Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: GNRH1
Cytogenetic location: 8p21.2 Genomic coordinates (GRCh38): 8:25,419,258-25,425,040 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8p21.2 | ?Hypogonadotropic hypogonadism 12 with or without anosmia | 614841 | Autosomal recessive | 3 |
Luteinizing hormone-releasing hormone (LHRH), a decapeptide, is a key molecule in the hypothalamic-pituitary-gonadal axis that controls human reproduction. It is produced by hypothalamic neurons, secreted in a pulsatile manner into the capillary plexus of the median eminence, and effects the release of luteinizing hormone and follicle-stimulating hormone from gonadotropic cells of the anterior pituitary. Seeburg and Adelman (1984) isolated cloned genomic and cDNA encoding the precursor of LHRH. These DNA sequences code for a protein of 92 amino acids in which the LHRH decapeptide is preceded by a signal peptide of 23 amino acids and followed by a gly-lys-arg sequence as expected for enzymatic cleavage of the decapeptide from its precursor and amidation of the C terminus of LHRH. LHRH, also referred to as 'gonadotropin-releasing hormone' (GNRH), and prolactin release-inhibiting factor (PIF) are derived from the same 92-amino acid precursor protein, which is encoded by a single gene. (PIF has also been used as the symbol for a parotid salivary protein; see 168730.)
Hayflick et al. (1989) reported the complete nucleotide sequence of the GNRH gene.
Adelman et al. (1986) determined that the GNRH genes of man and rat have a similar arrangement of 4 exons.
The GNRH1 gene is exclusively expressed in a discrete population of neurons in the hypothalamus. To explore the protein-DNA interactions that occur within the GNRH1 promoter and the role of these interactions in targeting GNRH1 gene expression, Eraly et al. (1998) mutagenized individual binding sites in the proximal promoter of the GNRH1 gene. DNAase I protection experiments revealed that footprint-2, a 51-bp sequence that confers a 20-fold induction of the GNRH1 gene, is composed of at least 3 independent protein-binding sites. Mutations in footprint-4 also decreased GNRH1 gene expression. Mobility shift cross-competition and antibody shift experiments demonstrated that OCT1 (602607) binds the octamer motifs within footprints-2 and -4. Eraly et al. (1998) concluded that OCT1 plays a critical role in the regulation of GNRH1 transcription, binding functional elements in both the distal enhancer and the proximal promoter conserved region.
Wolfe et al. (2002) used a transgenic mouse model to isolate cis-regulatory elements important for directing gene expression to Gnrh neurons in the hypothalamus. Cell-specific expression, with the criterion being luciferase expression directed to Gnrh neurons of the hypothalamus, was observed when 992 bp, but not 795 bp, of the human GNRH1 gene promoter were used. Tissue-specific expression was also observed when a deletion construct containing the region from -992 to -763 was fused to a minimal 48-bp promoter fragment fused to a luciferase reporter gene. These data indicate that the region between -992 and -795 contains elements both essential and sufficient for targeting gene expression to Gnrh neurons. This promoter region contains 2 DNA binding sites for the POU class of transcription factors, each of which specifically interacted with the POU homeodomain proteins Brn2 (600494) and Oct1. Functional studies demonstrated that Brn2 increased promoter activity of the human and mouse GNRH1 genes.
Neuron-specific expression of the GNRH1 gene is dependent on an upstream multicomponent enhancer. This enhancer is functional in a small population of GNRH1-producing hypothalamic neurons which, through the secretion of GNRH1, mediates central nervous system control of reproductive function. GNRH1 enhancer function requires activation by the GATA family of transcription factors that act through tandem consensus GATA-binding motifs, termed GATA-A and GATA-B. See GATA4 (600576). Lawson et al. (1998) showed that 2 newly identified DNA-binding factors, which they referred to as GBF-A1/A2 and GBF-B1, bind the GNRH1 enhancer at sites overlapping the GATA factor-binding motifs. In vitro bindings of GATA, GBF-A1/A2, and GBF-B1 to the GNRH1 enhancer sequences occurred independently. Utilizing a GNRH1-expressing neuronal cell line as a model system, they showed by transient transfection that GBF-B1 is necessary for enhancer activity and independently activates the GNRH1 promoter. Transactivation of the GNRH1 enhancer in GT1 cells and in NIH 3T3 cells by GATA4 was modulated by GBF-B1 binding, suggesting that GBF-B1 interferes with GATA factor binding through a steric mechanism.
