Alternative titles; symbols
HGNC Approved Gene Symbol: GNRHR
Cytogenetic location: 4q13.2 Genomic coordinates (GRCh38) : 4:67,737,118-67,754,388 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q13.2 | Hypogonadotropic hypogonadism 7 without anosmia | 146110 | Autosomal recessive | 3 |
Gonadotropin-releasing hormone (GNRH; 152760), a hypothalamic decapeptide, is a key neuroregulator of the reproductive process. It is synthesized by hypothalamic neurons, secreted in a pulsatile manner, and carried to the anterior lobe of the pituitary gland by way of the hypothalamohypophyseal portal circulation. The primary site of action of GNRH in the pituitary gland is the gonadotrope, the cell that expresses GNRH receptors and secretes gonadotropic hormones, which in turn regulate gametogenic and hormonal functions of the gonads. GNRH receptor is a member of the G protein-coupled, Ca(2+)-dependent family of receptors. Located on the cell surface of pituitary gonadotropes, GNRHR transduces signals from GNRH and modulates the synthesis and secretion of luteinizing hormone (152780) and follicle-stimulating hormone (136530).
Kakar et al. (1992) isolated a cDNA for the GNRH receptor and showed that it encodes a protein with a transmembrane topology similar to that of other G protein-coupled 7-transmembrane-domain receptors.
Grosse et al. (1997) used RT-PCR of human pituitary poly(A)+ RNA to clone the full-length GNRHR gene and a second truncated cDNA characterized by a 128-bp deletion between nucleotide positions 522 and 651. The deletion causes a frameshift in the open reading frame, thus generating new coding sequence for a further 75 amino acids. The truncated cDNA arises from alternative splicing that uses a cryptic 3-prime splice site in exon 2. Translation products of approximately 45 to 50 and 42 kD were immunoprecipitated from COS-7 cells transfected with wildtype and truncated GNRHR cDNAs, respectively. The splice variant was incapable of ligand binding and signal transduction. Coexpression of wildtype and truncated proteins in transiently or stably transfected cells, resulted in impaired signaling via the wildtype GNRHR by reducing maximal agonist-induced inositol phosphate accumulation. This inhibitory effect depended on the amount of splice variant cDNA cotransfected and was specific for GNRHR. Coexpression of the wildtype and truncated GNRHRs resulted in impaired insertion of wildtype GNRHR into the plasma membrane.
Using cDNA probes derived from a human pituitary cDNA library, Fan et al. (1994) screened a human genomic library and isolated 7 positive clones. The clones contained the entire protein coding region of the GNRHR gene, which is distributed among 3 exons and spans over 18.9 kb. The 2 introns, measuring 4.2 and 5.0 kb, were located within the open reading frame, indicating that the GNRHR gene is a member of the intron-containing class of the G protein-coupled receptor superfamily. Genomic Southern blot analysis demonstrated the presence of a single copy of the gene in the human genome.
Fan et al. (1995) showed that the GNRHR mRNA is approximately 5 kb long, of which 987 bp comprise the coding region. The gene appears to have large 5-prime and 3-prime untranslated regions, including, respectively, multiple transcription initiation sites and polyadenylation signals.
Kaiser et al. (1994) used mapping panels of human/rodent somatic cell hybrids containing different human chromosomes or different regions of human chromosome 4 to localize the GNRHR gene to 4q13.1-q21.1. Furthermore, using linkage analysis of single-strand conformation polymorphisms, they localized the murine homolog to mouse chromosome 5. Using PCR analysis of DNA from human/hamster somatic hybrid cell lines, Fan et al. (1994) assigned the GNRHR gene to chromosome 4. By in situ hybridization using a biotinylated cDNA probe, Morrison et al. (1994) localized the GNRHR gene to 4q13.2-q13.3. By fluorescence in situ hybridization using a larger genomic clone as a probe, Leung et al. (1995) apparently achieved a more precise localization of the GNRHR gene to 4q21.2.
Kottler et al. (1995) isolated YAC clones containing the GNRHR gene. Genetic analysis of the YACs showed that the gene lies between D4S409 and D4S392, which are located 76 and 77 cM, respectively, from the end of the short arm of chromosome 4. Furthermore, by fluorescence in situ hybridization, Kottler et al. (1995) demonstrated colocalization of GNRHR with the KIT gene (164920), which has been mapped to 4q12. Kakar and Neill (1995) mapped the gene to 4q13 by PCR analysis of genomic DNA from human/hamster somatic cell hybrids combined with fluorescence in situ hybridization.
