* 152790

LUTEINIZING HORMONE/CHORIOGONADOTROPIN RECEPTOR; LHCGR


Alternative titles; symbols

LUTROPIN-CHORIOGONADOTROPIN RECEPTOR; LCGR
LUTEINIZING HORMONE RECEPTOR; LHR
GONADOTROPIN RECEPTOR


HGNC Approved Gene Symbol: LHCGR

Cytogenetic location: 2p16.3     Genomic coordinates (GRCh38): 2:48,686,774-48,755,724 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
2p16.3 Leydig cell adenoma, somatic, with precocious puberty 176410 3
Leydig cell hypoplasia with hypergonadotropic hypogonadism 238320 AR 3
Leydig cell hypoplasia with pseudohermaphroditism 238320 AR 3
Luteinizing hormone resistance, female 238320 AR 3
Precocious puberty, male 176410 AD 3

TEXT

Description

The luteinizing hormone/choriogonadotropin receptor is a member of a subfamily of G protein-coupled receptors (GPCR) characterized by the presence of a large N-terminal extracellular domain containing several leucine-rich repeats (LRR). This glycoprotein hormone receptor family has been named the LRR-containing GPCR (LGR) family (Ascoli et al., 2002).


Cloning and Expression

McFarland et al. (1989) isolated a cDNA for the rat luteal lutropin-choriogonadotropin receptor with the use of a DNA probe generated in a PCR with oligonucleotide primers based on peptide sequences of purified receptor protein. The sequence consisted of a 26-residue signal peptide, a 341-residue extracellular domain displaying an internal repeat structure characteristic of members of the leucine-rich glycoprotein family, and a 333-residue region containing 7 transmembrane segments. The membrane-spanning region displayed sequence similarity with all members of the G protein-coupled receptor family. Loosfelt et al. (1989) essentially confirmed these findings in the porcine gene and made the additional discovery of variants which were thought to have arisen through alternative splicing and in which the putative transmembrane domain was absent.

Minegishi et al. (1990) isolated and cloned the human luteinizing hormone/choriogonadotropin receptor from an ovary cDNA library. The deduced protein contains 674 amino acids including a 335-amino acid extracellular domain with 6 putative glycosylation sites, a 267-amino acid region that displays 7 transmembrane segments (the serpentine region), and a 72-amino acid C-terminal intracellular domain. Minegishi et al. (1990) found evidence of alternative splicing. The human LHCGR membrane spanning domain shares 90% homology with the rat and porcine LHCGR receptors and approximately 70% with the human TSH (603372) and FSH (136435) receptors.

Tsai-Morris et al. (1998) isolated a human LHCGR gene from a human placenta genomic library and found that it differed in protein sequence and start site from the reported ovarian LHCGR. Although Tsai-Morris et al. (1998) thought they these represented 2 different LHCGR genes, it was later determined that the sequence identified by Tsai-Morris et al. (1998) was an LHCGR variant (152790.0017) (Ascoli et al., 2002).

See reviews of the luteinizing hormone receptor by Segaloff and Ascoli (1993) and Ascoli et al. (2002).


Mapping

Rousseau-Merck et al. (1990) assigned the LHCGR gene to chromosome 2p21.


Gene Structure

The LHCGR gene contains 11 exons and spans approximately 80 kb (Atger et al., 1995).


Gene Function

Gospodarowicz (1973), Lee and Ryan (1972), and others studied receptors for human luteinizing hormone in testis and ovary.

In the ovary, theca, stromal, late-stage (luteinizing) granulosa, and luteal cells contain LHCGR. In the testes, Leydig cells contain LHCGR (Themmen and Huhtaniemi, 2000).

Eblen et al. (2001) tested the hypothesis that human ejaculated sperm contain functional LHCG receptors. Their data indicated that LHCGR mRNA and protein that can bind CG are present. The receptors were functional, as indicated by an increase in cAMP levels and activation of sperm protein kinase A (see 176911) following treatment with CG or LH. However, treatment with these hormones had no effect on sperm protein kinase C (see 176960) activity. The authors concluded that since functional LHCGRs are found in human sperm, it is important to determine whether CG treatment could improve the outcome of infertility procedures.

Min and Ascoli (2000) examined the effects of several LHCGR mutations on the phosphorylation, internalization, and turnover of the cell surface receptor. Three gain-of-function mutations associated with Leydig cell hyperplasia, including 1 somatic mutation associated with Leydig cell adenomas (D578H; 152790.0019), were chosen for this study. One signaling-impaired mutation associated with Leydig cell hypoplasia (I625K; 152790.0016) and 2 laboratory-designed signaling-impaired mutations were also used. The signaling-impaired mutations showed a reduction in human CG-induced receptor phosphorylation and internalization. Mutation of the phosphorylation sites of these loss-of-function mutants had little or no additional effect on internalization. Cotransfection with G protein-coupled receptor kinase-2 (GRK2: 109635) rescued the CG-induced phosphorylation and internalization of the signaling-impaired mutations but only if the phosphorylation sites were intact. Overexpression of arrestin-3 (301770) rescued the rate of internalization regardless of whether or not the phosphorylation sites were intact. The authors concluded that the data obtained with the signaling-impaired and phosphorylation-deficient mutants of the LHCGR support a model whereby receptor phosphorylation and activation play a redundant role in the internalization of CG. The results obtained with the constitutively active mutants suggest that, when occupied by CG, these mutants assume a conformation that bypasses many of the steps involved in internalization.

Before ovulation in mammals, a cascade of events resembling an inflammatory and/or tissue remodeling process is triggered by LH in the ovarian follicle. Many LH effects, however, are thought to be indirect because of the restricted expression of its receptor to mural granulosa cells (Peng et al., 1991). Park et al. (2004) demonstrated that LH stimulation in wildtype mouse ovaries induces the transient and sequential expression of the epidermal growth factor family members amphiregulin (104640), epiregulin (602061), and betacellulin (600345). Incubation of follicles with these growth factors recapitulates the morphologic and biochemical events triggered by LH, including cumulus expansion and oocyte maturation. Thus, Park et al. (2004) concluded that these EGF-related growth factors are paracrine mediators that propagate the LH signal throughout the follicle.

To investigate the role of exon 10 in LHCGR action in vitro, Muller et al. (2003) created stable COS-7 cells expressing the LHR with or without exon 10 (see also 152790.0020). Binding experiments showed that the affinities of LH and CG to LHR with and without exon 10 were similar. The authors concluded that although exon 10 of the LHR plays no role in ligand binding, it is important for receptor activation by LH by a mechanism probably involving extracellular conformational changes.


Molecular Genetics

Loss-of-function mutations in the LHCGR gene in males cause Leydig cell hypoplasia, supporting the concept that a functional receptor is necessary for the early development of Leydig cells. Activating mutations of the receptor cause gonadotropin-independent male-limited precocious puberty, a disorder characterized by autonomous hyperplasia and hyperfunction of Leydig cells in association with inappropriate stimulation of adenylyl cyclase and the cAMP signaling pathway, but little or no activation of the phospholipase C pathway (summary by Liu et al., 1999).

Atger et al. (1995) described a leu-gln (LQ) insertion at position 55-60 of the LHCGR. They noted that the extracellular N-terminal domain of glycoprotein hormone receptors constitutes the high-affinity binding site responsible for the specificity in hormone recognition, suggesting that variations in the reported N-terminal sequences could have functional significance. Rodien et al. (1998) demonstrated that both sequences exist as allelic variants in the Caucasian population (152790.0017). In contrast, the LQ allele is virtually absent from the Japanese population.

Male-Limited Precocious Puberty

Laue et al. (1995) studied the constitutively activating mutations of the LHCGR gene in dominantly inherited male-limited precocious puberty (176410). They studied genomic DNA from 32 unrelated families. The inherited form of the disorder was present in 28, and of these, 24 were found to have an asp578-to-gly mutation (152790.0001). Other mutations were found, suggesting that the region spanning nucleotides 1624-1741 of exon 11 is a hotspot for point mutations that constitutively activate the LHCGR gene and cause male-limited precocious puberty.

Multiple activating mutations in the sixth transmembrane domain of the LHCGR have been identified in patients with male-limited precocious puberty. By computer analysis, Yano et al. (1997) found that these mutations have an effect on the secondary structure of the third cytoplasmic loop and sixth transmembrane domain. They also found that phe576, which might be important for receptor activity, is a critical conformational bridging residue between these 2 regions. To analyze the functional role of phe576, the authors made 4 amino acid substitutions, F576I, F576G, F576Y, and F576E, in the LHCGR. Computer analysis of the F576E mutant predicted that its secondary structure changed to a totally helical conformation in the region of the third intracellular and sixth transmembrane domain. In contrast, the secondary structures of the F576G, F576I, and F576Y mutants were predicted to change the helical conformation in the region to an extended conformation. In expression studies, mutations of phe576 produced functional changes in cAMP and inositol phosphate (IP) signaling and CG binding. Mutations predicted to cause an extended conformation exhibited 2 functional patterns: first, constitutively activating in cAMP signaling without changes in IP signaling or CG binding (F576I and F576G), and second, constitutively activating in cAMP signaling with decreased CG-induced cAMP and IP signaling and with both higher affinity and lower capacity of CG binding (F576Y). The mutation predicted to cause a totally helical conformation resulted in no cAMP responses and a minimal IP response to CG stimulation, with negligible CG binding (F576E). Yano et al. (1997) concluded that phe576 plays an important role in the human LHCGR with respect to receptor conformation, Gs coupling, and cAMP signaling consistent with predictions from mutations associated with male-limited precocious puberty.

Kremer et al. (1999) reported analysis of LHCGR gene mutations in a sample consisting of 17 independent families and sporadic cases (8 familial and 9 with a negative family history) with LH-independent precocious puberty. They detected 7 different mutations in 12 patients. Of these, 2 mutations were detected more than once. The ile542-to-leu mutation (152790.0018) was present in 4 Dutch kindreds, suggesting a common ancestor, although no genealogic relationship could be demonstrated. The met398-to-thr mutation (152790.0010) was found in 2 kindreds from Germany and in 1 patient from Sicily. In contrast to previous reports, the asp578-to-gly mutation (152790.0001) was not frequent in these 17 kindreds. In fact, none of the 10 European kindreds with LHCGR mutations in this study had the asp578-to-gly mutation, and the only family with this mutation was from the U.S. The authors suggested that there is a strong founder effect in the U.S., where greater than 90% of testotoxicosis families have the asp578-to-gly mutation. Only 12 LHCGR gene mutations had been reported in a total of 68 independent patients and families. The restricted number of LHCGR mutations found in affected kindreds as well as in sporadic cases strongly suggested that only mutations in specific areas of the receptor, in particular the sixth transmembrane region, can autonomously activate cAMP production.

Leydig Cell Hypoplasia

In 46,XY sibs with pseudohermaphroditism, offspring of consanguineous parents, who presented with female external genitalia, primary amenorrhea, and lack of breast development (238320), Kremer et al. (1995) identified homozygosity for an ala593-to-pro mutation in the LCGR gene (152790.0004).

Laue et al. (1995) demonstrated a nonsense mutation in the LCGR gene (152790.0007) in 2 46,XY sisters with Leydig cell hypoplasia, a form of male pseudohermaphroditism. The affected sibs were presumably compound heterozygotes. The father had the same mutation; the mother was presumed to have a different loss of function mutation which was not detected. In the family reported by Laue et al. (1995), Wu et al. (1998) identified a loss of function mutation in the mother (152790.0021). Genomic DNA-PCR showed that this defective maternal LHCGR allele was inherited by the 2 affected children, but RT-PCR showed that the maternal allele was not expressed. They concluded that Leydig cell hypoplasia in this family was the result of compound heterozygous loss-of-function mutations of the LHCGR gene.

