Alternative titles; symbols
HGNC Approved Gene Symbol: LHB
SNOMEDCT: 8829008; ICD10CM: E23.0;
Cytogenetic location: 19q13.33 Genomic coordinates (GRCh38): 19:49,015,980-49,019,498 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.33 | Hypogonadotropic hypogonadism 23 with or without anosmia | 228300 | Autosomal recessive | 3 |
The glycoprotein hormone family to which luteinizing hormone belongs includes follicle-stimulating hormone (FSH; 136530), thyroid-stimulating hormone (TSH; 188540), and chorionic gonadotropin (CG; 118860). Each of these hormones consists of a noncovalent dimer of alpha and beta subunits. The alpha subunit is the same for all 4 hormones (see CGA, 118850), and the beta subunits define the endocrine function of the dimer (Talmadge et al., 1983).
Talmadge et al. (1984) stated that the LH-beta subunit encodes a deduced 121-amino acid protein, 6 amino acids longer than described by Sairam and Li (1975). Luteinizing hormone is made in the pituitary and has a central role in promoting spermatogenesis and ovulation by stimulating the testes and ovaries to synthesize steroids (Talmadge et al., 1984).
Restriction enzyme mapping indicates that the genes for the beta chains of chorionic gonadotropin and luteinizing hormone are contiguous. Both CGB (118860) and LHB have been assigned to chromosome 19q13.2 (Mohrenweiser et al., 1991).
One of the major structural differences between the LHB and CGB subunits is the C-terminal region. Beyond residue 114, LHB has a hydrophobic heptapeptide stretch, whereas CGB contains a 31-residue hydrophilic C-terminal peptide (CTP) that is O-glycosylated. The CGB subunit is secreted quantitatively as a monomer and assembles efficiently, whereas secretion and assembly of LHB is inefficient. Muyan et al. (1996) tested the function of the heptapeptide and CTP domains by fusing them to their counterparts at residues 114 of CGB or LHB subunits. The secretion and assembly of these chimeras were examined in transfected Chinese hamster ovary (CHO) cells. Removal of the heptapeptide enhanced the amount of LHB subunit secreted 4-fold compared with intact LHB. Fusion of this heptapeptide to CGB 114, i.e., CGB lacking the CTP, decreased the amount of secreted subunit 2-fold compared with wildtype human CGB. These data supported the hypothesis that the C-terminal regions of LHB and CGB subunits play a role in the intracellular behavior of the corresponding heterodimers.
Both the LHB and FSHB genes are expressed in gonadotropes, but LHB is more dependent on GNRH (152760) input than is FSHB (Albanese et al., 1996).
Curtin et al. (2001) tested direct pituitary effects of the androgen dihydrotestosterone (DHT) to modulate the rat LH-beta promoter. The LH-beta promoter (-617 to +44 bp)-luciferase construct was stimulated in L-beta-T2 cells 7- to 10-fold by GNRH. Androgen treatment had little effect on basal promoter activity but suppressed GNRH stimulation by approximately 75%. GNRH stimulation of the LH-beta promoter requires interactions between a complex distal response element containing 2 specificity protein-1 (Sp1) binding sites and a CArG box, and a proximal element with 2 bipartite binding sites for steroidogenic factor-1 (SF1; 184757) and early growth response protein-1 (EGR1; 128990) (Weck et al., 2000; Kaiser et al., 2000). The distal response element does not bind androgen receptor (AR; 313700), but AR reduces Sp1 binding to this region.
Concentrations of LH and FSH are known to increase during normal pubertal development. Phillips et al. (1997) examined the median charge of serum LH and FSH using agarose in 81 normal children at pubertal stages I to V. In pubertal girls there were no significant differences in the median charge of LH. In boys there was a significant (p less than 0.01) shift to more acidic isoforms of LH by pubertal stage II. Further changes were not found later in puberty. Except for LH at pubertal stage I, where the median charge was similar for both sexes, the median charge was more basic (p less than 0.001) for LH in girls compared with boys at all 5 pubertal stages. The authors concluded that while there are few qualitative changes in the gonadotropins during normal female puberty, there is a dramatic shift to more acidic isoforms of LH early in male puberty.