The growth of sex hormone-dependent tumors is inhibited by analogs of luteinizing hormone-releasing hormone (LHRH; 152760). The use of LHRH agonists for treatment of prostatic and breast cancer is based on suppression of pituitary-gonadal function and the consequent creation of a state of sex-steroid deficiency. In addition, LHRH agonists and antagonists exert a direct effect on these tumors that probably is mediated by specific high-affinity LHRH receptors found on these cells. LHRH agonists and antagonists also suppress the growth of experimental pancreatic cancers. Szende et al. (1991) demonstrated that pancreatic tumor cells exhibit high-affinity binding sites for LHRH, but only in their nuclei; low-affinity sites are associated with the cell membranes. These binding sites appear to be LHRH receptors since electron microscopic immunohistochemical studies show that an antibody to the LHRH receptor reacted with sites in the nucleus of pancreatic tumor cells.
Maji et al. (2009) found that peptide and protein hormones, including GNRH, in secretory granules of the endocrine system are stored in an amyloid-like cross-beta-sheet-rich conformation, and concluded that functional amyloids in the pituitary and other organs can contribute to normal cell and tissue physiology.
In a sister and brother with normosmic idiopathic hypogonadotropic hypogonadism (HH7; 146110), de Roux et al. (1997) identified compound heterozygosity for 2 missense mutations in the GNRHR gene (Q106R, 138850.0001 and R262Q, 138850.0002).
Layman et al. (1998) screened 46 unrelated patients with normosmic idiopathic HH for GNRHR mutations and identified compound heterozygosity for the R262Q mutation and another missense mutation (Y284C; 138850.0003) in 1 family with 4 affected sibs.
In 3 sibs from a kindred with isolated HH, Caron et al. (1999) identified compound heterozygosity for R262Q and another missense mutation in the GNRHR gene (A129D; 138850.0004).
Kottler et al. (1999) analyzed in detail the GNRHR mutations in 7 independent familial and sporadic cases of idiopathic hypogonadotropic hypogonadism reported to that time. The Q106R and R262Q mutations were frequent in patients from all geographic areas (North and South America and Europe).
In a brother and 2 sisters with HH, de Roux et al. (1999) identified compound heterozygosity for the Q106R and R262Q mutations in the GNRHR gene; in addition, all 3 sibs carried another GNRHR missense mutation (S217R; 138850.0005) on the same allele with Q106R.
In a male patient with complete HH, Pralong et al. (1999) identified homozygosity for a missense mutation in GNRHR (S168R; 138850.0006).
In a woman with complete HH, Kottler et al. (2000) identified compound heterozygosity for Q106R and a nonsense mutation in the GNRHR gene (L314X; 138850.0007).
In a 26-year-old male with a mild form of hypogonadotropic hypogonadism, Pitteloud et al. (2001) identified homozygosity for the R262Q mutation in the GNRHR gene.
Costa et al. (2001) investigated 17 Brazilian patients with normosmic HH and identified homozygosity for a GNRHR missense mutation (R139H; 138850.0008) in a female with complete HH and compound heterozygosity for Q106R and another GNRHR missense mutation (N10K; 138850.0009) in 3 sibs with partial HH.
To determine the frequency and distribution of GNRHR mutations in a heterogeneous population of patients with idiopathic hypogonadotropic hypogonadism, Beranova et al. (2001) screened 108 probands with idiopathic hypogonadotropic hypogonadism for mutations in the coding sequence of GNRHR. Forty-eight of the 108 patients had a normal sense of smell, whereas the remaining 60 had anosmia or hyposmia (Kallmann syndrome). Five unrelated probands (3 men and 2 women), all normosmic, were documented to have changes in the coding sequence of the GNRHR. Two of these probands were from a subgroup of 5 kindreds consistent with a recessive mode of inheritance, establishing a GNRHR mutation frequency of 2 of 5 (40%) in patients with normosmic, autosomal recessive idiopathic hypogonadotropic hypogonadism. The remaining 3 probands with GNRHR mutations were from a subgroup of 18 patients without evidence of familial involvement, indicating a prevalence of 3 of 18 (16.7%) in patients with sporadic idiopathic hypogonadotropic hypogonadism and a normal sense of smell. Among the 5 individuals bearing GNRHR mutations, a broad spectrum of phenotypes was noted, including testicular sizes that varied from prepubertal to the normal adult male range. Three probands had compound heterozygous mutations, and 2 had homozygous mutations. Of the 8 DNA sequence changes identified, 4 were novel. COS-7 cells transiently transfected with cDNAs encoding the human GNRHR containing each of these 4 novel mutations failed to respond to GNRH agonist stimulation.