Dong et al. (1997) localized 4 specific nuclear protein-binding elements in the human GNRH1 upstream promoter. To test whether these 4 elements are reproductive tissue-specific, Dong et al. (2001) placed the 4 elements upstream to a thymidine kinase (188300) promoter/luciferase reporter gene and transfected the constructs into human placental choriocarcinoma (JEG-3) cells. Deletion of element 4 (E4, -987/-968) significantly decreased (4-fold) the luciferase activity. Further deletion of the other elements (E3, -960/-940 or E3 and E2 in combination, -919/-896) only slightly decreased the luciferase activity. In contrast, deletion of element 1 (E1, -876/-851) caused a 2-fold loss of luciferase activity and elimination of E2 and E3 only lost less than 2-fold of the luciferase activity. Furthermore, E4 DNA-protein complex was supershifted by antibodies against octamer-binding transcription factor-1 (OCT1), indicating that OCT1 binds to E4. The authors concluded that all 4 elements are required to confer tissue-specific expression of the GNRH1 gene in JEG-3 cells; however, E4 is the most important for the tissue-specific expression of the GNRH1 gene in JEG-3 cells. OCT1 factor binds with E4 and may be involved in the mediation of the human GNRH1 upstream promoter activity.
Duan et al. (2002) examined the regulatory elements and signal transduction pathways by which GNRH regulates Egr1 (128990) transcription. Deletion analysis of the murine Egr1 promoter identified 2 regions (-370 to -342 and -116 to -73) that are critical for GNRH responsiveness in alpha-T3 pituitary gonadotrope cells. The first region, which contains 2 serum response elements (SREs), contributed about 70 to 80% of GNRH inducibility, whereas the second region, which contains 2 SREs and 1 Ets binding site, conferred an additional 20 to 30% of activity. Using specific protein kinase inhibitors, GNRH stimulation of Egr1 expression was found to be dependent on PKC/ERK pathways (see 603607). The authors concluded that GNRH stimulation of Egr1 gene expression requires several distinct SREs/Ets elements and a cAMP response element and is mediated via activation of PKC/ERK signaling pathways.
The Gnrh gene is expressed exclusively in a highly restricted population of approximately 800 neurons in the mediobasal hypothalamus in the mouse. The Otx2 homeoprotein (600037) colocalizes with Gnrh in embryonic mouse brain. Kelley et al. (2000) identified a highly conserved bicoid-related Otx target sequence within the proximal promoter region of the Gnrh gene from several species. This element from the rat Gnrh promoter binds baculovirus-expressed Otx2 protein and Otx2 protein in nuclear extracts of a hypothalamic Gnrh-expressing mouse neuronal cell line, GT1-7. Transient transfection assays indicated that the Gnrh promoter Otx/bicoid site is required for specific expression of the Gnrh gene in GT1-7 cells. Thus, the Gnrh proximal promoter is regulated by the Otx2 homeoprotein. The authors concluded that Otx2 is important in the development of the Gnrh neuron and/or in the maintenance of Gnrh expression in the adult mouse hypothalamus.
Olfactory neurons and GNRH neurons share a common origin during development. In the nasal epithelia, GNRH neurons persist throughout fetal life and adulthood. Barni et al. (1999) reported that human olfactory cells express the GNRH1 gene and protein. The release of GNRH was time-dependent and was positively affected by sex steroids and odorants. The authors stated that this was the first time that primary cell cultures from human fetal olfactory neuroepithelium have been shown to express and release GNRH. They suggested that these cultures, which are sensitive to sex steroids and odorants, could be useful models in the study of the complex array of regulatory factors that finely tune GNRH secretion in humans.
Gametes and preimplantation embryos express GNRH and GNRH receptor (GNRHR; 138850) at both mRNA and protein levels. Casan et al. (2000) used RT-PCR and immunohistochemical techniques to investigate GNRH mRNA and protein expression in human fallopian tubes throughout the menstrual cycle of premenopausal fertile patients. Their results revealed cycle-dependent production of an oviductal GnRH with expression during the luteal phase. Moreover, GnRH immunostaining was localized in the tubal epithelium during the luteal phase. They concluded that during reproductive life, oviductal GNRH may play a substantial paracrine/autocrine role in human fertilization, early embryonic development, and implantation.