Latronico et al. (1998) reported a 46,XY pseudohermaphrodite who presented with female external genitalia and his 46,XX sister who had oligoamenorrhea and infertility, and enlarged cystic ovaries. Both sibs were found to be homozygous for a deletion at nucleotides 1822-1827 (CTGGTT), resulting in the deletion of leu608 (CTG) and val609 (GTT) in the seventh transmembrane helix of the LHCGR gene (152790.0015). Transfections of 293 cells with normal and mutant LHCGR constructs showed that very little of the mutant receptor was expressed at the cell surface. This was due to both a decrease in the total amount of receptor expressed as well as increased intracellular retention of the mutant receptor. While equilibrium binding assays showed that the cell surface mutant receptor bound CG with an affinity comparable to that of the wildtype receptor, cells expressing the mutant exhibited only a 1.5- to 2.4-fold stimulation of cAMP production in response to CG. In contrast, cells expressing comparably low levels of the normal receptor responded to CG with 11- to 30-fold increases of cAMP levels. Latronico et al. (1998) concluded that the majority of the mutant receptor is retained intracellularly, and that the small percentage of mutant receptor that is expressed at the cell surface binds hormone normally but is unable to activate the stimulatory G protein (Gs; see 139320).

Luteinizing Hormone Resistance, Female

Latronico et al. (1998) identified the same mutation in the LHCGR gene (152790.0015) in a 46,XX girl with oligomenorrhea and infertility (see 238320) and her 46,XY sib with Leydig cell hypoplasia and pseudohermaphroditism.

Toledo et al. (1996) evaluated a 46,XX sister of the two 46,XY male pseudohermaphrodites with Leydig cell hypoplasia described by Kremer et al. (1995). They found that the patient, who presented with amenorrhea due to hypergonadotropic hypogonadism but with structurally normal ovaries, had the same mutation in the LHCGR gene (152790.0004) as her 2 affected sibs.

Leydig Cell Adenomas

Leydig cell adenomas are the most frequent form of hormone-producing tumors of the testis and account for 1 to 3% of all testicular tumors. Most are benign, but 10% of tumors in adults are malignant. Boys with Leydig cell tumors typically have signs of isosexual precocity as a result of testosterone secretion by the tumor. The demonstrated role of the luteinizing hormone receptor in the proliferation of Leydig cells and the presence of germline and somatic mutations in the gene for the homologous thyrotropin receptor (TSHR; 603372) in familial nonimmunogenic hyperthyroidism (e.g., 603372.0004) and sporadic thyroid adenomas (e.g., 603372.0002), respectively, led Liu et al. (1999) to hypothesize that some Leydig cell adenomas are caused by activating somatic mutations in the LHCGR gene. Indeed, they described 3 boys with isosexual precocity presenting as early pubertal development 1 to 2 years before the discovery of Leydig cell tumors. All 3 were found to be heterozygous for a G-to-C transversion at nucleotide 1732 (1732G-C) in the tumor only. This novel somatic mutation, resulting in the change of GAT to CAT, encoded an asp578-to-his amino acid change (152790.0019). In 2 unrelated boys with gonadotropin-independent hypersecretion of testosterone due to Leydig cell adenomas, Canto et al. (2002) found the same 1732G-C heterozygous mutation in DNA from the tumors from both patients, but not from the adjacent normal tissue or blood leukocytes. Sequencing of the LHCGR gene showed that 50 normal individuals did not have this mutation.


ALLELIC VARIANTS ( 29 Selected Examples):

.0001 PRECOCIOUS PUBERTY, MALE-LIMITED

LHCGR, ASP578GLY
  
RCV000015461...

In individuals with familial male precocious puberty (FMPP; 176410) from 8 different families, Shenker et al. (1993) identified heterozygosity for a single A-to-G transition that resulted in substitution of glycine for aspartate at position 578 (D578G) in the sixth transmembrane helix of the LH receptor. Linkage of the mutation to the clinical disorder was supported by restriction-digest analysis. COS-7 cells expressing the mutant LH receptor exhibited markedly increased cyclic AMP production in the absence of agonist, suggesting that autonomous Leydig cell activity in this disorder is caused by a constitutively activated LH receptor.

Kosugi et al. (1995) stated that the asp578-to-gly mutation had been found in affected males from 9 American FMPP families. Since 7 of the 9 originated in the southeastern United States, the possibility of a shared common ancestor was raised. For that reason, they analyzed genomic DNA from affected males from 6 new FMPP families: 2 from Germany, 3 from France, and 1 from the western United States with mixed Caucasian-Native American ancestry. None of the 6 new samples contained the asp578-to-gly mutation, as indicated by the absence of digestion with MspI. PCR products were then screened for heterozygous mutations by temperature-gradient gel electrophoresis. DNA fragments from 2 of the patients migrated abnormally. Direct sequencing of the PCR product from 1 affected German male revealed a heterozygous mutation of the type described in another European family by Kremer et al. (1993); see 152790.0002.

In a screening of genomic DNA from 32 unrelated families with male-limited precocious puberty, Laue et al. (1995) found that 28 had the inherited form of the disorder, and of these, 24 had the D578G mutation. Four additional mutations were found among the remaining 4 families with the inherited form and in 4 sporadic cases of the disorder.

Yano et al. (1994) found the asp578-to-gly mutation in a sporadic case of male precocious puberty in a Japanese patient.

Kawate et al. (1995) found this same constitutively activating mutation of the LHCGR gene in a family with male-limited gonadotropin-independent precocious puberty (testotoxicosis). The family was ascertained through 2 affected brothers whose father had started puberty before his third birthday. His maternal uncle and maternal great uncle were also affected.

Rosenthal et al. (1996) evaluated the pituitary-gonadal axis in a mother after 2 of her sons with familial male-limited precocious puberty were found to have the constitutively activating D578G mutation of the LHCGR gene. Ovarian function was normal in the 36-year-old mother as assessed by LH dynamics and FSH and androgen levels were normal throughout her menstrual cycle. Hormonal responses to acute GnRH agonist (nafarelin) challenge, chronic GnRH agonist administration, and dexamethasone were also normal. Studies of the affected sons on presentation at 2.4 and 3.5 years of age revealed that acute LH responses to nafarelin were in the hypogonadotropic range, and the FSH responses were prepubertal despite the presence of late pubertal testosterone blood levels. These data showed that the activating D578G mutation does not cause functional ovarian hyperandrogenism but only incomplete pubertal activation of Leydig cells consistent with the relatively low constitutive activity of this mutation.

Martin et al. (1998) reported the development of a testicular seminoma in a 35-year-old man who had previously been diagnosed with familial male-limited precocious puberty and found to be heterozygous for the gain-of-function D578G mutation in the LHCGR gene. The authors stated that this represented the first case of a testicular germ cell tumor described in an FMPP patient.


.0002 PRECOCIOUS PUBERTY, MALE-LIMITED

LHCGR, MET571ILE
  
RCV000015462

Kremer et al. (1993) hypothesized that an abnormal configuration of the LH receptor might autonomously activate G protein coupling, and thereby cause the overproduction of testosterone in the absence of testicular stimulation by luteinizing hormone observed in familial male precocious puberty (176410). Therefore, they screened for mutations in a part of the LHCGR gene that is important for G protein binding, using the single-strand conformation polymorphism technique. DNA sequence variation was detected in 2 out of 5 families, and in each case the mutation cosegregated with the disorder (lod score 5.76 without recombination). Both mutations caused an amino acid substitution in the sixth transmembrane domain, close to the C-terminal portion of the third cytoplasmic loop, a region important for the binding of G proteins: a 1713G-A transition leading to a met571-to-ile (M571I) substitution, in family 1, and a 1733A-G transition, leading to an asp578-to-gly (D578G; 152790.0001) substitution, in family 2.

In a German male with FMPP, Kosugi et al. (1995) found the same M571I mutation. By transiently expressing the met571-to-ile mutation in COS-7 cells, they found that agonist affinity was unaffected by the mutation. However, like the asp578-to-gly mutant receptor, the met571-to-ile receptor triggered agonist-independent production of cAMP, but not of inositol phosphates. This suggested that autonomous testosterone production in FMPP can be explained by constitutive activation of the cAMP pathway alone.


.0003 MOVED TO 152790.0001


.0004 LEYDIG CELL HYPOPLASIA, TYPE I

LUTEINIZING HORMONE RESISTANCE, FEMALE, INCLUDED
LHCGR, ALA593PRO
  
RCV000015465...

In two 46,XY sibs with Leydig cell hypoplasia (238320) born to consanguineous parents, Kremer et al. (1995) found homozygosity for a missense ala593-to-pro mutation in the sixth transmembrane domain of the LHCGR gene. In vitro expression studies showed that this mutated receptor binds human choriogonadotropin normally, but the ligand binding does not result in increased production of cAMP. They concluded that a homozygous LH receptor gene mutation underlies the syndrome of autosomal recessive congenital Leydig cell hypoplasia in this family. The 2 sibs had presented with female external genitalia, primary amenorrhea, and lack of breast development. Their parents, who were first cousins, had 14 additional offspring. Both patients had short blind-ending vagina, without uterus or fallopian tubes. Sperm levels of testosterone and testosterone precursors were abnormally low and did not respond to stimulation with human choriogonadotropin. Basal levels of luteinizing hormone were markedly increased. On histologic examination, the gonads were found to be testes with normal Sertoli cells but no mature Leydig cells.

Toledo et al. (1996) evaluated a 46,XX sister of the two 46,XY male pseudohermaphrodites with Leydig cell hypoplasia described by Kremer et al. (1995). The patient presented with amenorrhea due to hypergonadotropic hypogonadism (see 238320), but had structurally normal ovaries. Analysis of her LH receptor genes showed that she was homozygous for the same mutation that caused an ala593-to-pro substitution in her 2 brothers. In vitro analysis of the mutant LH receptor in cultured human embryonic kidney 293 cells showed that the receptor is unable to stimulate adenylyl cyclase in response to CG. These results document the existence of inherited LH resistance as a cause of primary amenorrhea in women.


.0005 PRECOCIOUS PUBERTY, MALE-LIMITED

LHCGR, THR577ILE
  
RCV000015467...

In a male with familial precocious puberty (176410), Kosugi et al. (1995) demonstrated a thr577-to-ile mutation (ACC to ATT).


.0006 PRECOCIOUS PUBERTY, MALE-LIMITED

LHCGR, ALA572VAL
  
RCV000015468...

In 2 Japanese patients with male-limited precocious puberty (176410) without a family history of the disorder, Yano et al. (1995) found a heterozygous C-to-T transition at nucleotide 1715 leading to an alanine-to-valine substitution in codon 572 of transmembrane helix 6. Transfected into COS-7 cells, the A572V mutation exhibited constitutively high basal cAMP levels. Yano et al. (1995) concluded that the constitutively higher cAMP levels led to Leydig cell activation. The mother of 1 of the 2 patients had the same heterozygous mutation.


.0007 LEYDIG CELL HYPOPLASIA, TYPE I

LHCGR, CYS545TER
  
RCV000015469...

Laue et al. (1995) identified a cys545-to-ter mutation in exon 11 of the LHCGR gene in 2 46,XY sibs with male pseudohermaphroditism (238320). The mutation was an A-to-C transversion at nucleotide 1635 which caused loss of function of the receptor by introducing a stop codon at residue 545 in transmembrane helix 5 of the luteinizing hormone receptor. Surface expression of the truncated gene product in human embryonic kidney cells stably transfected with cDNA encoding the mutant protein was diminished compared to the wildtype gene, and hCG-induced cAMP accumulation was impaired. The mutation in the 2 sibs was present also in the normal father and was not present in the mother. The finding excludes the possibility of a dominant-negative mutation in the sisters and suggests that they are compound heterozygotes, the mutation inherited from the mother not being identified. The results of Laue et al. (1995) indicated that functional domains between transmembrane helix 5 and the C-terminal cytoplasmic tail of the gene are required for normal cell surface expression of the receptor and signal transduction. In the family reported by Laue et al. (1995), Wu et al. (1998) identified a loss of function mutation in the mother (152790.0021).