Janovick et al. (2002) showed pharmacologic rescue, assessed by ligand binding and restoration of receptor coupling to effector, of 5 naturally occurring GNRHR mutants identified from patients with hypogonadotropic hypogonadism, as well as rescue of other defective receptors manufactured with internal or terminal deletions or substitutions at sites expected to be involved in establishment of tertiary receptor structure. The pharmacologic agent used was a small, membrane-permeant molecule, originally designed as an orally active, nonpeptide receptor antagonist, but is believed to function as a folding template, capable of correcting the structural defects caused by the mutations and thereby restoring function. The rescued receptor, stabilized in the plasma membrane, coupled ligand binding to activation of the appropriate effector system. For comparison, low-, intermediate-, or high-affinity peptide antagonists of GNRHR (that do not penetrate the cell) were unable to effect rescue, as was a nonbinding peptidomimetic congener of the rescue agent; this latter effect demonstrates specificity of the rescue agent. Janovick et al. (2002) concluded that mutant GNRHRs frequently have not lost intrinsic functionality and are subject to rescue by techniques that enhance membrane expression.
Bedecarrats et al. (2003) analyzed 2 common mutations in GNRHR, gln106 to arg (Q106R; 138850.0001) and arg262 to gln (R262Q; 138850.0002), for their effects on the stimulation of gonadotropin subunit and GNRHR gene expression by GNRH. Despite similar impairment of GNRH-stimulated inositol phosphate production, dose-response analyses indicated that Q106R and R262Q both reduced the sensitivity of the FSH-beta (136530) gene promoter to a greater extent than LH-beta (152780) or the alpha-glycoprotein subunit (alpha-GSU; 118850), suggesting the involvement of more than one signaling pathway. Furthermore, although the sensitivities of the LH-beta and FSH-beta gene promoters to GNRH were similarly affected by both mutants, alpha-GSU sensitivity was decreased to a greater extent by R262Q than by Q106R. Similarly, GNRHR gene promoter sensitivity was significantly reduced only by R262Q. The authors concluded that differential stimulation of LH-beta, FSH-beta, and alpha-GSU gene expression may contribute to the varied phenotypes observed among patients harboring these mutations.
Leanos-Miranda et al. (2003) demonstrated that GNRHR mutants inhibited the function of wildtype GNRHR, measured by activation of effector and ligand binding. Inhibition varied depending on the particular GNRHR mutant coexpressed and the ratio of GNRHR mutant to wildtype GNRHR cDNA cotransfected. The GNRHR mutants did not interfere with the function of genetically modified GNRHRs bearing either a deletion of primate-specific lys191 or the carboxyl-terminal tail of catfish GNRHR. The dominant-negative effect of the naturally occurring receptor mutants occurred only for the wildtype GNRHR, which has intrinsic low maturation efficiency. The data suggested that this dominant-negative effect accompanies the diminished plasma membrane expression as a recent evolutionary event.
To determine whether genetic variation within either the GNRHR 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.
Oligogenic Inheritance
In 2 sisters with primary amenorrhea and no breast development at 25 and 18 years of age, respectively (146110), Seminara et al. (2000) identified compound heterozygosity for Q106R on one allele and R262Q (138850.0002) on the other. The apparently unaffected parents were heterozygous for the mutations. Pitteloud et al. (2007) reexamined the family studied by Seminara et al. (2000) and identified heterozygosity for an additional missense mutation in the FGFR1 gene (136350.0016) in the 2 sisters and in their father, who had a history of delayed puberty. Mutation analysis of the children of the younger sister revealed that her unaffected daughter, who had undergone normal puberty, was heterozygous for the mutation in FGFR1 but had no mutations in the GNRHR gene, and that her prepubertal 10-year-old twin sons, born without cryptorchidism or microphallus, were each heterozygous for 1 of the mutations in GNRHR but did not have any mutations in the FGFR1 gene. Pitteloud et al. (2007) concluded that defects in 2 different genes can synergize to produce a more severe phenotype in families with hypogonadotropic hypogonadism than either alone, and that this digenic model may account for some of the phenotypic heterogeneity seen in GnRH deficiency.