Chen et al. (2002) found that human normal and leukemic T cells produce GNRH2 (602352) and GNRH1. Exposure of normal or cancerous human or mouse T cells to GNRH2 or GNRH1 triggered de novo gene transcription and cell-surface expression of the laminin receptor (150370), which is involved in cellular adhesion and migration and in tumor invasion and metastasis. GNRH2 or GNRH1 also induced adhesion to laminin and chemotaxis toward SDF1A (600835), and augmented entry in vivo of metastatic T-lymphoma into the spleen and bone marrow. Homing of normal T cells into specific organs was reduced in mice lacking GNRH1. A specific GNRH1 receptor antagonist blocked GNRH1 but not GNRH2-induced effects, which was suggestive of signaling through distinct receptors. Chen et al. (2002) suggested that GNRH2 and GNRH1, secreted from nerves or autocrine or paracrine sources, interact directly with T cells and trigger gene transcription, adhesion, chemotaxis, and homing to specific organs.
To determine whether genetic variation within either the GNRHR (138850) or GNRH1 genes contributes to the regulation of pubertal timing in the general population, Sedlmeyer et al. (2005) performed sequence analysis and haplotype-based association studies in individuals with later than average pubertal development. All observed associations were relatively modest and only nominally statistically significant. The authors concluded that genetic variation in GHRH1 and GNRHR is not likely to be a substantial modulator of pubertal timing in the general population.
Zhang et al. (2013) showed that the hypothalamus is important for the development of whole-body aging in mice, and that the underlying basis involves hypothalamic immunity mediated by I-kappa-B kinase-beta (IKK-beta; 603258), NF-kappa-B (164011), and related microglia-neuron immune crosstalk. Several interventional models were developed showing that aging retardation and life span extension were achieved in mice by preventing aging-related hypothalamic or brain IKK-beta and NF-kappa-B activation. Mechanistic studies further revealed that IKK-beta and NF-kappa B inhibit GNRH to mediate aging-related hypothalamic GNRH decline, and GNRH treatment amends aging-impaired neurogenesis and decelerates aging. Zhang et al. (2013) concluded that the hypothalamus plays a programmatic role in aging development via immune-neuroendocrine integration.
Yang-Feng et al. (1986) used a cDNA clone from human placenta to assign the LHRH gene to 8p21-p11.2 by in situ hybridization and corroborated the assignment to chromosome 8 by Southern blot analysis of somatic hybrid cell DNAs. Williamson et al. (1991) mapped the Gnrh gene in the mouse to chromosome 14.
In a Romanian brother and sister from a Transylvanian mountain village who had normosmic hypogonadotropic hypogonadism (HH12; 614841), Bouligand et al. (2009) identified homozygosity for a 1-bp insertion in the GNRH1 gene (152760.0001). GnRH was undetectable in medium conditioned by AtT20 pituitary cells transfected with mutant GNRH1.
Chan et al. (2009) identified homozygosity for a 1-bp deletion in an Armenian boy with hypogonadotropic hypogonadism (152760.0002). The mutation status of his parents was not reported, but the deletion was not found in 192 controls.
Oligogenic Inheritance
In a cohort of 310 patients with normosmic HH, Chan et al. (2009) analyzed the HH-associated genes GNRH1, FGFR1 (136350), and PROKR2 (607123), and identified rare heterozygous variants in all 3 genes in the proband of a 3-generation pedigree: R31C in GNRH1, I239T in FGFR1, and S202G in PROKR2. The proband had affected twin daughters, one of whom carried the GNRH1 and FGFR1 variants, whereas the other twin and an affected niece carried only the GNRH1 variant.
In the rat, Adelman et al. (1987) found that whereas GNRH is encoded by 1 DNA strand, another DNA strand is transcribed into RNA of unknown function. The second gene, called SH, produces transcripts found in the heart, whereas GNRH is expressed in the central nervous system. The RNA transcribed from each of the 2 DNA strands is spliced and polyadenylated, and share significant exon domains. (The Gart locus of Drosophila, known to encode 3 purine pathway enzymatic activities (see 138440), contains an entire gene encoding a cuticle protein, 'nested,' within the first Gart intron and transcribed from the opposite DNA strand.)