.0008 LEYDIG CELL HYPOPLASIA, TYPE I

LUTEINIZING HORMONE RESISTANCE, FEMALE, INCLUDED
LHCGR, ARG554TER
  
RCV000015470...

In a sibship with 14 children, Latronico et al. (1996) identified 3 brothers with pseudohermaphroditism with Leydig cell hypoplasia (238320) and 1 sister with partial ovarian failure (see 238320). In all 4 sibs, they identified a homozygous substitution of thymine for cytosine at nucleotide 1660 of the LHCGR gene; the mutation changed codon 554 from one coding for arginine (CGA) to a stop codon (TGA) within the third cytosolic loop of the LH receptor. The sister had spontaneous gonadarche at the age of 13 years, and she had a single episode of vaginal bleeding at the age of 20 years. Her height and weight were normal, pubic-hair development was Tanner stage 5, and the breasts and external genitalia were those of a normal woman. Her karyotype was 46,XX. Serum LH concentration was very high and serum estradiol concentration and progesterone concentration were low.


.0009 LEYDIG HYPOPLASIA, TYPE I

LHCGR, SER616TYR
  
RCV000015472...

In a 6-year-old phenotypically male child who had been referred as a neonate for evaluation of micropenis (see 238320), Latronico et al. (1996) identified a C-to-A transversion of nucleotide 1847 of the LH-receptor cDNA, resulting in a change of codon 616 from one coding for serine (TCT) to one coding for tyrosine (TAT) within the seventh transmembrane region of the LH receptor. At birth, the length of the stretched phallus was 1.5 cm (more than 2.5 SD below the normal mean for age). Both testes were descended, with a volume of approximately 1 ml each.


.0010 PRECOCIOUS PUBERTY, MALE-LIMITED

LHCGR, MET398THR
  
RCV000015473...

Several affected members of a family with familial male precocious puberty (176410) and 1 affected subject in a second family showed a point mutation (T-to-C transition at nucleotide 1192), resulting in a met398-to-thr substitution in the second transmembrane domain of the LH receptor protein (Evans et al., 1996). In addition, 1 male in the first family had the mutation but showed no evidence of precocious puberty. All obligate carriers within this family were shown to have the mutation, and it was not detected in 94 chromosomes from unaffected and unrelated white subjects. In the second family, the index case was the only one to have the mutation.


.0011 MOVED TO 152790.0001


.0012 LEYDIG CELL HYPOPLASIA, TYPE II

LHCGR, ARG133CYS
  
RCV000015475

Misrahi et al. (1997) reported the case of an infant who presented at birth with hypoplastic phallus associated with hypospadias (see 238320). Conventional microscopic study of the testes showed fibroblastic cells in the interstitium. However, immunocytochemical analysis using anti-LH receptor and anti-P450c17 antibodies demonstrated that about one-third of these cells were Leydig cells or their precursors. The infant was homozygous for an arg133-to-cys substitution in the extracellular domain of LHCGR. COS-7 cells transfected with the mutant receptor showed a marked impairment of CG binding, but exhibited some cAMP production at high CG concentrations. The authors proposed that the partial impairment of LHCGR function, as reflected by the presence of Leydig cells, was responsible for the milder LCH phenotype observed.


.0013 PRECOCIOUS PUBERTY, MALE-LIMITED

LHCGR, ALA373VAL
  
RCV000015476

Gromoll et al. (1998) reported a patient with onset of puberty at the age of 5 years, who had accelerated growth, enlargement of genitalia, pubarche, and serum hormone levels compatible with noncentral precocious puberty (176410). They identified a heterozygous C-to-T transition at nucleotide position 1126, encoding an ala373-to-val substitution in the first transmembrane domain. The LHCGR sequences of the parents were normal. The mutated receptor displayed an increase in basal cAMP production (up to 7.5-fold) compared to that of the wildtype receptor in transiently transfected COS-7 cells. Treatment of the patient with ketoconazole resulted in inconsistent suppression of serum testosterone levels. At the age of 9.1 years, central activation of the hypothalamic-pituitary-gonadal axis occurred. Additional treatment with a GnRH agonist led to complete suppression of testosterone secretion.


.0014 LEYDIG CELL HYPOPLASIA, TYPE I

LUTEINIZING HORMONE RESISTANCE, FEMALE, INCLUDED
LHCGR, GLU354LYS
  
RCV000015477...

Stavrou et al. (1998) reported a homozygous mutation of the LHCGR gene in 3 sibs (two 46,XY and one 46,XX). The 46,XY sibs presented with female external genitalia, primary amenorrhea, and lack of breast development (238320). Hormonal evaluation revealed a markedly elevated LH level with a low testosterone level, which failed to increase after human CG stimulation. Histologic analysis of the inguinal gonads in a 46,XY sib revealed no Leydig cells, but Sertoli cells, spermatogonia, and primary spermatocytes were seen. The 46,XX sib had female external genitalia, normal breast development, cystic ovaries, and primary amenorrhea (see 238320). Hormonal analyses showed markedly elevated LH levels and low plasma 17-beta-estradiol levels. A homozygous missense mutation was found at exon 11 of the LHCGR gene. Guanine was replaced by adenine (GAA to AAA), resulting in a substitution of lysine for glutamic acid at amino acid position 354. Functional analysis of the mutation showed complete loss of function, indicated by the lack of cAMP production after human CG stimulation in transfected human embryonic kidney 293 cells. Screening of family members demonstrated heterozygosity for the mutation, indicating autosomal recessive inheritance.


.0015 LEYDIG CELL HYPOPLASIA, TYPE I

LUTEINIZING HORMONE RESISTANCE, FEMALE, INCLUDED
LHCGR, 6-BP DEL, NT1822
  
RCV000015479...

Latronico et al. (1998) reported a 46,XY pseudohermaphrodite who presented with female external genitalia (238320) and his 46,XX sister who had oligoamenorrhea and infertility, and enlarged cystic ovaries (see 238320). Both affected sibs were homozygous for a deletion of nucleotides 1822-1827 (CTGGTT), resulting in the deletion of leu608 (CTG) and val609 (GTT) in the seventh transmembrane helix of the LHCGR gene. This microdeletion caused impaired expression and reduced signal transduction activity of the LHCGR.


.0016 LEYDIG CELL HYPOPLASIA, TYPE II

LHCGR, ILE625LYS
  
RCV000015481

Martens et al. (1998) evaluated 3 brothers with Leydig cell hypoplasia who presented with micropenis, absence of pubertal signs, and infertility (see 238320). LH and FSH levels were elevated but responded normally to GnRH. Basal testosterone and androstenedione levels, however, were low and responded poorly to CG. Analysis of their LHCGR genes revealed a homozygous missense mutation resulting in an iso625-to-lys (I625K) substitution. In vitro analysis of the I625K mutant in HEK293 cells indicated that the signaling efficiency was significantly impaired, explaining the partial phenotype. The authors compared this mutant to 2 other LHCGR gene mutations, A593P (152790.0004) and S616Y (152790.0009). Although the ligand-binding affinity for all 3 mutant receptors was normal, the hormonal response of A593P was completely absent and that of S616Y and I625K was severely impaired. Low cell surface expression explained the reduced response of S616Y, while a combination of low cell surface expression and decreased coupling efficiency explained the diminished response of I625K. For A593P, the absence of a reduced response resulted from both poor cell surface expression and a complete deficiency in coupling. Martens et al. (1998) concluded that a clear correlation exists between the severity of the clinical phenotype of patients and overall receptor signal capacity, which is a combination of cell surface expression and coupling efficiency.


.0017 LUTEINIZING HORMONE/CHORIOGONADOTROPIN RECEPTOR, LQ VARIANT

LHCGR, LEU-GLN INS, CODON 19-20
  
RCV000283585...

Two different human LH receptor sequences have been published, differing by a 6-basepair insertion encoding leu-gln at position 55-60 (Minegishi et al., 1990; Atger et al., 1995). Rodien et al. (1998) demonstrated that both sequences exist as allelic variants in the Caucasian population. Allele frequencies of LQ variant and wildtype allele are 0.26 and 0.74 respectively. In contrast, the LQ allele is virtually absent from the Japanese population. Functional characterization of both alleles by transient expression in COS-7 cells did not reveal any difference between the 2 receptors, neither for cell surface expression nor for cAMP production and sensitivity to CG/LH.

Powell et al. (2003) investigated whether functional polymorphic variants in the LH signaling pathway are associated with the risk of breast cancer or its clinical phenotype. Women who were homozygous for the LQ allele were, on average, 8.3 years younger at diagnosis, compared with those homozygous for the wildtype LHR allele (mean age, 51.9 years vs 60.2 years; P = 0.03). Trends were observed for associations between LQ carriers and nodal involvement or larger tumor size. Patients who were LQ carriers revealed a significantly worse overall survival, compared with those who were homozygous for wildtype LHR. The authors concluded that their findings suggested that the LQ gene polymorphism determines an earlier age of disease onset and is prognostic for poor outcome of breast cancer.


.0018 PRECOCIOUS PUBERTY, MALE-LIMITED

LHCGR, ILE542LEU
  
RCV000015483...

Kremer et al. (1999) found that an ile542-to-leu substitution was present in 4 Dutch kindreds with male LH-independent precocious puberty (176410), suggesting a common ancestor as the cause for this clustering, although no genealogic relationship could be demonstrated. Laue et al. (1995) had found this mutation in 3 families and in one sporadic case from the U.S.


.0019 LEYDIG CELL ADENOMA, SOMATIC, WITH MALE-LIMITED PRECOCIOUS PUBERTY

LHCGR, ASP578HIS
  
RCV000015484

Liu et al. (1999) described 3 boys with isosexual precocity (176410) presenting as early pubertal development 1 to 2 years before the discovery of Leydig cell tumors. All 3 were found to be heterozygous for a G-to-C transversion at nucleotide 1732 of the LHCGR gene in the tumor only. This novel somatic mutation, resulting in the change of GAT to CAT, encoded an asp578-to-his amino acid change.

In 2 unrelated boys with gonadotropin-independent hypersecretion of testosterone due to Leydig cell adenomas, Canto et al. (2002) found the same 1732G-C heterozygous mutation in DNA from the tumors from both patients, but not from the adjacent normal tissue or blood leukocytes. Sequencing of the LHCGR gene showed that 50 normal individuals did not have this mutation.


.0020 LEYDIG CELL HYPOPLASIA, TYPE II

LHCGR, EX10DEL
   RCV000015485

Gromoll et al. (2000) reported a patient with partial Leydig cell hypoplasia (see 238320) caused by a genomic deletion resulting in the complete absence of exon 10 of the LHCGR gene. The patient presented at the age of 18 years with retarded pubertal development, small testicles, and delayed bone maturation. LH was highly elevated, with very low serum testosterone levels. Genetic analysis revealed a homozygous deletion of approximately 5 kb encompassing exon 10 of the LHCGR gene. Screening of family members demonstrated heterozygosity for the deletion, indicating autosomal recessive inheritance. At the time of examination, the patient displayed nearly normal male phenotype but lacked pubertal development and was hypogonadal. Fetal male development sustained by hCG was normal, whereas LH action was impaired. An hCG stimulation test induced testosterone biosynthesis and secretion within the normal range. The authors concluded that despite highly elevated endogenous LH serum levels, the response to hCG indicates a possible dual mechanism of hormone binding and signal transduction for hCG and LH on an LHCGR lacking exon 10. Furthermore, they stated that the patient represents the clinical counterpart of the normal male marmoset monkey, in which the expressed LHR lacks exon 10 in toto.


.0021 LEYDIG CELL HYPOPLASIA, TYPE I

LHCGR, 33-BP INS, NT54
  
RCV000015486...