In a sister and brother with hypogonadotropic hypogonadism (HH7; 146110), de Roux et al. (1997) identified compound heterozygosity for a 317G-A transition in the GNRHR gene, resulting in a gln106-to-arg (Q106R) substitution, and a 785G-A transition, resulting in an arg262-to-gln (R262Q; 138850.0002) substitution. Both residues are highly conserved and are located in the first extracellular and third intracellular loop of the GNRH receptor, respectively. The unaffected parents and sister, who were clinically and endocrinologically normal, were each heterozygous for 1 of the mutations. Functional analysis demonstrated that GNRH binding was markedly reduced, but not eliminated, with the Q106R mutant, whereas GNRH binding was similar to wildtype with the R262Q mutant.
In a brother and 2 sisters with HH, de Roux et al. (1999) identified compound heterozygosity for the Q106R and R262Q mutations in the GNRHR gene; in addition, all 3 sibs carried another GNRHR missense mutation (S217R; 138850.0005) on the same allele with Q106R.
In 2 sisters with primary amenorrhea and no breast development at 25 and 18 years of age, respectively, Seminara et al. (2000) identified compound heterozygosity for the Q106R and R262Q mutations in the GNRHR gene. The apparently unaffected parents were heterozygous for the mutations. Pitteloud et al. (2007) reexamined this family and identified heterozygosity for an additional missense mutation in the FGFR1 gene (136350.0016) in the 2 sisters and in their father, who had a history of delayed puberty. Mutation analysis of the children of the younger sister revealed that her unaffected daughter, who underwent normal puberty, was heterozygous for the mutation in FGFR1 but had no mutations in the GNRHR gene, and that her prepubertal 10-year-old twin sons, born without cryptorchidism or microphallus, were each heterozygous for 1 of the mutations in the GNRHR gene but did not have any mutations in the FGFR1 gene. Pitteloud et al. (2007) concluded that defects in 2 different genes can synergize to produce a more severe phenotype in families with hypogonadotropic hypogonadism than either alone, and that this digenic model may account for some of the phenotypic heterogeneity seen in GnRH deficiency.
In a woman with complete HH, Kottler et al. (2000) identified compound heterozygosity for Q106R and a nonsense mutation in the GNRHR gene (L314X; 138850.0007).
In a 26-year-old male with mild HH, who had hypogonadal testosterone levels, detectable but apulsatile gonadotropin secretion, and normal testicular size, and who developed sperm after treatment with CG (see 118860), Pitteloud et al. (2001) identified homozygosity for the Q106R mutation in the GNRHR gene. The authors noted that de Roux et al. (1997) had previously shown that GNRH binding is decreased, but not eliminated, with the Q106R mutant.
In 4 Brazilian sibs with partial HH, Costa et al. (2001) identified compound heterozygosity for Q106R and another missense mutation in the GNRHR gene (N10K; 138850.0009).
In 2 brothers with severe HH, Karges et al. (2003) identified compound heterozygosity for Q106R and another missense mutation in the GNRHR gene (A171T; 138850.0012).
For discussion of the arg262-to-gln (R262Q) mutation in the GNRHR gene that was found in compound heterozygous state in patients with hypogonadotropic hypogonadism (HH7; 146110) by de Roux et al. (1997) and Seminara et al. (2000), see 138850.0001.
The R262Q mutation in GNRHR was also found in compound heterozygous state in 4 sibs with HH by Layman et al. (1998) (see 138850.0003) and in 3 sibs with HH by Caron et al. (1999) (see 138850.0004).
De Roux et al. (1999) found the R262Q mutation in compound heterozygous state in 3 sibs with HH, who carried both the Q106R (138850.0001) and S217R (138850.0005) mutations on the other allele.
