LHCGR (luteinizing hormone/choriogonadotropin receptor)

2012-04-01 Chon-Hwa Tsai-Morris , Maria L Dufau Affiliation

Endocrinology Section, NICHD, NIH, Bldg. 49 Rm. 6A-36, Bethesda MD 20892-4510, USA

Identity

HGNC

LHCGR

LOCATION

2p16.3

LOCUSID

3973

ALIAS

HHG,LCGR,LGR2,LH/CG-R,LH/CGR,LHR,LHRHR,LSH-R,ULG5

DNA/RNA

A: Human LHR gene organization. B: 5 flanking regulatory domains and the 176 bp promoter with its functional domains (Geng et al., 1999; Dufau and Tsai-Morris, 2007). B-I Promoter associated transcription factor Sp1 bound to cognate DNA sites, Sp1-I and Sp1-II, constitutively (Geng et al., 1999). Co-repressor complex (HDAC/mSin3A) associates with Sp1-I (Zhang et al., 2000; Zhang et al., 2001; Zhang et al., 2002; Zhang et al., 2003; Zhang et al., 2004). Upstream inhibitory domain (ERE-DR Motif) that bind orphan receptors EAR2 and EAR3, inhibitory and TR4, stimulatory (arrows). B-II, Histone deacetylase inhibitor (TSA)-induced LHR transcriptional activation through chromatin changes cause release of cell specific phosphatases (PP1, PP2A) (Zhang et al 2008). This permits phosphorylation of Sp1 at S641 via PI3K/PKCzeta (Zhang, 2006), and the release of repressor p107 and corepressor HDAC/mSin3A (Zhang et al., 2008; Dufau et al., 2010). Recruitment of Positive Coactivator4 PC4 induced by changes in chromatin structure is required for transcriptional activation that follows recruitment of TFIIB and Pol II (Liao et al., 2008; Liao et al., 2011). PC4 might function as a linker to bridge Sp1 to PIC through a not-yet identified protein(s) (red circle). Triangle: multiple transcriptional start sites. PA: polyadenylation sites. Open arrow, up: activation, down: inhibition. ERE: estrogen response element. DR: direct repeat. OR: orphan receptor. Sp1 I, Sp1 II: Sp1 sites. PIC: preinitiation complex.

Description

Human LHR gene is encoded by a single copy gene. The human LHR gene (> 80 Kb) consists of 11 coding exons separated by 10 introns (Atger et al., 1995). At least seven alternatively spliced variants of the hLHR were reported (deletion of exon 8 or 9 or 10, or partial deletion of exon 11 combined with or without deletion of exon 9, and insertion of exon 6A) (Laue et al., 1996; Gromoll et al., 2000; Madhra et al., 2004; Kossack et al., 2008).

Transcription

Multiple LHR mRNA transcriptional start sites are located within the -176 bp TATA-less 5 flanking promoter domain (Geng et al., 1999; Dufau and Tsai-Morris, 2007). Additional upstream transcriptional start sites (> -176 bp) were identified in human testicular mRNA and human choriocarcinoma JAR cell. EREhs (-161 to -171 bp) and upstream sequences (-177 to -2056 bp) are inhibitory. Activation of the human LHR promoter through Sp1 and Sp3 factors at Sp1 sites is negatively regulated by cross-talk among the transcription factors EAR3/COUP-TFI, Sp1, TFIIB, and independently by histone deacetylase-mSin3A co-repressor complex, p107 repressor at the Sp1 I site (review: Zhang and Dufau, 2004; Dufau and Tsai-Morris, 2007; Dufau et al., 2010).

Pseudogene

No known pseudogenes.

Proteins

Schematic representation of human LHR variants, as deduced from the alternative splicing of the transcripts. Arrow-head: LQ insertion. Exon 6A resides in intron 6, transcripts are terminated by a poly A tail (terminal) or via internal splice sites to produce a 150 bp (short) or 207 bp (long) internal exon and continue to exon 7-11 (Kossack et al., 2008). In all cases a truncated LHR protein of 209 aa is generated. Arrow: Stop codon.

Description

The cDNA for the human LHR encodes 699 amino acids (Minegishi et al., 1990; Jia et al., 1991). The receptor is composed of two functional units: the extracellular hormone-binding domain and the seven-membrane transmembrane/cytoplasmic module, which is the anchoring unit that transduces the signal initiated in the extracellular domain and couples to G proteins. The large extracellular domain binds LH and hCG with high affinity.