In the family reported by Laue et al. (1995) in which 2 sibs with Leydig cell hypoplasia type I (238320) inherited a cys545-to-ter mutation (152790.0007) on the paternal allele, Wu et al. (1998) identified a 33-bp insertion in the maternal LHCGR allele. This insertion occurred between nucleotides 54 and 55 and might be the result of a partial gene duplication. Genomic DNA-PCR showed that this defective maternal LHCGR allele was inherited by the 2 affected children, but RT-PCR showed that the maternal allele was not expressed. They concluded that Leydig cell hypoplasia in this family was the result of compound heterozygous loss-of-function mutations of the LHCGR gene.


.0022 PRECOCIOUS PUBERTY, MALE-LIMITED

LHCGR, LEU368PRO
  
RCV000015487

Latronico et al. (2000) examined 3 Brazilian boys, 2 brothers and 1 unrelated boy, with gonadotropin-independent precocious puberty (176410). Direct sequencing of the entire exon 11 of the LHCGR gene in the 2 brothers showed a heterozygous substitution of T for C at nucleotide 1103, resulting in the substitution of leu368 to pro (L368P) in the first transmembrane helix. Cells expressing the novel L368P mutation displayed up to a 12-fold increase in basal cAMP production compared with cells expressing the same number of cell surface wildtype LHCGR, indicating constitutive activation of the mutant receptor.


.0023 PRECOCIOUS PUBERTY, MALE-LIMITED

LHCGR, ALA568VAL
  
RCV000015488

In a Brazilian boy with gonadotropin-independent precocious puberty (176410) examined by Latronico et al. (2000), sequencing of exon 11 of the LHCGR gene revealed homozygosity for a nucleotide substitution causing an ala568-to-val (A568V) substitution in the third cytoplasmic loop of the receptor. This mutation had been found previously in 2 unrelated Brazilian boys in heterozygous state (Latronico et al. (1995, 1998)). Clinical and hormonal data of the homozygous A568V patient were not different from those of heterozygotes. The phenotype caused by dominant activating mutations of the LHCGR gene is not altered when both alleles carry a mutant sequence. The authors concluded that the A568V mutation is the most frequent cause of male-limited precocious puberty in Brazilian boys.


.0024 PRECOCIOUS PUBERTY, MALE-LIMITED

LHCGR, LEU457ARG
  
RCV000015489

Latronico et al. (1998) examined 2 unrelated Brazilian boys with gonadotropin-independent precocious puberty (176410) caused by 2 different heterozygous activating mutations of LHCGR. Direct sequencing of the entire exon 11 in one affected boy revealed a heterozygous substitution of T for G at nucleotide 1370 that converted leu457 to arg (L457R) in the third transmembrane helix of the LHCGR. His parents had a normal LHCGR gene sequence, establishing the sporadic nature of this mutation. Human embryonic 293 cells expressing mutant or wildtype LHCGR bound CG with high affinity. However, cells expressing LHCGR 457R exhibited significantly higher basal levels of cAMP (7- to 14-fold) than cells expressing the wildtype receptor, indicating constitutive activation. Furthermore, cells expressing the mutant were unresponsive to further stimulation by CG. This finding was confirmed in the patient by lack of an increase in serum testosterone after CG stimulation. The authors concluded that the conformation of the L457R mutant represents a different activated receptor state (R*) than the agonist-occupied wildtype receptor. The other mutation identified was ala568 to val (152790.0023).


.0025 LEYDIG CELL HYPOPLASIA, TYPE I

LHCGR, CYS343SER
  
RCV000015490

Martens et al. (2002) reported the identification of 2 LHCGR mutations in a compound heterozygous case of complete Leydig hypoplasia (238320) and determined the cause of the signaling deficiency at a molecular level. On the paternal allele of the patient they identified in codon 343 a T-to-A transversion that changes a conserved cysteine in the hinge region of the receptor to serine (C343S); on the maternal allele a T-to-C transition causes another conserved cysteine at codon 543 in transmembrane segment 5 to be altered to arginine (C543R). Both of these mutant receptors are completely devoid of hormone-induced cAMP reporter gene activation. Using Western blotting of expressed LH receptor protein with a hemagglutinin tag, they showed that despite complete absence of total and cell surface hormone binding, protein levels of both mutant LH receptors are only moderately affected. Expression and study of enhanced green fluorescent protein (GFP)-tagged receptors demonstrated that although initial translocation to the endoplasmic reticulum of these mutant receptors was normal, translocation was halted or misrouted, and as a result, neither mutant ever reached the cell surface, and they could not bind hormone. The authors concluded that complete lack of signaling by the identified mutant LH receptors is caused by insufficient processing from the endoplasmic reticulum to the cell surface and results in complete Leydig cell hypoplasia in this patient.


.0026 LEYDIG CELL HYPOPLASIA, TYPE I

LHCGR, CYS543ARG
  
RCV000015464

For discussion of the cys543-to-arg (C543R) mutation in the LHCGR gene that was found in a patient with complete Leydig hypoplasia (238320) by Martens et al. (2002), see 152790.0025.


.0027 LEYDIG CELL HYPOPLASIA, TYPE I

LHCGR, LEU502PRO
  
RCV000015491

In a 19-year-old patient with female phenotype and 46,XY karyotype (238320), Leung et al. (2004) identified a homozygous 1505T-C transversion in exon 11 of the LHCGR gene, resulting in a leu502-to-pro (L502P) substitution at a conserved residue in the fourth transmembrane helix of the protein. The mutation caused inactivation of the LH receptor and resulted in Leydig cell hypoplasia. Testicular histology and hormonal profile of the patient were considered typical for Leydig cell hypoplasia. The mutation was present in heterozygous state in both parents.


.0028 LEYDIG CELL HYPOPLASIA, TYPE I

LHCGR, VAL144PHE
  
RCV000015492

In a patient with Leydig cell hypoplasia (238320) who presented as a 46,XY girl, Richter-Unruh et al. (2004) detected a G-to-T transversion at nucleotide 430 in exon 5 of the LHCGR gene, resulting in an amino acid change from valine to phenylalanine at codon 144 (V144F). The father, mother, and one of the patient's brothers were heterozygous for the mutation. Human embryonic kidney cells transfected with the mutant LHCG receptor exhibited a marked impairment of human chorionic gonadotropin binding. Western blot analysis of the expressed V144F mutant receptor protein showed the absence of the glycosylated cell surface form. Treatment of the mutant LHCG receptor with N-glycosidase F or endoglycosidase-H demonstrated that the mutant receptor is retained in the endoplasmic reticulum. Expression and study of enhanced green fluorescent protein-tagged receptors confirmed that the mutant receptors do not migrate to the cell surface.


.0029 PRECOCIOUS PUBERTY, MALE-LIMITED

LHCGR, ASP564GLY
  
RCV000015493...

In a boy who was diagnosed with gonadotropin-independent precocious puberty (176410) at 4 years of age, Leschek et al. (2001) identified an asp564-to-gly (D564G) substitution in exon 11 of the LHCGR gene in peripheral blood leukocytes. At 10.8 years of age, routine ultrasound examination led to the discovery of 2 right testicular masses; after excisional biopsy, histologic examination showed nodular Leydig cell hyperplasia surrounded by normal-appearing seminiferous tubules with spermatogenesis, and DNA from tumor tissue revealed the same D564G mutation that was present in peripheral blood leukocytes.


See Also:

REFERENCES

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  50. Yano, K., Kohn, L. D., Saji, M., Okuno, A., Cutler, G. B., Jr. Phe576 plays an important role in the secondary structure and intracellular signaling of the human luteinizing hormone/chorionic gonadotropin receptor. J. Clin. Endocr. Metab. 82: 2586-2591, 1997. [PubMed: 9253338, related citations] [Full Text]

  51. Yano, K., Saji, M., Hidaka, A., Moriya, N., Okuno, A., Kohn, L. D., Cutler, G. B. A new constitutively activating point mutation in the luteinizing hormone/choriogonadotropin receptor gene in cases of male-limited precocious puberty. J. Clin. Endocr. 80: 1162-1168, 1995. [PubMed: 7714085, related citations] [Full Text]


Marla J. F. O'Neill - updated : 4/29/2009
Carol A. Bocchini - updated : 4/9/2009
John A. Phillips, III - updated : 10/27/2005
Victor A. McKusick - updated : 11/23/2004
Ada Hamosh - updated : 3/10/2004
John A. Phillips, III - updated : 8/25/2003
John A. Phillips, III - updated : 8/25/2003
John A. Phillips, III - updated : 8/25/2003
John A. Phillips, III - updated : 1/16/2003
Sonja A. Rasmussen - updated : 4/18/2002
John A. Phillips, III - updated : 3/5/2002
John A. Phillips, III - updated : 10/10/2001
John A. Phillips, III - updated : 10/1/2001
John A. Phillips, III - updated : 7/2/2001
John A. Phillips, III - updated : 3/5/2001
Victor A. McKusick - updated : 7/13/2000
John A. Phillips, III - updated : 4/3/2000
Victor A. McKusick - updated : 12/3/1999
John A. Phillips, III - updated : 9/9/1999
John A. Phillips, III - updated : 4/13/1999
John A. Phillips, III - updated : 10/1/1998
John A. Phillips, III - updated : 6/24/1998
John A. Phillips, III - updated : 5/21/1998
John A. Phillips, III - updated : 9/18/1997
John A. Phillips, III - updated : 4/1/1997
John A. Phillips, III - updated : 2/25/1997
Creation Date:
Victor A. McKusick : 9/26/1989
alopez : 07/18/2017
carol : 06/29/2015
carol : 6/11/2015
mcolton : 6/9/2015
carol : 6/20/2011
wwang : 5/5/2009
terry : 4/29/2009
terry : 4/10/2009
carol : 4/9/2009
carol : 4/9/2009
wwang : 10/15/2008
carol : 5/14/2007
terry : 3/14/2007
alopez : 10/27/2005
tkritzer : 11/30/2004
terry : 11/23/2004
terry : 11/3/2004
carol : 3/17/2004
alopez : 3/11/2004
terry : 3/10/2004
alopez : 1/29/2004
alopez : 10/2/2003
carol : 9/12/2003
alopez : 8/25/2003
alopez : 8/25/2003
alopez : 8/25/2003
alopez : 8/25/2003
alopez : 1/16/2003
carol : 4/19/2002
terry : 4/18/2002
terry : 3/6/2002
alopez : 3/5/2002
mcapotos : 12/20/2001
cwells : 10/31/2001
cwells : 10/12/2001
cwells : 10/10/2001
alopez : 10/1/2001
mcapotos : 10/1/2001
mcapotos : 8/2/2001
mcapotos : 7/31/2001
cwells : 7/31/2001
cwells : 7/5/2001
cwells : 7/5/2001
cwells : 7/2/2001
mgross : 3/5/2001
alopez : 7/21/2000
terry : 7/13/2000
mgross : 5/17/2000
terry : 4/3/2000
alopez : 3/24/2000
mgross : 12/6/1999
mgross : 12/6/1999
mgross : 12/3/1999
terry : 12/3/1999
joanna : 11/5/1999
alopez : 9/9/1999
alopez : 9/9/1999
mgross : 4/16/1999
mgross : 4/13/1999
carol : 10/1/1998
dkim : 9/11/1998
dholmes : 6/29/1998
dholmes : 6/24/1998
alopez : 5/21/1998
alopez : 5/14/1998
dholmes : 11/11/1997
dholmes : 11/11/1997
dholmes : 11/11/1997
dholmes : 10/30/1997
dholmes : 10/30/1997
dholmes : 10/29/1997
jenny : 4/1/1997
jenny : 3/4/1997
jenny : 2/25/1997
jenny : 2/24/1997
mark : 4/3/1996
terry : 3/29/1996
mark : 3/14/1996
terry : 3/7/1996
mark : 2/5/1996
terry : 1/30/1996
mark : 11/6/1995
carol : 2/15/1995
mimadm : 11/6/1994
carol : 12/13/1993
carol : 12/10/1993
carol : 11/16/1993

* 152790

LUTEINIZING HORMONE/CHORIOGONADOTROPIN RECEPTOR; LHCGR


Alternative titles; symbols

LUTROPIN-CHORIOGONADOTROPIN RECEPTOR; LCGR
LUTEINIZING HORMONE RECEPTOR; LHR
GONADOTROPIN RECEPTOR


HGNC Approved Gene Symbol: LHCGR

SNOMEDCT: 56212008, 725295005;  


Cytogenetic location: 2p16.3     Genomic coordinates (GRCh38): 2:48,686,774-48,755,724 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
2p16.3 Leydig cell adenoma, somatic, with precocious puberty 176410 3
Leydig cell hypoplasia with hypergonadotropic hypogonadism 238320 Autosomal recessive 3
Leydig cell hypoplasia with pseudohermaphroditism 238320 Autosomal recessive 3
Luteinizing hormone resistance, female 238320 Autosomal recessive 3
Precocious puberty, male 176410 Autosomal dominant 3

TEXT

Description

The luteinizing hormone/choriogonadotropin receptor is a member of a subfamily of G protein-coupled receptors (GPCR) characterized by the presence of a large N-terminal extracellular domain containing several leucine-rich repeats (LRR). This glycoprotein hormone receptor family has been named the LRR-containing GPCR (LGR) family (Ascoli et al., 2002).