In 2 brothers with HH7, Lin et al. (2006) identified homozygosity for the R262Q mutation in the GNRHR gene. The proband, who presented at 15 years of age with delayed puberty, responded to a short course of testosterone with appropriate progress through puberty, whereas his younger brother showed little response after treatment. Lin et al. (2006) concluded that homozygous partial loss-of-function mutations in GNRHR, such as R262Q, can cause variable phenotypes, including apparent delayed puberty.
In 4 sibs with hypogonadotropic hypogonadism (HH7; 146110), Layman et al. (1998) identified compound heterozygosity for the R262Q mutation in the GNRHR gene (138850.0002) and an A-G transition resulting in a tyr284-to-cys (Y284C; 138850.0003) substitution in transmembrane region 6. The mutations were not found in an unaffected sib or in 75 unrelated controls. At least 1 of the affected females ovulated in response to exogenous gonadotropins. The 2 GNRHR mutations had minimal effects on receptor affinity, but receptor expression was decreased for both.
In 3 sibs with isolated hypogonadotropic hypogonadism (HH7; 146110), Caron et al. (1999) identified compound heterozygosity for the R262Q mutation in the GNRHR gene (138850.0002) and a 386C-A transversion, resulting in an ala129-to-asp (A129D) substitution. Their unaffected parents were each heterozygous for 1 of the mutations.
For discussion of the ser217-to-arg (S217R) mutation in the GNRHR gene that was found in compound heterozygous state in 3 sibs with hypogonadotropic hypogonadism (HH7; 146110) by de Roux et al. (1999), see 138850.0001.
Pralong et al. (1999) described a male patient with complete hypogonadotropic hypogonadism (HH7; 146110) who presented primary failure of pulsatile GNRH (152760) therapy, but responded to exogenous gonadotropin administration. The patient had a T-to-A transversion at codon 168 of the gene encoding the GNRH receptor (GNRHR), resulting in a ser168-to-arg (S168R) change in the fourth transmembrane domain of GNRHR. This mutation was present in homozygous state in the patient, whereas it was in heterozygous state in both phenotypically normal parents. When introduced into GNRHR cDNA, S168R resulted in complete loss of the receptor-mediated signaling response to GNRH.
In a woman with complete hypogonadotropic hypogonadism (HH7; 146110), Kottler et al. (2000) identified compound heterozygosity for 2 mutations in the GNRHR gene: the Q106R mutation (138850.0001) and a leu314-to-ter (L314X) substitution, resulting in partial deletion of the seventh transmembrane domain. The L314X mutant receptor showed neither measurable binding nor inositol phosphate production when transfected in CHO-K1 cells compared to the wildtype receptor. Family members who were heterozygous for either mutation had normal pubertal development and fertility.
In a Brazilian woman with complete hypogonadotropic hypogonadism (HH7; 146110), Costa et al. (2001) identified homozygosity for an arg139-to-his (R139H) substitution located in the conserved DRS motif at the junction of the third transmembrane and the second intracellular loop of the GNRHR gene. The R139H mutation completely eliminated detectable GNRH-binding activity and prevented GNRH-induced stimulation of inositol phosphate accumulation in vitro. The patient had undetectable serum basal LH and FSH levels that failed to respond to GNRH stimulation.
In 4 Brazilian sibs with partial hypogonadotropic hypogonadism (HH7; 146110), who had low serum basal LH levels that were responsive to GNRH stimulation, Costa et al. (2001) identified compound heterozygosity for the Q106R mutation in the GNRHR gene (138850.0001) and an asn10-to-lys (N10K; 138850.0009) substitution in the extracellular amino-terminal domain. The Q106R mutation had been shown by de Roux et al. (1997) to bind GNRH with reduced affinity, and in vitro analysis also demonstrated decreased affinity for GNRH with the N10K mutant compared to wildtype GNRHR.