Mason et al. (1986) demonstrated that hypogonadism in the hpg (hypogonadal) mouse is caused by a deletional mutation of at least 33.5 kb encompassing the distal half of the gene for the common biosynthetic precursor of gonadotropin-releasing hormone and GNRH-associated peptide (GAP). The partially deleted gene was found to be transcriptionally active as revealed by in situ hybridization histochemistry of hpg hypothalamic tissue sections, but immunocytochemical analysis failed to show the presence of antigen corresponding to any part of the precursor protein. GAP is the same as PIF; it possesses potent prolactin release inhibitory activity (Nikolics et al., 1985). Interestingly, the part of the gene coding for the GNRH decapeptide is left intact. The lack of GNRH in the hpg mouse remains unexplained. Mason et al. (1986) found that introduction of an intact GNRH gene into the genome of the hpg mouse resulted in complete reversal of the hypogonadal phenotype. Transgenic hpg/hpg homozygotes of both sexes were capable of mating and producing offspring. Cattanach et al. (1977) gave the original description of the hpg mouse. They suggested that the hpg mouse might be analogous to the human disorder described by Ewer (1968) as familial monotropic pituitary insufficiency transmitted as an autosomal recessive; see 614841. Gibson et al. (1984) demonstrated that preoptic area brain grafts restored the capacity for mating and pregnancy in the hpg female mouse described by Cattanach et al. (1977).
In a Romanian brother and sister from a Transylvanian mountain village who had normosmic hypogonadotropic hypogonadism (HH12; 614841), Bouligand et al. (2009) identified homozygosity for a 1-bp insertion (18insA) in the GNRH1 gene, predicted to result in an aberrant peptide with a truncated peptide-signal sequence devoid of its hydrophobic core and a total length of 42 amino acids instead of the normal 92. The unaffected parents and an unaffected sister were heterozygous for the mutation, as was 1 of 200 ancestrally matched Romanian controls; haplotype analysis suggested a founding event 8 to 50 generations earlier. The mutation was not found in 100 unrelated Caucasian eugonadal individuals or in 145 unrelated Caucasian patients with sporadic normosmic IHH. Transfection studies using AtT20 pituitary cells showed that GnRH was present in medium conditioned by cells transfected with wildtype GNRH1, but was undetectable in medium conditioned by cells transfected with the GNRH1 18insA mutant.
This variant is classified as a variant of unknown significance because its contribution to hypogonadotropic hypogonadism (see 614841) has not been confirmed.
Chan et al. (2009) analyzed the GNRH1 gene in 310 patients with normosmic hypogonadotropic hypogonadism (HH), and identified homozygosity for a 1-bp deletion (c.87delA) in an Armenian boy. The mutation causes a frameshift predicted to result in a premature termination codon (Gly29GlyfsTer12). The mutation status of his unaffected parents, who came from the same small village in Armenia, was not reported; however, the deletion was not found in 192 controls. The authors also sequenced the FGFR1 (136350) and PROKR2 (607123) genes in the proband but detected no mutations. The affected boy, who was initially evaluated at 8.75 years of age for micropenis and cryptorchidism, had no skeletal or midline defects. Luteinizing hormone (LH; 152780) and follicle-stimulating hormone (FSH; see 136530) levels were less than 0.5 IU/L; anti-mullerian hormone (AMH; 600957) was low normal, indicating the presence of testicular Sertoli cells. A human chorionic gonadotropin (hCG; see 118860) stimulation test produced no change in serum testosterone. Testicular biopsies at the time of orchiopexy showed immature seminiferous tubules with no lumen, gonocyte-like cells, immature Sertoli cells, and interstitial fibrosis with spindle-shaped myofibroblasts. At 13.5 years of age, he underwent a GnRH stimulation test due to lack of pubertal development, with minimal increases in LH and FSH. He had a normal sense of smell on formal testing. Testosterone treatment resulted in linear growth and development of secondary sexual characteristics, which at 15.5 years of age included facial hair and Tanner stage V pubic hair.
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