Cloning and Expression

McFarland et al. (1989) isolated a cDNA for the rat luteal lutropin-choriogonadotropin receptor with the use of a DNA probe generated in a PCR with oligonucleotide primers based on peptide sequences of purified receptor protein. The sequence consisted of a 26-residue signal peptide, a 341-residue extracellular domain displaying an internal repeat structure characteristic of members of the leucine-rich glycoprotein family, and a 333-residue region containing 7 transmembrane segments. The membrane-spanning region displayed sequence similarity with all members of the G protein-coupled receptor family. Loosfelt et al. (1989) essentially confirmed these findings in the porcine gene and made the additional discovery of variants which were thought to have arisen through alternative splicing and in which the putative transmembrane domain was absent.

Minegishi et al. (1990) isolated and cloned the human luteinizing hormone/choriogonadotropin receptor from an ovary cDNA library. The deduced protein contains 674 amino acids including a 335-amino acid extracellular domain with 6 putative glycosylation sites, a 267-amino acid region that displays 7 transmembrane segments (the serpentine region), and a 72-amino acid C-terminal intracellular domain. Minegishi et al. (1990) found evidence of alternative splicing. The human LHCGR membrane spanning domain shares 90% homology with the rat and porcine LHCGR receptors and approximately 70% with the human TSH (603372) and FSH (136435) receptors.

Tsai-Morris et al. (1998) isolated a human LHCGR gene from a human placenta genomic library and found that it differed in protein sequence and start site from the reported ovarian LHCGR. Although Tsai-Morris et al. (1998) thought they these represented 2 different LHCGR genes, it was later determined that the sequence identified by Tsai-Morris et al. (1998) was an LHCGR variant (152790.0017) (Ascoli et al., 2002).

See reviews of the luteinizing hormone receptor by Segaloff and Ascoli (1993) and Ascoli et al. (2002).


Mapping

Rousseau-Merck et al. (1990) assigned the LHCGR gene to chromosome 2p21.


Gene Structure

The LHCGR gene contains 11 exons and spans approximately 80 kb (Atger et al., 1995).


Gene Function

Gospodarowicz (1973), Lee and Ryan (1972), and others studied receptors for human luteinizing hormone in testis and ovary.

In the ovary, theca, stromal, late-stage (luteinizing) granulosa, and luteal cells contain LHCGR. In the testes, Leydig cells contain LHCGR (Themmen and Huhtaniemi, 2000).

Eblen et al. (2001) tested the hypothesis that human ejaculated sperm contain functional LHCG receptors. Their data indicated that LHCGR mRNA and protein that can bind CG are present. The receptors were functional, as indicated by an increase in cAMP levels and activation of sperm protein kinase A (see 176911) following treatment with CG or LH. However, treatment with these hormones had no effect on sperm protein kinase C (see 176960) activity. The authors concluded that since functional LHCGRs are found in human sperm, it is important to determine whether CG treatment could improve the outcome of infertility procedures.

Min and Ascoli (2000) examined the effects of several LHCGR mutations on the phosphorylation, internalization, and turnover of the cell surface receptor. Three gain-of-function mutations associated with Leydig cell hyperplasia, including 1 somatic mutation associated with Leydig cell adenomas (D578H; 152790.0019), were chosen for this study. One signaling-impaired mutation associated with Leydig cell hypoplasia (I625K; 152790.0016) and 2 laboratory-designed signaling-impaired mutations were also used. The signaling-impaired mutations showed a reduction in human CG-induced receptor phosphorylation and internalization. Mutation of the phosphorylation sites of these loss-of-function mutants had little or no additional effect on internalization. Cotransfection with G protein-coupled receptor kinase-2 (GRK2: 109635) rescued the CG-induced phosphorylation and internalization of the signaling-impaired mutations but only if the phosphorylation sites were intact. Overexpression of arrestin-3 (301770) rescued the rate of internalization regardless of whether or not the phosphorylation sites were intact. The authors concluded that the data obtained with the signaling-impaired and phosphorylation-deficient mutants of the LHCGR support a model whereby receptor phosphorylation and activation play a redundant role in the internalization of CG. The results obtained with the constitutively active mutants suggest that, when occupied by CG, these mutants assume a conformation that bypasses many of the steps involved in internalization.

Before ovulation in mammals, a cascade of events resembling an inflammatory and/or tissue remodeling process is triggered by LH in the ovarian follicle. Many LH effects, however, are thought to be indirect because of the restricted expression of its receptor to mural granulosa cells (Peng et al., 1991). Park et al. (2004) demonstrated that LH stimulation in wildtype mouse ovaries induces the transient and sequential expression of the epidermal growth factor family members amphiregulin (104640), epiregulin (602061), and betacellulin (600345). Incubation of follicles with these growth factors recapitulates the morphologic and biochemical events triggered by LH, including cumulus expansion and oocyte maturation. Thus, Park et al. (2004) concluded that these EGF-related growth factors are paracrine mediators that propagate the LH signal throughout the follicle.

To investigate the role of exon 10 in LHCGR action in vitro, Muller et al. (2003) created stable COS-7 cells expressing the LHR with or without exon 10 (see also 152790.0020). Binding experiments showed that the affinities of LH and CG to LHR with and without exon 10 were similar. The authors concluded that although exon 10 of the LHR plays no role in ligand binding, it is important for receptor activation by LH by a mechanism probably involving extracellular conformational changes.


Molecular Genetics

Loss-of-function mutations in the LHCGR gene in males cause Leydig cell hypoplasia, supporting the concept that a functional receptor is necessary for the early development of Leydig cells. Activating mutations of the receptor cause gonadotropin-independent male-limited precocious puberty, a disorder characterized by autonomous hyperplasia and hyperfunction of Leydig cells in association with inappropriate stimulation of adenylyl cyclase and the cAMP signaling pathway, but little or no activation of the phospholipase C pathway (summary by Liu et al., 1999).

Atger et al. (1995) described a leu-gln (LQ) insertion at position 55-60 of the LHCGR. They noted that the extracellular N-terminal domain of glycoprotein hormone receptors constitutes the high-affinity binding site responsible for the specificity in hormone recognition, suggesting that variations in the reported N-terminal sequences could have functional significance. Rodien et al. (1998) demonstrated that both sequences exist as allelic variants in the Caucasian population (152790.0017). In contrast, the LQ allele is virtually absent from the Japanese population.

Male-Limited Precocious Puberty

Laue et al. (1995) studied the constitutively activating mutations of the LHCGR gene in dominantly inherited male-limited precocious puberty (176410). They studied genomic DNA from 32 unrelated families. The inherited form of the disorder was present in 28, and of these, 24 were found to have an asp578-to-gly mutation (152790.0001). Other mutations were found, suggesting that the region spanning nucleotides 1624-1741 of exon 11 is a hotspot for point mutations that constitutively activate the LHCGR gene and cause male-limited precocious puberty.

Multiple activating mutations in the sixth transmembrane domain of the LHCGR have been identified in patients with male-limited precocious puberty. By computer analysis, Yano et al. (1997) found that these mutations have an effect on the secondary structure of the third cytoplasmic loop and sixth transmembrane domain. They also found that phe576, which might be important for receptor activity, is a critical conformational bridging residue between these 2 regions. To analyze the functional role of phe576, the authors made 4 amino acid substitutions, F576I, F576G, F576Y, and F576E, in the LHCGR. Computer analysis of the F576E mutant predicted that its secondary structure changed to a totally helical conformation in the region of the third intracellular and sixth transmembrane domain. In contrast, the secondary structures of the F576G, F576I, and F576Y mutants were predicted to change the helical conformation in the region to an extended conformation. In expression studies, mutations of phe576 produced functional changes in cAMP and inositol phosphate (IP) signaling and CG binding. Mutations predicted to cause an extended conformation exhibited 2 functional patterns: first, constitutively activating in cAMP signaling without changes in IP signaling or CG binding (F576I and F576G), and second, constitutively activating in cAMP signaling with decreased CG-induced cAMP and IP signaling and with both higher affinity and lower capacity of CG binding (F576Y). The mutation predicted to cause a totally helical conformation resulted in no cAMP responses and a minimal IP response to CG stimulation, with negligible CG binding (F576E). Yano et al. (1997) concluded that phe576 plays an important role in the human LHCGR with respect to receptor conformation, Gs coupling, and cAMP signaling consistent with predictions from mutations associated with male-limited precocious puberty.

Kremer et al. (1999) reported analysis of LHCGR gene mutations in a sample consisting of 17 independent families and sporadic cases (8 familial and 9 with a negative family history) with LH-independent precocious puberty. They detected 7 different mutations in 12 patients. Of these, 2 mutations were detected more than once. The ile542-to-leu mutation (152790.0018) was present in 4 Dutch kindreds, suggesting a common ancestor, although no genealogic relationship could be demonstrated. The met398-to-thr mutation (152790.0010) was found in 2 kindreds from Germany and in 1 patient from Sicily. In contrast to previous reports, the asp578-to-gly mutation (152790.0001) was not frequent in these 17 kindreds. In fact, none of the 10 European kindreds with LHCGR mutations in this study had the asp578-to-gly mutation, and the only family with this mutation was from the U.S. The authors suggested that there is a strong founder effect in the U.S., where greater than 90% of testotoxicosis families have the asp578-to-gly mutation. Only 12 LHCGR gene mutations had been reported in a total of 68 independent patients and families. The restricted number of LHCGR mutations found in affected kindreds as well as in sporadic cases strongly suggested that only mutations in specific areas of the receptor, in particular the sixth transmembrane region, can autonomously activate cAMP production.

Leydig Cell Hypoplasia

In 46,XY sibs with pseudohermaphroditism, offspring of consanguineous parents, who presented with female external genitalia, primary amenorrhea, and lack of breast development (238320), Kremer et al. (1995) identified homozygosity for an ala593-to-pro mutation in the LCGR gene (152790.0004).

Laue et al. (1995) demonstrated a nonsense mutation in the LCGR gene (152790.0007) in 2 46,XY sisters with Leydig cell hypoplasia, a form of male pseudohermaphroditism. The affected sibs were presumably compound heterozygotes. The father had the same mutation; the mother was presumed to have a different loss of function mutation which was not detected. In the family reported by Laue et al. (1995), Wu et al. (1998) identified a loss of function mutation in the mother (152790.0021). Genomic DNA-PCR showed that this defective maternal LHCGR allele was inherited by the 2 affected children, but RT-PCR showed that the maternal allele was not expressed. They concluded that Leydig cell hypoplasia in this family was the result of compound heterozygous loss-of-function mutations of the LHCGR gene.