Expression

LHR is predominantly expressed in gonads. The LHR has also been identified in several non-gonadal tissues (review, Rao, 2001), including human nonpregnant uterus, placenta (Reshef et al., 1990), fallopian tubes (Lei et al., 1993), uterine vessels, (Toth et al., 1994), umbilical cord (Rao et al., 1993), brain (Lei et al., 1993), breast (Meduri et al., 1997; Carlson et al., 2004), and adrenal gland (Lehmann et al., 1975).

Localisation

Predominantly localized in the cell membrane.

Function

The LHR mediates gonadotropin signaling and triggers intracellular responses that participate in gonadal maturation and function, as well as in the regulation of steroidogenesis and gametogenesis (review, Richards et al., 1988; Dufau, 1998; Dufau and Tsai-Morris, 2007). Luteinizing hormone through its surface receptors on the Leydig cell maintains general metabolic processes and steroidogenic enzymes to regulate the production of androgens. In the ovary, LH promotes follicular development, at stages beyond early antral follicles including the formation of preovulatory follicles and corpora lutea. Target disruption of LH receptor in the mouse revealed a normal prenatal development and lack of postnatal sexual development (Lei et al., 2001; Zhang et al., 2001). This indicated that LH/LHR action in male rodents is not required or can be compensated by other hormone(s) or factors during fetal life which is in sharp contrast with the situation in the human. The major changes in sexual development observed after birth in the mouse included significant inhibition of testis growth and descent and of sex accessory organs. Testosterone could partially restore spermatogenesis and fertility (Pakarainen et al., 2005; Yuan et al., 2006).

Homology

The percent identity below represents identity using Global pairwise alignment function (GAP).
M. musculus: 83,2
R. Norvegicus: 85,2
D. Melanogaster: 40,1
A. gambiae: 39,7
C. elegans: 30,7

Mutations

Note

Polymorphisms were detected in exon 1, 4, 8, 10 and 11. Nucleotides insertion / deletion, single nucleotide mutation were detected in exons 1, 5, 7, 8, 10 and 11. Deletions of exon 8 or 9 or 10 (splice variants) were also detected (See reviews Themmen and Huhtaniemi, 2000; Dufau and Tsai-Morris, 2007 and Segaloff, 2009). Mutations were also found in the unique cryptic exon 6A (Kossack et al., 2008).
Polymorphism: Without a known effect- missense mutation: R124Q, N291S, N312S. Silent mutation: L204, D355.
Activating mutations: Most of these mutations are located in the sixth TM domain (TM6) and C terminal region of the third intracellular loop. Mutations also occur in other transmembrane helices except TM4 and TM7 (see figure).
TM1: L368P, A373V; TM2: M398T; TM3: L457R; TM5: I542L; ICL3: D564G, A568V; TM6: M571I, A572V, I575L, T577I, D578G/Y/H/E, C581R. TM: transmembrane., ICL: intracellular loop.
Inactivating mutations: I114F, C131R, V144F, F194V, C343S, E354K, I374T, T392I, W491X, L502P, C543R, C545X, R554X, A589X, A593P, Y612X, S616Y and I625K. Deletion - ΔL608/V609, aa 203-227 (exon 8), aa 228-289 (exon 9), aa 290-316 (exon 10), ΔY317-S324 (exon 11). Insertion: aa18 - LLKLLLLLQLQ. A cryptic exon 6A (resides in intron 6) with mutations (A557C or G558C).

EC: Extracellular domain. TM: Transmembrane domain. IC: Intracellular domain. Triangle box: the putative signal peptide. Vertical lines indicate exons. Normal amino acid residue (white circle). X: Stop. Activating mutations noted as green in familial male precocious puberty (FMPP)-autosomal dominant and/or sporadic male-limited precocious puberty (SMPP) or other; inactivating mutations in Leydig cells hypoplasia (LCH) noted in yellow. Polymorphism noted in blue. Underlined: N-glycosylation sites.

Implicated in

Disease

Review: Themmen and Huhtaniemi, 2000; Dufau and Tsai-Morris, 2007; Segaloff, 2009. Refer to these reviews for individual mutations.

Entity name

Breast cancer

Note

The ¹⁸LQ insertion associated with adverse outcome in breast cancer patients could result from estrogen exposure in female carriers via increased LHR activity (Powell et al., 2003; Piersma et al., 2006).

Prognosis

Mutations may be linked to breast cancer prognosis.

