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HPMR

follicle stimulating hormone subunit beta

OKDB#: 71

	Symbols:	FSHB		Species:	human
	Synonyms:	HH24		Locus:	11p14.1 in Homo sapiens

For retrieval of Nucleotide and Amino Acid sequences please go to: OMIM Entrez Gene
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R-L INTERACTIONS MGI

General Comment

The alpha and beta chains of follitropin (follicle-stimulating hormone; FSH) and lutropin (luteinizing hormone; LH) have been isolated from the anterior pituitary gland and their cDNAs completely sequenced. The alpha chains are identical; the beta chains differ. The high affinity, non-covalent binding between the alpha and beta subunits leads to the formation of functional heterodimers important for gonadal cell growth and differentiation.///////////////Evaluation of in vivo bioactivities of recombinant hypo- (FSH(21/18)) and fully- (FSH(24)) glycosylated human FSH glycoforms in Fshb null mice. Wang H et al. (2016) The hormone - specific FSHβ subunit of the human FSH heterodimer consists of N-linked glycans at Asn(7) and Asn(24) residues that are co-translationally attached early during subunit biosynthesis. Differences in the number of N-glycans (none, one or two) on the human FSHβ subunit contribute to macroheterogeneity in the FSH heterodimer. The resulting FSH glycoforms are termed hypo-glycosylated (FSH(21/18), missing either an Asn(24) or Asn(7) N-glycan chain on the β - subunit, respectively) or fully glycosylated (FSH(24), possessing of both Asn(7) and Asn(24) N-linked glycans on the β - subunit) FSH. The recombinant versions of human FSH glycoforms (FSH(21/18) and FSH(24)) have been purified and biochemically characterized. In vitro functional studies have indicated that FSH(21/18) exhibits faster FSH- receptor binding kinetics and is much more active than FSH(24) in every assay tested to date. However, the in vivo bioactivity of the hypo-glycosylated FSH glycoform has never been tested. Here, we evaluated the in vivo bioactivities of FSH glycoforms in Fshb null mice using a pharmacological rescue approach. In Fshb null female mice, both hypo- and fully-glycosylated FSH elicited an ovarian weight gain response by 48 h and induced ovarian genes in a dose- and time-dependent manner. Quantification by real time qPCR assays indicated that hypo-glycosylated FSH(21/18) was bioactive in vivo and induced FSH-responsive ovarian genes similar to fully-glycosylated FSH(24). Western blot analyses followed by densitometry of key signaling components downstream of the FSH-receptor confirmed that the hypo-glycosylated FSH(21/18) elicited a response similar to that by fully-glycosylated FSH(24) in ovaries of Fshb null mice. When injected into Fshb null males, hypo-glycosylated FSH(21/18) was more active than the fully-glycosylated FSH(24) in inducing FSH-responsive genes and Sertoli cell proliferation. Thus, our data establish that recombinant hypo-glycosylated human FSH(21/18) glycoform elicits bioactivity in vivo similar to the fully-glycosylated FSH. Our studies may have clinical implications particularly in formulating FSH-based ovarian follicle induction protocols using a combination of different human FSH glycoforms.//////////////////

NCBI Summary: The pituitary glycoprotein hormone family includes follicle-stimulating hormone, luteinizing hormone, chorionic gonadotropin, and thyroid-stimulating hormone. All of these glycoproteins consist of an identical alpha subunit and a hormone-specific beta subunit. This gene encodes the beta subunit of follicle-stimulating hormone. In conjunction with luteinizing hormone, follicle-stimulating hormone induces egg and sperm production. Alternative splicing results in two transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