Latronico et al. (1998) reported a 46,XY pseudohermaphrodite who presented with female external genitalia and his 46,XX sister who had oligoamenorrhea and infertility, and enlarged cystic ovaries. Both sibs were found to be homozygous for a deletion at nucleotides 1822-1827 (CTGGTT), resulting in the deletion of leu608 (CTG) and val609 (GTT) in the seventh transmembrane helix of the LHCGR gene (152790.0015). Transfections of 293 cells with normal and mutant LHCGR constructs showed that very little of the mutant receptor was expressed at the cell surface. This was due to both a decrease in the total amount of receptor expressed as well as increased intracellular retention of the mutant receptor. While equilibrium binding assays showed that the cell surface mutant receptor bound CG with an affinity comparable to that of the wildtype receptor, cells expressing the mutant exhibited only a 1.5- to 2.4-fold stimulation of cAMP production in response to CG. In contrast, cells expressing comparably low levels of the normal receptor responded to CG with 11- to 30-fold increases of cAMP levels. Latronico et al. (1998) concluded that the majority of the mutant receptor is retained intracellularly, and that the small percentage of mutant receptor that is expressed at the cell surface binds hormone normally but is unable to activate the stimulatory G protein (Gs; see 139320).

Luteinizing Hormone Resistance, Female

Latronico et al. (1998) identified the same mutation in the LHCGR gene (152790.0015) in a 46,XX girl with oligomenorrhea and infertility (see 238320) and her 46,XY sib with Leydig cell hypoplasia and pseudohermaphroditism.

Toledo et al. (1996) evaluated a 46,XX sister of the two 46,XY male pseudohermaphrodites with Leydig cell hypoplasia described by Kremer et al. (1995). They found that the patient, who presented with amenorrhea due to hypergonadotropic hypogonadism but with structurally normal ovaries, had the same mutation in the LHCGR gene (152790.0004) as her 2 affected sibs.

Leydig Cell Adenomas

Leydig cell adenomas are the most frequent form of hormone-producing tumors of the testis and account for 1 to 3% of all testicular tumors. Most are benign, but 10% of tumors in adults are malignant. Boys with Leydig cell tumors typically have signs of isosexual precocity as a result of testosterone secretion by the tumor. The demonstrated role of the luteinizing hormone receptor in the proliferation of Leydig cells and the presence of germline and somatic mutations in the gene for the homologous thyrotropin receptor (TSHR; 603372) in familial nonimmunogenic hyperthyroidism (e.g., 603372.0004) and sporadic thyroid adenomas (e.g., 603372.0002), respectively, led Liu et al. (1999) to hypothesize that some Leydig cell adenomas are caused by activating somatic mutations in the LHCGR gene. Indeed, they described 3 boys with isosexual precocity presenting as early pubertal development 1 to 2 years before the discovery of Leydig cell tumors. All 3 were found to be heterozygous for a G-to-C transversion at nucleotide 1732 (1732G-C) in the tumor only. This novel somatic mutation, resulting in the change of GAT to CAT, encoded an asp578-to-his amino acid change (152790.0019). In 2 unrelated boys with gonadotropin-independent hypersecretion of testosterone due to Leydig cell adenomas, Canto et al. (2002) found the same 1732G-C heterozygous mutation in DNA from the tumors from both patients, but not from the adjacent normal tissue or blood leukocytes. Sequencing of the LHCGR gene showed that 50 normal individuals did not have this mutation.


ALLELIC VARIANTS 29 Selected Examples):

.0001   PRECOCIOUS PUBERTY, MALE-LIMITED

LHCGR, ASP578GLY
SNP: rs121912518, ClinVar: RCV000015461, RCV000517056, RCV000583503, RCV000763499

In individuals with familial male precocious puberty (FMPP; 176410) from 8 different families, Shenker et al. (1993) identified heterozygosity for a single A-to-G transition that resulted in substitution of glycine for aspartate at position 578 (D578G) in the sixth transmembrane helix of the LH receptor. Linkage of the mutation to the clinical disorder was supported by restriction-digest analysis. COS-7 cells expressing the mutant LH receptor exhibited markedly increased cyclic AMP production in the absence of agonist, suggesting that autonomous Leydig cell activity in this disorder is caused by a constitutively activated LH receptor.

Kosugi et al. (1995) stated that the asp578-to-gly mutation had been found in affected males from 9 American FMPP families. Since 7 of the 9 originated in the southeastern United States, the possibility of a shared common ancestor was raised. For that reason, they analyzed genomic DNA from affected males from 6 new FMPP families: 2 from Germany, 3 from France, and 1 from the western United States with mixed Caucasian-Native American ancestry. None of the 6 new samples contained the asp578-to-gly mutation, as indicated by the absence of digestion with MspI. PCR products were then screened for heterozygous mutations by temperature-gradient gel electrophoresis. DNA fragments from 2 of the patients migrated abnormally. Direct sequencing of the PCR product from 1 affected German male revealed a heterozygous mutation of the type described in another European family by Kremer et al. (1993); see 152790.0002.

In a screening of genomic DNA from 32 unrelated families with male-limited precocious puberty, Laue et al. (1995) found that 28 had the inherited form of the disorder, and of these, 24 had the D578G mutation. Four additional mutations were found among the remaining 4 families with the inherited form and in 4 sporadic cases of the disorder.

Yano et al. (1994) found the asp578-to-gly mutation in a sporadic case of male precocious puberty in a Japanese patient.

Kawate et al. (1995) found this same constitutively activating mutation of the LHCGR gene in a family with male-limited gonadotropin-independent precocious puberty (testotoxicosis). The family was ascertained through 2 affected brothers whose father had started puberty before his third birthday. His maternal uncle and maternal great uncle were also affected.

Rosenthal et al. (1996) evaluated the pituitary-gonadal axis in a mother after 2 of her sons with familial male-limited precocious puberty were found to have the constitutively activating D578G mutation of the LHCGR gene. Ovarian function was normal in the 36-year-old mother as assessed by LH dynamics and FSH and androgen levels were normal throughout her menstrual cycle. Hormonal responses to acute GnRH agonist (nafarelin) challenge, chronic GnRH agonist administration, and dexamethasone were also normal. Studies of the affected sons on presentation at 2.4 and 3.5 years of age revealed that acute LH responses to nafarelin were in the hypogonadotropic range, and the FSH responses were prepubertal despite the presence of late pubertal testosterone blood levels. These data showed that the activating D578G mutation does not cause functional ovarian hyperandrogenism but only incomplete pubertal activation of Leydig cells consistent with the relatively low constitutive activity of this mutation.

Martin et al. (1998) reported the development of a testicular seminoma in a 35-year-old man who had previously been diagnosed with familial male-limited precocious puberty and found to be heterozygous for the gain-of-function D578G mutation in the LHCGR gene. The authors stated that this represented the first case of a testicular germ cell tumor described in an FMPP patient.


.0002   PRECOCIOUS PUBERTY, MALE-LIMITED

LHCGR, MET571ILE
SNP: rs121912519, ClinVar: RCV000015462

Kremer et al. (1993) hypothesized that an abnormal configuration of the LH receptor might autonomously activate G protein coupling, and thereby cause the overproduction of testosterone in the absence of testicular stimulation by luteinizing hormone observed in familial male precocious puberty (176410). Therefore, they screened for mutations in a part of the LHCGR gene that is important for G protein binding, using the single-strand conformation polymorphism technique. DNA sequence variation was detected in 2 out of 5 families, and in each case the mutation cosegregated with the disorder (lod score 5.76 without recombination). Both mutations caused an amino acid substitution in the sixth transmembrane domain, close to the C-terminal portion of the third cytoplasmic loop, a region important for the binding of G proteins: a 1713G-A transition leading to a met571-to-ile (M571I) substitution, in family 1, and a 1733A-G transition, leading to an asp578-to-gly (D578G; 152790.0001) substitution, in family 2.

In a German male with FMPP, Kosugi et al. (1995) found the same M571I mutation. By transiently expressing the met571-to-ile mutation in COS-7 cells, they found that agonist affinity was unaffected by the mutation. However, like the asp578-to-gly mutant receptor, the met571-to-ile receptor triggered agonist-independent production of cAMP, but not of inositol phosphates. This suggested that autonomous testosterone production in FMPP can be explained by constitutive activation of the cAMP pathway alone.


.0003   MOVED TO 152790.0001


.0004   LEYDIG CELL HYPOPLASIA, TYPE I

LUTEINIZING HORMONE RESISTANCE, FEMALE, INCLUDED
LHCGR, ALA593PRO
SNP: rs121912520, ClinVar: RCV000015465, RCV000015466

In two 46,XY sibs with Leydig cell hypoplasia (238320) born to consanguineous parents, Kremer et al. (1995) found homozygosity for a missense ala593-to-pro mutation in the sixth transmembrane domain of the LHCGR gene. In vitro expression studies showed that this mutated receptor binds human choriogonadotropin normally, but the ligand binding does not result in increased production of cAMP. They concluded that a homozygous LH receptor gene mutation underlies the syndrome of autosomal recessive congenital Leydig cell hypoplasia in this family. The 2 sibs had presented with female external genitalia, primary amenorrhea, and lack of breast development. Their parents, who were first cousins, had 14 additional offspring. Both patients had short blind-ending vagina, without uterus or fallopian tubes. Sperm levels of testosterone and testosterone precursors were abnormally low and did not respond to stimulation with human choriogonadotropin. Basal levels of luteinizing hormone were markedly increased. On histologic examination, the gonads were found to be testes with normal Sertoli cells but no mature Leydig cells.

Toledo et al. (1996) evaluated a 46,XX sister of the two 46,XY male pseudohermaphrodites with Leydig cell hypoplasia described by Kremer et al. (1995). The patient presented with amenorrhea due to hypergonadotropic hypogonadism (see 238320), but had structurally normal ovaries. Analysis of her LH receptor genes showed that she was homozygous for the same mutation that caused an ala593-to-pro substitution in her 2 brothers. In vitro analysis of the mutant LH receptor in cultured human embryonic kidney 293 cells showed that the receptor is unable to stimulate adenylyl cyclase in response to CG. These results document the existence of inherited LH resistance as a cause of primary amenorrhea in women.


.0005   PRECOCIOUS PUBERTY, MALE-LIMITED

LHCGR, THR577ILE
SNP: rs121912521, ClinVar: RCV000015467, RCV002466405

In a male with familial precocious puberty (176410), Kosugi et al. (1995) demonstrated a thr577-to-ile mutation (ACC to ATT).


.0006   PRECOCIOUS PUBERTY, MALE-LIMITED

LHCGR, ALA572VAL
SNP: rs121912522, ClinVar: RCV000015468, RCV002472931

In 2 Japanese patients with male-limited precocious puberty (176410) without a family history of the disorder, Yano et al. (1995) found a heterozygous C-to-T transition at nucleotide 1715 leading to an alanine-to-valine substitution in codon 572 of transmembrane helix 6. Transfected into COS-7 cells, the A572V mutation exhibited constitutively high basal cAMP levels. Yano et al. (1995) concluded that the constitutively higher cAMP levels led to Leydig cell activation. The mother of 1 of the 2 patients had the same heterozygous mutation.


.0007   LEYDIG CELL HYPOPLASIA, TYPE I

LHCGR, CYS545TER
SNP: rs121912523, gnomAD: rs121912523, ClinVar: RCV000015469, RCV002490374, RCV003546456

Laue et al. (1995) identified a cys545-to-ter mutation in exon 11 of the LHCGR gene in 2 46,XY sibs with male pseudohermaphroditism (238320). The mutation was an A-to-C transversion at nucleotide 1635 which caused loss of function of the receptor by introducing a stop codon at residue 545 in transmembrane helix 5 of the luteinizing hormone receptor. Surface expression of the truncated gene product in human embryonic kidney cells stably transfected with cDNA encoding the mutant protein was diminished compared to the wildtype gene, and hCG-induced cAMP accumulation was impaired. The mutation in the 2 sibs was present also in the normal father and was not present in the mother. The finding excludes the possibility of a dominant-negative mutation in the sisters and suggests that they are compound heterozygotes, the mutation inherited from the mother not being identified. The results of Laue et al. (1995) indicated that functional domains between transmembrane helix 5 and the C-terminal cytoplasmic tail of the gene are required for normal cell surface expression of the receptor and signal transduction. In the family reported by Laue et al. (1995), Wu et al. (1998) identified a loss of function mutation in the mother (152790.0021).