Entity name

Familial male precocious puberty (FMPP) and sporadic male-limited precocious puberty (SMPP)

Note

FMPP is a gonadotropin independent precocious puberty, also known as testotoxicosis characterized by premature Leydig cell differentiation, hyperplasia and early spermatogenesis. It presents a clinical phenotype in the heterozygous form of LHR activating mutations. Signs of puberty are found at 1 to 4 yr old of age with elevated androgen production due to LHR mutations in transmembranes 1, 2, 3, 5 and 6 (see mutation section-activating mutation). Those mutants are constitutively active. Mutations cause elevated basal levels of cAMP compared to WT in cells transfected with mutated LHR construct. A similar phenotype is observed in sporadic cases of this disorder. Association of FMPP and SMPP with development of testicular tumors are due to a missense mutation (D578G) which is the most common form of the condition in USA. Somatic mutation of the LHR (D578H) was found in the patients with Leydig cell adenoma and no history of FMPP.

Entity name

Male pseudohermaphroditism or Leydig cell hypoplasia (LCH) with various degree of hypogonadism severity

Note

There are two types of LCH associated with inactivating mutation of LHR. Clinical phenotype expressed in homozygous (most cases) or compound heterozygous (few cases) is caused by deletion, insertion, truncation or missense mutation (see mutation section) in extracellular or transmembrane regions of the LHR. Also, a genomic defect with mutation in the cryptic exon 6A (residing in the intron 6) could lead to LCH. Type I LCH with 46XY disorder of sex development reveals a complete disruption of LH/hCG signaling in male patients characterized by a female external phenotype with a blind-ending vagina and cryptochidism. Type II LCH is characterized by reduced response to LH/hCG signaling, micropenis and/or hypospadias. 46XX siblings (carrying similar inactivating mutation of LHR) of affected 46XY individuals are infertile with normal female external genitalia but enlarged cystic ovaries and primary or secondary amenorrhea. Elevated serum LH is shown in both genders of patients. The underlining mechanism of the LCH caused by inactivating mutation of LHR might be associated with misfolding, reduced LH/hCG binding affinity and/or intracellular retention of the mutant LHR.

Bibliography

Pubmed ID	Last Year	Title	Authors
7556872	1995	Structure of the human luteinizing hormone-choriogonadotropin receptor gene: unusual promoter and 5' non-coding regions.	Atger M et al
15292356	2004	Presence of luteinizing hormone/human chorionic gonadotropin receptors in male breast tissues.	Carlson HE et al
19464346	2010	Participation of signaling pathways in the derepression of luteinizing hormone receptor transcription.	Dufau ML et al
9558473	1998	The luteinizing hormone receptor.	Dufau ML et al
10491299	1999	The human luteinizing hormone receptor gene promoter: activation by Sp1 and Sp3 and inhibitory regulation.	Geng Y et al
10852464	2000	Male hypogonadism caused by homozygous deletion of exon 10 of the luteinizing hormone (LH) receptor: differential action of human chorionic gonadotropin and LH.	Gromoll J et al
1922095	1991	Expression of human luteinizing hormone (LH) receptor: interaction with LH and chorionic gonadotropin from human but not equine, rat, and ovine species.	Jia XC et al
18433292	2008	Mutations in a novel, cryptic exon of the luteinizing hormone/chorionic gonadotropin receptor gene cause male pseudohermaphroditism.	Kossack N et al
8843415	1996	Compound heterozygous mutations of the luteinizing hormone receptor gene in Leydig cell hypoplasia.	Laue LL et al
178853	1975	HCG + ACTH stimulation of in vitro dehydroepiandrosterone production in human fetal adrenals from precursor cholesterol and delta5-pregnenolone.	Lehmann WD et al
11145749	2001	Targeted disruption of luteinizing hormone/human chorionic gonadotropin receptor gene.	Lei ZM et al
21193408	2011	Coactivator function of positive cofactor 4 (PC4) in Sp1-directed luteinizing hormone receptor (LHR) gene transcription.	Liao M et al
15169923	2004	Alternative splicing of the human luteal LH receptor during luteolysis and maternal recognition of pregnancy.	Madhra M et al
9041186	1997	Luteinizing hormone/human chorionic gonadotropin receptors in breast cancer.	Meduri G et al
2244890	1990	Cloning and sequencing of human LH/hCG receptor cDNA.	Minegishi T et al
12679452	2003	Luteinizing hormone signaling and breast cancer: polymorphisms and age of onset.	Powell BL et al
11394207	2001	An overview of the past, present, and future of nongonadal LH/hCG actions in reproductive biology and medicine.	Rao CV et al
1688865	1990	The presence of gonadotropin receptors in nonpregnant human uterus, human placenta, fetal membranes, and decidua.	Reshef E et al
3288100	1988	Molecular aspects of hormone action in ovarian follicular development, ovulation, and luteinization.	Richards JS et al
20374734	2009	Diseases associated with mutations of the human lutropin receptor.	Segaloff DL et al
11041448	2000	Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitary-gonadal function.	Themmen APN et al
8027246	1994	Expression of functional human chorionic gonadotropin/human luteinizing hormone receptor gene in human uterine arteries.	Toth P et al
11145748	2001	Normal prenatal but arrested postnatal sexual development of luteinizing hormone receptor knockout (LuRKO) mice.	Zhang FP et al
15193450	2004	Gene silencing by nuclear orphan receptors.	Zhang Y et al
18596044	2008	Unlocking repression of the human luteinizing hormone receptor gene by trichostatin A-induced cell-specific phosphatase release.	Zhang Y et al