Reproduction depends on regulated expression of the LH-beta gene. Tandem copies of regulatory elements that bind early growth response protein-1 (Egr1; 128990) and steroidogenic factor-1 (SF1; 184757) are located in the proximal region of the LH-beta promoter and make essential contributions to its activity as well as mediate responsiveness to GNRH (152760). Located between these tandem elements is a single site capable of binding the homeodomain protein Pitx1 (602149). Quirk et al. (2001) reassessed the requirement for a Pitx1 element in the promoter of the LH-beta gene using homologous cell lines and transgenic mice. Their analysis indicated a striking requirement for the Pitx1 regulatory element. When assayed by transient transfection using a gonadotrope-derived cell line, an LH-beta promoter construct harboring a mutant Pitx1 element displayed attenuated transcriptional activity but retained responsiveness to GNRH. In contrast, analysis of wildtype and mutant expression vectors in transgenic mice indicated that LH-beta promoter activity is completely dependent on the presence of a functional Pitx1 binding site. The authors concluded that collectively, their data reinforce the concept that activity of the LH-beta promoter is determined, in part, through highly cooperative interactions between SF1, Egr1, and Pitx1. While Egr1 can be regarded as a key downstream effector of GNRH, and Pitx1 as a critical partner that activates SF1, they suggested that their data firmly establish that the Pitx1 element plays a vital role in permitting these functions to occur in vivo.
Manna et al. (2002) synthesized recombinant forms of wildtype and variant LH in human embryonic kidney (HEK) 293 cells. Although the mutations in variant LH-beta did not significantly affect the affinity of LH receptor (LHR; 152790) binding, variant LH had higher in vitro biopotency than wildtype LH, in terms of LTC1 mouse Leydig tumor cell cAMP and progesterone production, and steroidogenic acute regulatory protein expression. In addition, in HEK293 cells expressing the human LH receptor, variant LH demonstrated 1.8-fold higher response of inositol trisphosphate (IP3) production than wildtype LH. Furthermore, HEK293 cells expressing the ELK1 trans-reporting plasmids displayed 2.7-fold greater luciferase response to variant LH than wildtype LH, documenting stimulation of the mitogen-activated protein kinase (MAPK) pathway. The in vivo half-life of variant LH was clearly faster than that of wildtype LH and human chorionic gonadotropin when injected into rat circulation. Analysis by matrix-assisted laser desorption ionization mass spectrometry demonstrated clear differences in structures of carbohydrate side chains attached to the 2 forms of recombinant LHs, including incomplete processing of high mannose glycans in variant LH, suggesting different pathways in its intracellular trafficking.
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 (LHR) 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.
In a man with hypogonadotropic hypogonadism due to biologically inactive LH (HH23; 228300), Weiss et al. (1992) identified homozygosity for a missense mutation in the LHB gene (Q54R; 152780.0001). His unaffected mother and sister were heterozygous for the mutation, as were 3 maternal uncles who were infertile but displayed normal secondary sexual characteristics. Functional analysis demonstrated that the mutation eliminates the ability of LH to bind to its receptor.
A G102S variant in the LHB gene (152780.0003) was first described by Roy et al. (1996) and subsequently found to be associated with various infertility-related phenotypes in both male and female Singapore Chinese patients (Liao et al., 1998; Ramanujam et al. (1999, 2000)). Liao et al. (2002) performed functional in vitro studies in Chinese hamster ovary (CHO) cells and concluded that the variant might be a contributing factor to the pathogenesis of infertility in carriers. However, Kim et al. (2001) and Lee et al. (2003) did not detect the G102S variant in infertile Korean women or men, respectively; Lee et al. (2003) thus stated that they could not confirm any association with infertility in the Korean population.
An association between some variants of luteinizing hormone and ovulatory disorders, including infertility, is observed in Japan. Takahashi et al. (2003) searched for other polymorphisms and interactions with the LHB variant as a potential basis for the association with ovulatory disorders in 3 Japanese groups: 43 females with ovulatory disorders, 79 females with normal ovulation, and 23 healthy males. PCR-amplified LH beta subunit gene sequencing detected 5 novel silent polymorphisms. A 1036C-A allele was most frequent (0.945), with no homozygotes for wildtype observed, and was detected significantly more often in patients with polycystic ovary syndrome (184700), endometriosis (131200), premature ovarian failure, and luteal insufficiency compared to healthy women. Three other novel alleles (894C-T, 1098C-T, and 1423C-T) were found significantly more frequently in women with ovulatory disorders, as was the overall incidence of point mutations. There was linkage disequilibrium in the presence of the LHB variant; 87.5% of women with the LHB variant and ovulatory disorders also had silent polymorphisms, although the silent polymorphisms were infrequent in the subset without ovulatory disorders. Takahashi et al. (2003) concluded that the silent polymorphisms could influence the LHB variant association with ovulatory disorders in the Japanese population.