.0008   LEYDIG CELL HYPOPLASIA, TYPE I

LUTEINIZING HORMONE RESISTANCE, FEMALE, INCLUDED
LHCGR, ARG554TER
SNP: rs121912524, gnomAD: rs121912524, ClinVar: RCV000015470, RCV000015471, RCV001781270, RCV002251907

In a sibship with 14 children, Latronico et al. (1996) identified 3 brothers with pseudohermaphroditism with Leydig cell hypoplasia (238320) and 1 sister with partial ovarian failure (see 238320). In all 4 sibs, they identified a homozygous substitution of thymine for cytosine at nucleotide 1660 of the LHCGR gene; the mutation changed codon 554 from one coding for arginine (CGA) to a stop codon (TGA) within the third cytosolic loop of the LH receptor. The sister had spontaneous gonadarche at the age of 13 years, and she had a single episode of vaginal bleeding at the age of 20 years. Her height and weight were normal, pubic-hair development was Tanner stage 5, and the breasts and external genitalia were those of a normal woman. Her karyotype was 46,XX. Serum LH concentration was very high and serum estradiol concentration and progesterone concentration were low.


.0009   LEYDIG HYPOPLASIA, TYPE I

LHCGR, SER616TYR
SNP: rs121912525, gnomAD: rs121912525, ClinVar: RCV000015472, RCV002514103, RCV003137526

In a 6-year-old phenotypically male child who had been referred as a neonate for evaluation of micropenis (see 238320), Latronico et al. (1996) identified a C-to-A transversion of nucleotide 1847 of the LH-receptor cDNA, resulting in a change of codon 616 from one coding for serine (TCT) to one coding for tyrosine (TAT) within the seventh transmembrane region of the LH receptor. At birth, the length of the stretched phallus was 1.5 cm (more than 2.5 SD below the normal mean for age). Both testes were descended, with a volume of approximately 1 ml each.


.0010   PRECOCIOUS PUBERTY, MALE-LIMITED

LHCGR, MET398THR
SNP: rs121912526, ClinVar: RCV000015473, RCV000581515

Several affected members of a family with familial male precocious puberty (176410) and 1 affected subject in a second family showed a point mutation (T-to-C transition at nucleotide 1192), resulting in a met398-to-thr substitution in the second transmembrane domain of the LH receptor protein (Evans et al., 1996). In addition, 1 male in the first family had the mutation but showed no evidence of precocious puberty. All obligate carriers within this family were shown to have the mutation, and it was not detected in 94 chromosomes from unaffected and unrelated white subjects. In the second family, the index case was the only one to have the mutation.


.0011   MOVED TO 152790.0001


.0012   LEYDIG CELL HYPOPLASIA, TYPE II

LHCGR, ARG133CYS
SNP: rs121912527, ClinVar: RCV000015475

Misrahi et al. (1997) reported the case of an infant who presented at birth with hypoplastic phallus associated with hypospadias (see 238320). Conventional microscopic study of the testes showed fibroblastic cells in the interstitium. However, immunocytochemical analysis using anti-LH receptor and anti-P450c17 antibodies demonstrated that about one-third of these cells were Leydig cells or their precursors. The infant was homozygous for an arg133-to-cys substitution in the extracellular domain of LHCGR. COS-7 cells transfected with the mutant receptor showed a marked impairment of CG binding, but exhibited some cAMP production at high CG concentrations. The authors proposed that the partial impairment of LHCGR function, as reflected by the presence of Leydig cells, was responsible for the milder LCH phenotype observed.


.0013   PRECOCIOUS PUBERTY, MALE-LIMITED

LHCGR, ALA373VAL
SNP: rs121912528, ClinVar: RCV000015476

Gromoll et al. (1998) reported a patient with onset of puberty at the age of 5 years, who had accelerated growth, enlargement of genitalia, pubarche, and serum hormone levels compatible with noncentral precocious puberty (176410). They identified a heterozygous C-to-T transition at nucleotide position 1126, encoding an ala373-to-val substitution in the first transmembrane domain. The LHCGR sequences of the parents were normal. The mutated receptor displayed an increase in basal cAMP production (up to 7.5-fold) compared to that of the wildtype receptor in transiently transfected COS-7 cells. Treatment of the patient with ketoconazole resulted in inconsistent suppression of serum testosterone levels. At the age of 9.1 years, central activation of the hypothalamic-pituitary-gonadal axis occurred. Additional treatment with a GnRH agonist led to complete suppression of testosterone secretion.


.0014   LEYDIG CELL HYPOPLASIA, TYPE I

LUTEINIZING HORMONE RESISTANCE, FEMALE, INCLUDED
LHCGR, GLU354LYS
SNP: rs121912529, ClinVar: RCV000015477, RCV000015478

Stavrou et al. (1998) reported a homozygous mutation of the LHCGR gene in 3 sibs (two 46,XY and one 46,XX). The 46,XY sibs presented with female external genitalia, primary amenorrhea, and lack of breast development (238320). Hormonal evaluation revealed a markedly elevated LH level with a low testosterone level, which failed to increase after human CG stimulation. Histologic analysis of the inguinal gonads in a 46,XY sib revealed no Leydig cells, but Sertoli cells, spermatogonia, and primary spermatocytes were seen. The 46,XX sib had female external genitalia, normal breast development, cystic ovaries, and primary amenorrhea (see 238320). Hormonal analyses showed markedly elevated LH levels and low plasma 17-beta-estradiol levels. A homozygous missense mutation was found at exon 11 of the LHCGR gene. Guanine was replaced by adenine (GAA to AAA), resulting in a substitution of lysine for glutamic acid at amino acid position 354. Functional analysis of the mutation showed complete loss of function, indicated by the lack of cAMP production after human CG stimulation in transfected human embryonic kidney 293 cells. Screening of family members demonstrated heterozygosity for the mutation, indicating autosomal recessive inheritance.


.0015   LEYDIG CELL HYPOPLASIA, TYPE I

LUTEINIZING HORMONE RESISTANCE, FEMALE, INCLUDED
LHCGR, 6-BP DEL, NT1822
SNP: rs2104352652, ClinVar: RCV000015479, RCV000015480

Latronico et al. (1998) reported a 46,XY pseudohermaphrodite who presented with female external genitalia (238320) and his 46,XX sister who had oligoamenorrhea and infertility, and enlarged cystic ovaries (see 238320). Both affected sibs were homozygous for a deletion of nucleotides 1822-1827 (CTGGTT), resulting in the deletion of leu608 (CTG) and val609 (GTT) in the seventh transmembrane helix of the LHCGR gene. This microdeletion caused impaired expression and reduced signal transduction activity of the LHCGR.


.0016   LEYDIG CELL HYPOPLASIA, TYPE II

LHCGR, ILE625LYS
SNP: rs121912530, ClinVar: RCV000015481

Martens et al. (1998) evaluated 3 brothers with Leydig cell hypoplasia who presented with micropenis, absence of pubertal signs, and infertility (see 238320). LH and FSH levels were elevated but responded normally to GnRH. Basal testosterone and androstenedione levels, however, were low and responded poorly to CG. Analysis of their LHCGR genes revealed a homozygous missense mutation resulting in an iso625-to-lys (I625K) substitution. In vitro analysis of the I625K mutant in HEK293 cells indicated that the signaling efficiency was significantly impaired, explaining the partial phenotype. The authors compared this mutant to 2 other LHCGR gene mutations, A593P (152790.0004) and S616Y (152790.0009). Although the ligand-binding affinity for all 3 mutant receptors was normal, the hormonal response of A593P was completely absent and that of S616Y and I625K was severely impaired. Low cell surface expression explained the reduced response of S616Y, while a combination of low cell surface expression and decreased coupling efficiency explained the diminished response of I625K. For A593P, the absence of a reduced response resulted from both poor cell surface expression and a complete deficiency in coupling. Martens et al. (1998) concluded that a clear correlation exists between the severity of the clinical phenotype of patients and overall receptor signal capacity, which is a combination of cell surface expression and coupling efficiency.


.0017   LUTEINIZING HORMONE/CHORIOGONADOTROPIN RECEPTOR, LQ VARIANT

LHCGR, LEU-GLN INS, CODON 19-20
SNP: rs71245621, gnomAD: rs71245621, ClinVar: RCV000283585, RCV000303287, RCV000319880, RCV000378063, RCV002057704, RCV002270219

Two different human LH receptor sequences have been published, differing by a 6-basepair insertion encoding leu-gln at position 55-60 (Minegishi et al., 1990; Atger et al., 1995). Rodien et al. (1998) demonstrated that both sequences exist as allelic variants in the Caucasian population. Allele frequencies of LQ variant and wildtype allele are 0.26 and 0.74 respectively. In contrast, the LQ allele is virtually absent from the Japanese population. Functional characterization of both alleles by transient expression in COS-7 cells did not reveal any difference between the 2 receptors, neither for cell surface expression nor for cAMP production and sensitivity to CG/LH.

Powell et al. (2003) investigated whether functional polymorphic variants in the LH signaling pathway are associated with the risk of breast cancer or its clinical phenotype. Women who were homozygous for the LQ allele were, on average, 8.3 years younger at diagnosis, compared with those homozygous for the wildtype LHR allele (mean age, 51.9 years vs 60.2 years; P = 0.03). Trends were observed for associations between LQ carriers and nodal involvement or larger tumor size. Patients who were LQ carriers revealed a significantly worse overall survival, compared with those who were homozygous for wildtype LHR. The authors concluded that their findings suggested that the LQ gene polymorphism determines an earlier age of disease onset and is prognostic for poor outcome of breast cancer.


.0018   PRECOCIOUS PUBERTY, MALE-LIMITED

LHCGR, ILE542LEU
SNP: rs121912531, ClinVar: RCV000015483, RCV001851873, RCV003407338

Kremer et al. (1999) found that an ile542-to-leu substitution was present in 4 Dutch kindreds with male LH-independent precocious puberty (176410), suggesting a common ancestor as the cause for this clustering, although no genealogic relationship could be demonstrated. Laue et al. (1995) had found this mutation in 3 families and in one sporadic case from the U.S.


.0019   LEYDIG CELL ADENOMA, SOMATIC, WITH MALE-LIMITED PRECOCIOUS PUBERTY

LHCGR, ASP578HIS
SNP: rs121912532, gnomAD: rs121912532, ClinVar: RCV000015484

Liu et al. (1999) described 3 boys with isosexual precocity (176410) presenting as early pubertal development 1 to 2 years before the discovery of Leydig cell tumors. All 3 were found to be heterozygous for a G-to-C transversion at nucleotide 1732 of the LHCGR gene in the tumor only. This novel somatic mutation, resulting in the change of GAT to CAT, encoded an asp578-to-his amino acid change.

In 2 unrelated boys with gonadotropin-independent hypersecretion of testosterone due to Leydig cell adenomas, Canto et al. (2002) found the same 1732G-C heterozygous mutation in DNA from the tumors from both patients, but not from the adjacent normal tissue or blood leukocytes. Sequencing of the LHCGR gene showed that 50 normal individuals did not have this mutation.