Other Information

Locus ID:

NCBI: 3973
MIM: 152790
HGNC: 6585
Ensembl: ENSG00000138039

Variants:

dbSNP: 3973
ClinVar: 3973
TCGA: ENSG00000138039
COSMIC: LHCGR

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000138039	ENST00000294954	P22888
ENSG00000138039	ENST00000401907	E7EQB5
ENSG00000138039	ENST00000403273	E7ESK4
ENSG00000138039	ENST00000405626	E7ENI1
ENSG00000138039	ENST00000428232	H7C226

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Calcium signaling pathway	KEGG	ko04020
Neuroactive ligand-receptor interaction	KEGG	ko04080
Calcium signaling pathway	KEGG	hsa04020
Neuroactive ligand-receptor interaction	KEGG	hsa04080
Ovarian steroidogenesis	KEGG	hsa04913
Ovarian steroidogenesis	KEGG	ko04913
Prolactin signaling pathway	KEGG	hsa04917
Prolactin signaling pathway	KEGG	ko04917
Signal Transduction	REACTOME	R-HSA-162582
Signaling by GPCR	REACTOME	R-HSA-372790
GPCR ligand binding	REACTOME	R-HSA-500792
Class A/1 (Rhodopsin-like receptors)	REACTOME	R-HSA-373076
Hormone ligand-binding receptors	REACTOME	R-HSA-375281
GPCR downstream signaling	REACTOME	R-HSA-388396
G alpha (s) signalling events	REACTOME	R-HSA-418555

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
19598235	2009	Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and Asperger syndrome.	92
15889138	2005	Glycoprotein hormone receptors: link between receptor homodimerization and negative cooperativity.	91
23071612	2012	LH and hCG action on the same receptor results in quantitatively and qualitatively different intracellular signalling.	43
12091390	2002	Silencing of transcription of the human luteinizing hormone receptor gene by histone deacetylase-mSin3A complex.	39
20734064	2010	A large-scale candidate gene association study of age at menarche and age at natural menopause.	38
22659248	2012	LH-receptor gene expression in human granulosa and cumulus cells from antral and preovulatory follicles.	37
19086053	2009	Identification of new putative susceptibility genes for several psychiatric disorders by association analysis of regulatory and non-synonymous SNPs of 306 genes involved in neurotransmission and neurodevelopment.	34
16135786	2005	Coordinated changes in DNA methylation and histone modifications regulate silencing/derepression of luteinizing hormone receptor gene transcription.	33
23118426	2013	Evidence for chromosome 2p16.3 polycystic ovary syndrome susceptibility locus in affected women of European ancestry.	33
14507927	2003	GIPC binds to the human lutropin receptor (hLHR) through an unusual PDZ domain binding motif, and it regulates the sorting of the internalized human choriogonadotropin and the density of cell surface hLHR.	31

Citation

Chon-Hwa Tsai-Morris ; Maria L Dufau

LHCGR (luteinizing hormone/choriogonadotropin receptor)

Atlas Genet Cytogenet Oncol Haematol. 2012-04-01

Online version: http://atlasgeneticsoncology.org/gene/288/lhcgr

Historical Card

2004-08-01 LHCGR (luteinizing hormone/choriogonadotropin receptor) by Chon-Hwa Tsai-Morris,Maria L Dufau Affiliation

Endocrinology Section, NICHD, NIH, Bldg. 49 Rm. 6A-36, Bethesda MD 20892-4510, USA