In a 30-year-old man from Cameroon with hypogonadotropic hypogonadism due to lack of LH, Valdes-Socin et al. (2004) sequenced the LHB gene and identified homozygosity for a G36D mutation (152780.0004). Treatment with hCG in this patient resulted in spermatogenesis adequate for conception by intracytoplasmic sperm injection (Valdes-Socin et al., 2009).
In 3 sibs from a consanguineous Brazilian family with hypogonadism due to isolated LH deficiency, Lofrano-Porto et al. (2007) identified homozygosity for a splice site mutation in the LHB gene (152780.0005).
In a brother and sister from a consanguineous Moroccan family with hypogonadotropic hypogonadism due to partial loss of LH function, Achard et al. (2009) identified homozygosity for a 9-bp deletion in the LHB gene (152780.0006). The authors noted that the male proband presented an unusual case by exhibiting complete and quantitatively normal spermatogenesis despite extremely low levels of LH activity postnatally and at puberty.
In a brother and sister from a nonconsanguineous Chilean family with hypogonadism due to isolated LH deficiency, Basciani et al. (2012) identified compound heterozygosity for a 12-bp deletion (152780.0007) and a splice site mutation (152780.0008) in the LHB gene. Their unaffected parents were each heterozygous for 1 of the mutations.
Ma et al. (2004) found that targeted disruption of the Lhb gene in mice did not affect embryonic development and viability, but it resulted in postnatal defects in gonadal growth and function, resulting in infertility. Mutant males had decreased testis size, prominent Leydig cell hypoplasia, defects in expression of genes encoding steroid biosynthesis pathway enzymes, reduced testosterone levels, and blockage of spermatogenesis at the round spermatid stage. Mutant female mice were hypogonadal and demonstrated decreased levels of serum estradiol and progesterone. Ovarian histology demonstrated normal thecal layer, defective folliculogenesis with many degenerating antral follicles, and absence of corpora lutea. FSH levels were unaffected in null mice, and the phenotype could be rescued by exogenous human chorionic gonadotropin, indicating that LH responsiveness of the target cells was not irreversibly lost.
In a man with hypogonadotropic hypogonadism due to biologically inactive LH (HH23; 228300), from a consanguineous kindred originally reported by Axelrod et al. (1979), Weiss et al. (1992) identified homozygosity for a 161A-G transition in exon 3 of the LHB gene, resulting in a gln54-to-arg (Q54R) substitution. The proband's unaffected mother and sister, who had normal pubertal development and regular menstrual cycles and were fertile, were heterozygous for the mutation. Three maternal uncles, who had normal secondary sexual characteristics but were infertile, were also heterozygous for the mutation.. Weiss et al. (1992) noted that the proband's father, from whom DNA was unavailable, was presumably an obligate heterozygote; thus, the heterozygous condition is not invariably associated with infertility in men. Functional analysis in transfected CHO cells demonstrated that mutant and wildtype LHB were detected in equivalent amounts by radioimmunoassay; however, the mutant hormone was undetectable by radioreceptor assay, whereas the wildtype hormone was readily measured, indicating that the absence of biologic activity in the Q54R mutant is due to inability to bind to its receptors.
In a healthy woman who was fertile and had normal levels of all other hormones measured, Pettersson et al. (1992) identified an immunologically anomalous form of LH (see HH23, 228300). Later, the immunologic abnormality was found to be due to 2 point mutations in the LHB gene.
In 3 Japanese women with infertility, Furui et al. (1994) found the same 2 mutations: codon 8, TGG to CGG; codon 15, ATC to ACC. One of the mutations introduced an extra glycosylation signal to the LH beta chain. This site is glycosylated, as is the case with an identical structure in the chorionic gonadotropin beta chain (CGB; 118860). The mutated LH form would probably differ from normal LH in its biologic behavior.
Haavisto et al. (1995) found that the frequency of the aberrant LH form in the Finnish population was 24.1% for heterozygotes and 3.6% for homozygotes, with similar proportions in each sex. The ratio of in vitro bioactivity to immunoreactivity of the variant LH was significantly increased, but no difference was observed in LH pulsatility or in the responses of LH immunoreactivity to GNRH stimulation. Haavisto et al. (1995) speculated that, although the subjects homozygous for the LH polymorphism were apparently healthy, the altered bioactivity and in vivo kinetics may induce subtle changes in LH action, either predisposing affected persons to or protecting them from disease conditions related to LH action.