.0020   LEYDIG CELL HYPOPLASIA, TYPE II

LHCGR, EX10DEL
ClinVar: RCV000015485

Gromoll et al. (2000) reported a patient with partial Leydig cell hypoplasia (see 238320) caused by a genomic deletion resulting in the complete absence of exon 10 of the LHCGR gene. The patient presented at the age of 18 years with retarded pubertal development, small testicles, and delayed bone maturation. LH was highly elevated, with very low serum testosterone levels. Genetic analysis revealed a homozygous deletion of approximately 5 kb encompassing exon 10 of the LHCGR gene. Screening of family members demonstrated heterozygosity for the deletion, indicating autosomal recessive inheritance. At the time of examination, the patient displayed nearly normal male phenotype but lacked pubertal development and was hypogonadal. Fetal male development sustained by hCG was normal, whereas LH action was impaired. An hCG stimulation test induced testosterone biosynthesis and secretion within the normal range. The authors concluded that despite highly elevated endogenous LH serum levels, the response to hCG indicates a possible dual mechanism of hormone binding and signal transduction for hCG and LH on an LHCGR lacking exon 10. Furthermore, they stated that the patient represents the clinical counterpart of the normal male marmoset monkey, in which the expressed LHR lacks exon 10 in toto.


.0021   LEYDIG CELL HYPOPLASIA, TYPE I

LHCGR, 33-BP INS, NT54
SNP: rs71245621, gnomAD: rs71245621, ClinVar: RCV000015486, RCV002513064

In the family reported by Laue et al. (1995) in which 2 sibs with Leydig cell hypoplasia type I (238320) inherited a cys545-to-ter mutation (152790.0007) on the paternal allele, Wu et al. (1998) identified a 33-bp insertion in the maternal LHCGR allele. This insertion occurred between nucleotides 54 and 55 and might be the result of a partial gene duplication. Genomic DNA-PCR showed that this defective maternal LHCGR allele was inherited by the 2 affected children, but RT-PCR showed that the maternal allele was not expressed. They concluded that Leydig cell hypoplasia in this family was the result of compound heterozygous loss-of-function mutations of the LHCGR gene.


.0022   PRECOCIOUS PUBERTY, MALE-LIMITED

LHCGR, LEU368PRO
SNP: rs121912533, ClinVar: RCV000015487

Latronico et al. (2000) examined 3 Brazilian boys, 2 brothers and 1 unrelated boy, with gonadotropin-independent precocious puberty (176410). Direct sequencing of the entire exon 11 of the LHCGR gene in the 2 brothers showed a heterozygous substitution of T for C at nucleotide 1103, resulting in the substitution of leu368 to pro (L368P) in the first transmembrane helix. Cells expressing the novel L368P mutation displayed up to a 12-fold increase in basal cAMP production compared with cells expressing the same number of cell surface wildtype LHCGR, indicating constitutive activation of the mutant receptor.


.0023   PRECOCIOUS PUBERTY, MALE-LIMITED

LHCGR, ALA568VAL
SNP: rs121912534, ClinVar: RCV000015488

In a Brazilian boy with gonadotropin-independent precocious puberty (176410) examined by Latronico et al. (2000), sequencing of exon 11 of the LHCGR gene revealed homozygosity for a nucleotide substitution causing an ala568-to-val (A568V) substitution in the third cytoplasmic loop of the receptor. This mutation had been found previously in 2 unrelated Brazilian boys in heterozygous state (Latronico et al. (1995, 1998)). Clinical and hormonal data of the homozygous A568V patient were not different from those of heterozygotes. The phenotype caused by dominant activating mutations of the LHCGR gene is not altered when both alleles carry a mutant sequence. The authors concluded that the A568V mutation is the most frequent cause of male-limited precocious puberty in Brazilian boys.


.0024   PRECOCIOUS PUBERTY, MALE-LIMITED

LHCGR, LEU457ARG
SNP: rs121912535, ClinVar: RCV000015489

Latronico et al. (1998) examined 2 unrelated Brazilian boys with gonadotropin-independent precocious puberty (176410) caused by 2 different heterozygous activating mutations of LHCGR. Direct sequencing of the entire exon 11 in one affected boy revealed a heterozygous substitution of T for G at nucleotide 1370 that converted leu457 to arg (L457R) in the third transmembrane helix of the LHCGR. His parents had a normal LHCGR gene sequence, establishing the sporadic nature of this mutation. Human embryonic 293 cells expressing mutant or wildtype LHCGR bound CG with high affinity. However, cells expressing LHCGR 457R exhibited significantly higher basal levels of cAMP (7- to 14-fold) than cells expressing the wildtype receptor, indicating constitutive activation. Furthermore, cells expressing the mutant were unresponsive to further stimulation by CG. This finding was confirmed in the patient by lack of an increase in serum testosterone after CG stimulation. The authors concluded that the conformation of the L457R mutant represents a different activated receptor state (R*) than the agonist-occupied wildtype receptor. The other mutation identified was ala568 to val (152790.0023).


.0025   LEYDIG CELL HYPOPLASIA, TYPE I

LHCGR, CYS343SER
SNP: rs121912536, ClinVar: RCV000015490

Martens et al. (2002) reported the identification of 2 LHCGR mutations in a compound heterozygous case of complete Leydig hypoplasia (238320) and determined the cause of the signaling deficiency at a molecular level. On the paternal allele of the patient they identified in codon 343 a T-to-A transversion that changes a conserved cysteine in the hinge region of the receptor to serine (C343S); on the maternal allele a T-to-C transition causes another conserved cysteine at codon 543 in transmembrane segment 5 to be altered to arginine (C543R). Both of these mutant receptors are completely devoid of hormone-induced cAMP reporter gene activation. Using Western blotting of expressed LH receptor protein with a hemagglutinin tag, they showed that despite complete absence of total and cell surface hormone binding, protein levels of both mutant LH receptors are only moderately affected. Expression and study of enhanced green fluorescent protein (GFP)-tagged receptors demonstrated that although initial translocation to the endoplasmic reticulum of these mutant receptors was normal, translocation was halted or misrouted, and as a result, neither mutant ever reached the cell surface, and they could not bind hormone. The authors concluded that complete lack of signaling by the identified mutant LH receptors is caused by insufficient processing from the endoplasmic reticulum to the cell surface and results in complete Leydig cell hypoplasia in this patient.


.0026   LEYDIG CELL HYPOPLASIA, TYPE I

LHCGR, CYS543ARG
SNP: rs121912537, ClinVar: RCV000015464

For discussion of the cys543-to-arg (C543R) mutation in the LHCGR gene that was found in a patient with complete Leydig hypoplasia (238320) by Martens et al. (2002), see 152790.0025.


.0027   LEYDIG CELL HYPOPLASIA, TYPE I

LHCGR, LEU502PRO
SNP: rs121912538, ClinVar: RCV000015491

In a 19-year-old patient with female phenotype and 46,XY karyotype (238320), Leung et al. (2004) identified a homozygous 1505T-C transversion in exon 11 of the LHCGR gene, resulting in a leu502-to-pro (L502P) substitution at a conserved residue in the fourth transmembrane helix of the protein. The mutation caused inactivation of the LH receptor and resulted in Leydig cell hypoplasia. Testicular histology and hormonal profile of the patient were considered typical for Leydig cell hypoplasia. The mutation was present in heterozygous state in both parents.


.0028   LEYDIG CELL HYPOPLASIA, TYPE I

LHCGR, VAL144PHE
SNP: rs121912539, gnomAD: rs121912539, ClinVar: RCV000015492

In a patient with Leydig cell hypoplasia (238320) who presented as a 46,XY girl, Richter-Unruh et al. (2004) detected a G-to-T transversion at nucleotide 430 in exon 5 of the LHCGR gene, resulting in an amino acid change from valine to phenylalanine at codon 144 (V144F). The father, mother, and one of the patient's brothers were heterozygous for the mutation. Human embryonic kidney cells transfected with the mutant LHCG receptor exhibited a marked impairment of human chorionic gonadotropin binding. Western blot analysis of the expressed V144F mutant receptor protein showed the absence of the glycosylated cell surface form. Treatment of the mutant LHCG receptor with N-glycosidase F or endoglycosidase-H demonstrated that the mutant receptor is retained in the endoplasmic reticulum. Expression and study of enhanced green fluorescent protein-tagged receptors confirmed that the mutant receptors do not migrate to the cell surface.


.0029   PRECOCIOUS PUBERTY, MALE-LIMITED

LHCGR, ASP564GLY
SNP: rs121912540, ClinVar: RCV000015493, RCV000712217

In a boy who was diagnosed with gonadotropin-independent precocious puberty (176410) at 4 years of age, Leschek et al. (2001) identified an asp564-to-gly (D564G) substitution in exon 11 of the LHCGR gene in peripheral blood leukocytes. At 10.8 years of age, routine ultrasound examination led to the discovery of 2 right testicular masses; after excisional biopsy, histologic examination showed nodular Leydig cell hyperplasia surrounded by normal-appearing seminiferous tubules with spermatogenesis, and DNA from tumor tissue revealed the same D564G mutation that was present in peripheral blood leukocytes.


See Also:

Lee and Ryan (1971)

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Contributors:
Marla J. F. O'Neill - updated : 4/29/2009
Carol A. Bocchini - updated : 4/9/2009
John A. Phillips, III - updated : 10/27/2005
Victor A. McKusick - updated : 11/23/2004
Ada Hamosh - updated : 3/10/2004
John A. Phillips, III - updated : 8/25/2003
John A. Phillips, III - updated : 8/25/2003
John A. Phillips, III - updated : 8/25/2003
John A. Phillips, III - updated : 1/16/2003
Sonja A. Rasmussen - updated : 4/18/2002
John A. Phillips, III - updated : 3/5/2002
John A. Phillips, III - updated : 10/10/2001
John A. Phillips, III - updated : 10/1/2001
John A. Phillips, III - updated : 7/2/2001
John A. Phillips, III - updated : 3/5/2001
Victor A. McKusick - updated : 7/13/2000
John A. Phillips, III - updated : 4/3/2000
Victor A. McKusick - updated : 12/3/1999
John A. Phillips, III - updated : 9/9/1999
John A. Phillips, III - updated : 4/13/1999
John A. Phillips, III - updated : 10/1/1998
John A. Phillips, III - updated : 6/24/1998
John A. Phillips, III - updated : 5/21/1998
John A. Phillips, III - updated : 9/18/1997
John A. Phillips, III - updated : 4/1/1997
John A. Phillips, III - updated : 2/25/1997

Creation Date:
Victor A. McKusick : 9/26/1989

Edit History:
alopez : 07/18/2017
carol : 06/29/2015
carol : 6/11/2015
mcolton : 6/9/2015
carol : 6/20/2011
wwang : 5/5/2009
terry : 4/29/2009
terry : 4/10/2009
carol : 4/9/2009
carol : 4/9/2009
wwang : 10/15/2008
carol : 5/14/2007
terry : 3/14/2007
alopez : 10/27/2005
tkritzer : 11/30/2004
terry : 11/23/2004
terry : 11/3/2004
carol : 3/17/2004
alopez : 3/11/2004
terry : 3/10/2004
alopez : 1/29/2004
alopez : 10/2/2003
carol : 9/12/2003
alopez : 8/25/2003
alopez : 8/25/2003
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alopez : 3/5/2002
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cwells : 10/31/2001
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alopez : 10/1/2001
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alopez : 7/21/2000
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mgross : 5/17/2000
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alopez : 3/24/2000
mgross : 12/6/1999
mgross : 12/6/1999
mgross : 12/3/1999
terry : 12/3/1999
joanna : 11/5/1999
alopez : 9/9/1999
alopez : 9/9/1999
mgross : 4/16/1999
mgross : 4/13/1999
carol : 10/1/1998
dkim : 9/11/1998
dholmes : 6/29/1998
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alopez : 5/21/1998
alopez : 5/14/1998
dholmes : 11/11/1997
dholmes : 11/11/1997
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dholmes : 10/30/1997
dholmes : 10/30/1997
dholmes : 10/29/1997
jenny : 4/1/1997
jenny : 3/4/1997
jenny : 2/25/1997
jenny : 2/24/1997
mark : 4/3/1996
terry : 3/29/1996
mark : 3/14/1996
terry : 3/7/1996
mark : 2/5/1996
terry : 1/30/1996
mark : 11/6/1995
carol : 2/15/1995
mimadm : 11/6/1994
carol : 12/13/1993
carol : 12/10/1993
carol : 11/16/1993