In 2 sibs with the complete form of hypogonadotropic hypogonadism (HH7; 146110), Soderlund et al. (2001) detected a novel homozygous G-to-A transition at nucleotide 268 of the GNRHR gene, which resulted in a glu90-to-lys (E90K) amino acid substitution. This mutation is located in the second transmembrane domain of the GNRH receptor. To assess the functional role of E90, Maya-Nunez et al. (2002) performed mutation analysis of the E90K substitution. Transient expression of the mutant receptor in COS-7 cells resulted in a virtual abolition of GNRH agonist binding and agonist-stimulated phosphoinositide turnover, initially suggesting that E90 may be essential for GNRH binding. To examine the role of a site known to suppress GNRHR function, mutants with deletion of K191 from the GNRHR and/or addition of catfish Gnrhr intracellular C-terminal tail to GNRHR were prepared. Activation of intracellular signaling in response to buserelin was restored by deletion of K191 from the E90K mutant receptor but minimally by addition of the catfish GNRHR C-terminal tail. This study provided evidence that the E90K mutation impairs GNRHR-effector coupling. Maya-Nunez et al. (2002) concluded that the observation that sequence modifications that enhance surface expression of the receptor restore function presents the possibility that loss of surface expression may underlie the severe phenotype exhibited by hypogonadotropic hypogonadism patients bearing this mutation.
In a woman with complete GNRH resistance (HH7; 146110), Silveira et al. (2002) identified homozygosity for a G-A transition at the intron 1/exon 2 boundary. RT-PCR analysis of RNA showed a transcript lacking all of exon 2, with splicing of exon 1 to exon 3 and creation of a frameshift, generating a coding sequence for 3 new amino acids followed by a stop codon. Although it was not clear whether the mutant receptor was actually expressed, the resultant mRNA sequence was presumed to produce a truncated receptor with no binding or signaling capacity. The proband presented with primary amenorrhea and absent thelarche and pubarche. Dynamic tests demonstrated absent spontaneous gonadotropin pulsatility, and there was no response to either exogenous pulsatile or acute GNRH administration. However, the patient responded to exogenous gonadotropin administration with a resulting normal pregnancy. Her unaffected sister was heterozygous for the mutation.
In 2 brothers with severe hypogonadotropic hypogonadism (HH7; 146110), Karges et al. (2003) identified compound heterozygosity for 2 mutations in the GNRHR gene: Q106R (138850.0001) and a 511G-A transition that results in an ala171-to-thr (A171T) substitution at transmembrane helix 4 (TMH4). After in vitro expression in human embryonic kidney 293T cells, the A171T mutant LHCGR exhibited a lack of phospholipase C activity in signal transduction. Specific receptor binding of radioisotope-labeled GNRH ligand was undetectable in transfected cells. Molecular modeling and dynamic simulation of the mutant receptor suggested the introduction of a stable hydrogen bond that impeded conformational mobility of the TMH3 and TMH4 domains required for sequential ligand binding and receptor activation, thus stabilizing the LHCGR in its inactive conformation.
Meysing et al. (2004) reported a normosmic woman with congenital idiopathic hypogonadotropic hypogonadism (HH7; 146110) in whom treatment with pulsatile GNRH resulted in an unusual response. The woman not only required an increased dose of pulsatile GNRH for ovarian follicular development, but LH secretion did not increase appropriately, estradiol levels remained low, and she did not ovulate spontaneously. Sequencing of the GNRHR coding sequence revealed compound heterozygosity for a 30T-A transversion in exon 1 of the GNRHR gene, resulting in a 2-amino acid substitution on one allele (N10K+Q11K), and a missense mutation on the other allele (P320L; 138850.0014). Introduction of the P320L mutation into the GNRH receptor led to failure of detectable ligand binding and failure of stimulation of inositol phosphate production and gonadotropin subunit gene promoter activity in response to GnRH in transiently transfected cells. Introduction of the N10K+Q11K mutation into the GNRH receptor resulted in reduced binding of a GNRH agonist to 25% of the wildtype receptor. In addition, the EC50 value for GNRH stimulation of inositol phosphate production was significantly increased, and the dose-response curves for stimulation of alpha-gonadotropin subunit (118850), LH-beta (152780), and FSH-beta (136530) gene transcription by GNRH were similarly shifted to the right. The authors proposed that these GNRHR mutations result in a rightward shift of the dose-response curves of gonadotropin responses to pulsatile GNRH in the subject and unmask the differential sensitivities of LH and FSH to GNRH, resulting in low LH and estradiol levels despite appropriate FSH secretion and follicular growth.
For discussion of the pro320-to-leu (P320L) mutation in the GNRHR gene that was found in compound heterozygous state in a woman with hypogonadotropic hypogonadism (HH7; 146110) by Meysing et al. (2004), see 138850.0013.
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