To assess the effect of the trp8-to-arg and ile15-to-thr LH variant on LH action, Raivio et al. (1996) correlated its presence in a group of 49 healthy boys with the onset and progression of puberty. This group was followed-up longitudinally from a mean age of 11.7 +/- 0.1 years for 3 years at 3-month intervals. In addition, they studied the prevalence of the variant in boys with constitutional pubertal delay (testicular volume less than 4 ml after 13.5 years of age). Of the boys with pubertal onset at a normal age, 36 (74%) were homozygous for the wildtype LH-beta allele, 12 (24%) were heterozygous, and 1 (2%) was homozygous for the variant LH-beta allele. Clear differences in pubertal parameters were found between the boys with normal and mutant (homo- or heterozygous) LH genotypes. During follow-up, boys with the trp8-to-arg and ile15-to-thr genotype had smaller testicular volumes (p less than 0.03), were shorter (p less than 0.02), had slower growth rates (p less than 0.04), and had lower serum insulin-like growth factor I-binding protein-3 levels (p less than 0.03) than the boys with the normal LH genotype. Raivio et al. (1996) concluded that during the progression of puberty, the variant LH may be less active than wildtype LH in stimulating testicular growth.
Tapanainen et al. (1999) studied the frequency of the trp8-to-arg and ile15-to-thr variant LH allele in groups of polycystic ovary syndrome (PCOS; 184700) patients from Finland, the Netherlands, the U.K., and the U.S. The LH status was determined by 2 immunofluorometric assays from a total of 1,466 subjects. The carrier frequency of the variant LH allele in the whole study population was 18.5%, being highest (28.9%) in Finland and lowest (11.2%) in the Netherlands. In the individual countries, the frequency of the variant LH allele was similar in obese and nonobese controls, but in the Netherlands and Finland, it was 5- to 7-fold lower in obese PCOS subjects compared with the other groups (2 to 4.5% vs 10.3 to 33.3%; P less than 0.05). A similar tendency was found in the U.S. (5.7% vs 11.1 to 25.0%) but not in the U.K. The overall high prevalence of the variant LH allele in healthy women and women with PCOS suggested that it is compatible with fertility. The similar frequency of the variant LH allele in healthy nonobese and obese women indicated that obesity per se is not related to the variant. In contrast, the lower frequency of the variant LH allele in obese PCOS patients suggested that the variant may protect obese women from developing symptomatic PCOS. However, the authors concluded that regional differences in this finding between patients with apparently similar diagnostic criteria emphasizes the multifactorial nature of PCOS, and that its pathogenesis may vary according to genetic background.
Van den Beld et al. (1999) studied the correlations between serum LH concentration and the clinical characteristics of frailty and determined the presence and concentration of the trp8-to-arg and ile15-to-thr LH variant. An independently living population of 403 healthy elderly men (aged 73 to 94 years) were randomly selected from a population-based sample. Total testosterone (T), sex hormone-binding globulin (SHBG; 182205), and leptin (164160) were determined by RIA. Non-SHBG-bound T was calculated. LH and the presence of the LH variant were measured using immunofluorometric assays. The characteristics of frailty were leg extensor strength using dynamometry, bone mineral density of total body and proximal femur, and body composition, including lean mass and fat mass, measured by dual energy x-ray absorptiometry. LH significantly increased with age and inversely correlated with T and non-SHBG-bound T. LH was inversely related to muscle strength and lean mass, and both relations were independent of T. LH was positively related to self-reported disability. Of the study population, 12.5% were heterozygous for the LH variant allele. T levels and the degree of frailty were not different in the wildtype LH group compared with those heterozygous for the LH variant. A significant positive relation between LH and fat mass as well as leptin was only present in the heterozygous group. The results indicated that serum LH levels increase with age in independently living elderly men and these levels correlate inversely with a variety of indicators of frailty. The observed relation between LH and frailty, independent of T, suggested that LH reflects serum androgen activity in a different way than T, possibly reflecting more closely the combined feedback effect of estrogen and androgen. A difference in biologic response between the 2 LH forms was suggested, as a difference existed in the relation between LH and fat mass, respectively, and leptin in the subjects heterozygous for the LH variant compared with wildtype LH subjects.
Ramanujam et al. (2000) analyzed the LHB gene in 145 infertile and 200 healthy fertile men, and identified the W8R/I15T polymorphism in heterozygosity in 12 infertile and 14 fertile men. In addition, 1 fertile man was homozygous for the variant. The prevalence of W8R/I15T did not differ significantly between fertile and infertile men.
In a study of 95 infertile and 200 fertile men from South Korea, Lee et al. (2003) found heterozygosity for W8R/I15T in 12.6% of the infertile and 14.5% of the fertile men.
