadotropic hypogonadism, Brioude et al. (2013) analyzed 9 HH-associated genes and identified mutations in the KISS1R gene in both families (604161.0003, 604161.0005, and 604161.0008). The authors noted that the observed pituitary and gonadal response to pulsatile GNRH administration in these patients supported the hypothesis that disruption of the gonadotropic axis due to KISS1R loss of function occurs exclusively in the hypothalamus.
Central Precocious Puberty 1
Gonadotropin-dependent, or central, precocious puberty (see 176400) is caused by early maturation of the hypothalamic-pituitary-gonadal axis. Teles et al. (2008) identified an autosomal dominant GPR54 mutation (R386P; 604161.0006) in an adopted girl with idiopathic central precocious puberty. In vitro studies showed that this mutation led to prolonged activation of intracellular signaling pathways in response to kisspeptin, the ligand of GPR54.
Gaytan et al. (2014) studied Kiss1r-haploinsufficient and -null mice. Kiss1r hypomorphic mice displayed a premature decline in ovulatory rate, followed by progressive loss of antral follicles, oocyte loss, and a reduction in all categories of preantral follicles; these alterations were accompanied by reduced fertility. Mice over 48 weeks of age showed atrophic ovaries that lacked growing follicles and corpora lutea. This was associated with a drop in ovarian Kiss1r mRNA expression, but without a decrease in circulating gonadotropins: rather, FSH levels increased in aged hypomorphic mice, reflecting loss of follicular function. Kiss1r-null mice, which did not spontaneously ovulate and had arrested follicle development, failed to show normal ovulatory responses to standard gonadotropin priming and required GnRH prestimulation for 1 week to achieve gonadotropin-induced ovulation. However, the magnitude of ovulatory responses was only half of that seen in immature wildtype control mice. Gaytan et al. (2014) concluded that KISS1R haploinsufficiency induces a state of premature ovarian failure (see POF1, 311360) that is not attributable to defective gonadotropin secretion and cannot be fully rescued by gonadotropin replacement, suggesting a direct ovarian role for kisspeptin signaling.
Bo-Abbas et al. (2003) described a large Saudi Arabian family in which 2 brothers and a sister in 1 sibship married 2 sisters and a brother in a first-cousin sibship. The family sought medical attention for infertility. Six of the 19 offspring in the 3 sibships (4 men and 2 women), at least 1 from each mating, met the standard diagnostic criteria for idiopathic hypogonadotropic hypogonadism (HH8; 614837) (inappropriately low gonadotropin concentrations in the presence of prepubertal concentrations of sex steroids, normal anterior pituitary function, and normal findings on imaging of the brain) and had responsiveness to exogenous, pulsatile, gonadotropin-releasing hormone (see 152760 and 602352). In all 6 affected members, Seminara et al. (2003) identified a 443T-C transition in exon 3 of the GPR54 gene, resulting in a leu148-to-ser (L148S) substitution in the second intracellular loop.
In HEK293 cells, Wacker et al. (2008) performed biochemical, immunocytochemical, and pharmacologic analysis of the L148S mutation, located at a highly conserved residue in the second intracellular loop of GPR54. They found that L148S mutation did not affect the expression, ligand-binding properties, or protein interaction network of GPR54. In contrast, diverse GPR54 functional responses were markedly inhibited by the L148S mutation, with the mutant receptor neither initiating G-protein dissociation nor activating phospholipase C (see 172420) or ERK1/2 (see 176948). Fluorescence resonance energy transfer analysis strongly suggested that the L148S mutation impaired the ligand-induced catalytic activity of G-alpha.
Seminara et al. (2003) studied 63 unrelated patients with normosmic idiopathic hypogonadotropic hypogonadism and 20 patients with anosmic hypogonadotropic hypogonadism. In 1 patient, a black man with idiopathic hypogonadotropic hypogonadism (HH8; 614837), they identified compound heterozygosity for a 991C-T transition in exon 5 of the GPR54 gene, causing replacement of an arginine at residue 331 with a premature stop codon (R331X), and a 1195T-A transversion in exon 5, which replaced the stop codon at residue 399 with an arginine (X399R; 604161.0003). This nonstop mutation resulted in the continuation of the open reading frame to the poly(A) signal, with no intervening stop codon.
For discussion of the ter399-to-arg (X399R) mutation in the KISS1R gene that was found in compound heterozygous state in a patient with idiopathic hypogonadotropic hypogonadism (HH8; 614837) by Seminara et al. (2003), see 604161.0002.
In a French Caucasian man with normosmic hypogonadotropic hypogonadism, Brioude et al. (2013) identified compound heterozygosity for the X399R and L102P (604161.0005) substitutions in the KISS1R gene. His unaffected mother was heterozygous for the L102P mutation; neither mutation was found in 200 eugonadal Caucasian individuals.
By homozygosity mapping, de Roux et al. (2003) found that a locus on 19p13 was involved in hypogonadotropic hypogonadism (HH8; 614837) in affected members of a sibship whose parents were first cousins. Sequencing of several genes localized within this region showed that all affected sibs carried a homozygous 155-bp deletion in the GPR54 gene encompassing the splice acceptor site of the intron 4/exon 5 junction and part of exon 5.
In 5 patients with isolated hypogonadotropic hypogonadism (HH8; 614837) from 2 unrelated Arab Muslim families from Syria and Israel, Tenenbaum-Rakover et al. (2007) identified homozygosity for a 305T-C transition in the GPR54 gene, leading to a leu102-to-pro (L102P) substitution, which completely inhibited GPR54 signaling. Phenotypic analysis revealed variable expressivity in the same family, either partial or complete gonadotropic deficiency. LH pulsatility analysis showed peaks with normal frequency but low amplitude. Repeated GnRH tests performed between 12 and 21 years of age in 1 affected male revealed progressive changes in pituitary response from an early pubertal to an almost full pubertal pattern. Tenenbaum-Rakover et al. (2007) concluded that GPR54 inactivation does not impede neuroendocrine onset of puberty; rather, it delays and slows down pubertal maturation of the gonadotropic axis. The L102P loss of function mutation in GPR54 results in a more quantitative than qualitative defect of gonadotropic axis activation.
For discussion of the L102P mutation in the KISS1R gene that was found in compound heterozygous state in a patient with HH8 by Brioude et al. (2013), see 604161.0003.
Teles et al. (2008) identified a heterozygous arg386-to-pro (R386P) activating mutation in the GPR54 gene in an adopted girl with idiopathic central precocious puberty (CPPB1; 176400). Functional studies indicated that the mutation prolonged intracellular GPR54 signaling in response to kisspeptin (603286).
In a male patient with congenital hypogonadotropic hypogonadism with anosmia (HH8; 614837), who also had hearing loss, Miraoui et al. (2013) identified heterozygosity for a c.581C-A transversion in the KISS1R gene, resulting in an ala194-to-asp (A194D) substitution. The patient was also heterozygous for a missense mutation in the IL17RD gene (A735V; 606807.0003). The patient had a sister who had hypogonadotropic hypogonadism with anosmia, and their parents were unaffected; family member genotypes were unavailable.
In a brother and 2 sisters from a consanguineous Portuguese family with normosmic hypogonadotropic hypogonadism (HH8; 614837), Brioude et al. (2013) identified homozygosity for a c.937T-C transition in the KISS1R gene, resulting in a tyr313-to-his (Y313H) substitution at a highly conserved residue in the seventh transmembrane domain. Their unaffected parents were heterozygous for the mutation, which was not found in 200 chromosomes from eugonadal Caucasian individuals.
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