This variant, formerly titled INFERTILITY, MALE AND FEMALE, has been reclassified based on the findings of Kim et al. (2001) and Lee et al. (2003).
The gly102-to-ser (G102S) mutation of LHB, resulting from a 1502G-A transition in exon 3, was first described by Roy et al. (1996) and subsequently found to be associated with various infertility-related phenotypes in both male and female Singapore Chinese patients (Liao et al., 1998; Ramanujam et al. (1999, 2000)). Liao et al. (2002) performed functional in vitro studies in Chinese hamster ovary (CHO) cells and concluded that the variant may be a contributing factor to the pathogenesis of infertility in carriers of the variant.
Kim et al. (2001) analyzed the LHB gene in 108 infertile women from South Korea (40 with endometriosis and 68 with menstrual disorders due to polycystic ovary syndrome (PCOS; see 184700)) and 59 healthy controls, but did not detect the G102S variant in any of the women. Noting that the variant was also not found in Malay or Indian women by Ramanujam et al. (1998), the authors concluded that the pathophysiologic and clinical significance of the variant in infertile patients with endometriosis and PCOS remained to be determined.
Lee et al. (2003) analyzed the LHB gene in 95 infertile men from South Korea and 200 fertile controls, but did not detect the G102S variant in any of the men. Noting that the variant was also not found in infertile Korean women (Kim et al., 2001), Lee et al. (2003) concluded that they could not confirm any association with infertility in this population.
In a 30-year-old Cameroonian man who presented with delayed puberty and infertility and was found to have hypogonadism associated with absence of circulating luteinizing hormone (HH23; 228300), Valdes-Socin et al. (2004) identified a homozygous gly36-to-asp (G36D) substitution in exon 2 of the LHB gene. The mutation disrupted a vital cystine knot motif and abrogated the heterodimerization and secretion of luteinizing hormone. Treatment with human chorionic gonadotropin (hCG) increased circulating testosterone, promoted virilization, and was associated with the appearance of normal spermatozoa in low concentrations. This case illustrated the important physiologic role that luteinizing hormone plays in male sexual maturation and fertility. Treatment with hCG in this patient eventually resulted in spermatogenesis adequate for conception by intracytoplasmic sperm injection (Valdes-Socin et al., 2009).
In 2 brothers and a sister from a consanguineous Brazilian family with hypogonadism due to deficiency of luteinizing hormone (HH23; 228300), Lofrano-Porto et al. (2007) identified homozygosity for a G-to-C transversion at the conserved 5-prime splice donor site (IVS2+1G-C) of intron 2 of the LHB gene, resulting in the inclusion of the entire 236-nucleotide intron 2 into the transcript and causing a frameshift in exon 3. Their asymptomatic parents and 2 unaffected sisters, 1 brother, and 1 nephew were heterozygous for the mutation, which was not found in 100 Brazilian controls. All heterozygotes were fertile and had normal basal gonadotropin and sex steroid levels for their ages, except for the 66-year-old mother who had unexpectedly low LH levels for her menopausal state. The affected sister had normal pubertal development, secondary amenorrhea, and infertility due to chronic anovulation.
In a brother and sister from a consanguineous Moroccan family with hypogonadotropic hypogonadism due to partial loss of LH function (HH23; 228300), Achard et al. (2009) identified homozygosity for an in-frame 9-bp deletion in exon 2 of the LHB gene, resulting in deletion of codons 10 to 12 (his-pro-ile). Their mother and asymptomatic sibs were heterozygous for the deletion. Studies in transfected HEK293T cells showed a more than 30-fold reduction in secretion of the mutant hormone compared to wildtype. In addition, the mutant hormone had markedly lower bioactivity, with residual function that was less than 1% of wildtype. Achard et al. (2009) noted that the male proband presented an unusual case by exhibiting complete and quantitatively normal spermatogenesis despite extremely low levels of LH activity postnatally and at puberty.
In a Chilean brother and sister with hypogonadism due to deficiency of luteinizing hormone (HH23; 228300), Basciani et al. (2012) identified compound heterozygosity for a 12-bp deletion and a splice site mutation (IVS2+1G-T; 152780.0008) in the LHB gene. Analysis of transcription products showed that the in-frame 12-bp deletion (28_39del) in exon 2 results in deletion of 4 leucine residues (codons 10-13) within the hydrophobic core of the signal peptide, whereas the transversion in the 5-prime splice donor site of intron 2 causes retention of the entire 236-bp intron 2. The unaffected parents were each heterozygous for 1 of the mutations; neither mutation was found in a SNP database.
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