General function

Ligand, Hormone

Comment

Development and characterization of a novel long-acting recombinant follicle stimulating hormone agonist by fusing Fc to an FSH-β subunit. Zhang YL et al. (2015) Does a novel long-acting recombinant human FSH, KN015, a heterodimer composed of FSHα and FSHβ-Fc/Fc, offer a potential FSH alternative? KN015 had in vitro activity and superior in vivo bioactivity than recombinant human FSH (rhFSH), suggesting KN015 could serve as a potential FSH agonist for clinical therapy. WHAT IS KNOWN ALREADY: rhFSH has very short half-life so that repeat injections are needed, resulting in discomfort and inconvenience for patients. The longest-acting rhFSH available in clinics is corifollitropin alpha (FSH-CTP), but its half-life is not long enough to sustain the whole therapy period, and additional injections of rhFSH are needed. Plasmids containing FSHα, FSHβ-Fc and Fc cDNA were transfected into Chinese hamster ovary (CHO) cells for KN015 production. The pharmacokinetics of KN015 was investigated in 6-week-old SD rats (n = 6/group) and healthy Cynomolgus monkeys in two different dose groups (n = 2/group). A series of experiments were designed for in vitro and in vivo characterization of the bioactivity of KN015 relative to rhFSH. The purity and molecular weight of KN015 were determined by reducing and non-reducing SDS-PAGE. To measure KN015 half-life, sera were collected at increasing time points and the remaining FSH concentration was measured by enzyme-linked immunosorbent assay. To assess the bioactivity of KN015 versus rhFSH in vitro, firstly cAMP production was assessed in CHO cells expressing FSH receptor (FSHR) with the treatment of Fc/Fc, rhFSH or KN015 at eight different doses (0.03, 0.09, 0.28, 0.83, 2.5, 7.5, 22.5, 67.5 nM), and secondly cumulus oocyte complexes (COCs; n = 20/group) of ICR mice (primed-PMSG 44 h before sacrificed) were collected and cultured in medium containing 1.25 pM Fc/Fc, rhFSH or KN015 at 37°C and then germinal vesicle breakdown (GVBD) and COC expansion were observed at 4 and 16 h, respectively. The in vivo activity of KN015 was compared with rhFSH by ovary weight gain and ovulation assays. In the former, ovary weight gains in 21-day-old female SD rats, after a single subcutaneous injection of KN015, were compared with those after several injections of rhFSH over a range of doses (n = 8/group). Sera were harvested for estradiol (E2) analysis, and the ovaries were processed for hematoxylin and eosin (HE) staining, immunohistochemistry (IHC), TdT (terminal deoxynucleotidyl transferase)-mediated dUDP nick-end labeling (TUNEL), RT-PCR and western blot. In the latter, 26-day-old female SD rats (n = 8/group) were injected with different doses of KN015 or rhFSH, and were sacrificed at 24 h after an injection of hCG (20 IU/rat). Moreover, the molecular responses stimulated by KN015 or rhFSH in the ovary were also analyzed through detecting expression of the FSH target genes (Cyp19a1, Fshr and Lhcgr) and phosphatidylinositide 3-kinase (PI3K) pathway activation. KN015 has a molecular weight of 82 kD and its half-life is 84 h in SD rats (10-fold longer than that of rhFSH) and 215 h in Cynomolgus monkeys. The EC50 value of the cAMP induction in CHO cells (KN015 versus rhFSH, 1.84 versus 0.87 nM), COC expansion and oocyte maturation assays showed KN015 had approximately half of rhFSH's activity in vitro. A single dose of KN015 (1.5 pmol/rat, 166.1 ± 19.7 mg, P < 0.01) stimulated significantly larger ovary weight gain than several injections of rhFSH (1.5 pmol/rat, 59.3 ± 28.1 mg, P < 0.01). The serum E2 level in the KN015 group was significantly higher than that in rhFSH group. The number of oocytes obtained by ovulation induction was comparable with or higher in the KN015 group than in the rhFSH group. KN015 was more effective than rhFSH in inducing FSH target genes (Cyp19a1, Fshr, Lhcgr) or activating the PI3K pathway in vivo. Moreover, a single injection of KN015 promoted granulosa cell proliferation and prevented follicle atresia to the same extent as several injections of rhFSH. All assays in this study were operated only in animals and clinical trials are needed to confirm they can be extrapolated to humans. KN015 is a valuable alternative to FSH and may have great potential for therapeutic applications. This study was supported by National Basic Research Program of China (2011|CB944504, 2012CB944403) and National Natural Science Foundation of China (81172473, 31371449). The authors have no conflicts of interest to declare.////////////////// Hypo-glycosylated hFSH has greater bioactivity than fully-glycosylated recombinant hFSH in human granulosa cells. Jiang C et al. (2015) Previous studies indicate that aging in women is associated with a reduction in hypo-glycosylated forms of FSH. Experiments were performed to determine whether glycosylation of the FSHβ subunit modulates the biological activity of FSH in human granulosa cells. Recombinant hFSH derived from GH3 pituitary cells was purified into fractions containing hypo-glycosylated hFSH(21/18) and fully-glycosylated hFSH(24). The response to FSH glycoforms was evaluated using the well-characterized, FSH-responsive human granulosa cell line, KGN. Settling: Academic medical center. Granulosa cells were treated with increasing concentrations of fully- or hypo-glycosylated FSH glycoforms for periods up to 48 h. The main outcomes were indices of cAMP-dependent cell signaling and estrogen and progesterone synthesis. We observed that hypo-glycosylated FSH(21/18) was significantly more effective than fully-glycosylated FSH(24) at stimulating cAMP accumulation, protein kinase A activity and CREB (S133) phosphorylation. FSH(21/18) was also much more effective than hFSH(24) on the stimulation CRE-mediated transcription, expression of aromatase and STAR proteins, and synthesis of estrogen and progesterone. Adenoviral-mediated expression of the endogenous inhibitor of PKA, inhibited FSH(21/18)- and FSH(24)-stimulated CREB phosphorylation and steroidogenesis. Hypo-glycosylated FSH(21/18) has greater bioactivity than fully-glycosylated hFSH(24), suggesting that age dependent decreases in hypo-glycosylated hFSH contribute to reduced ovarian responsiveness. Hypo-glycosylated FSH may be useful in follicle stimulation protocols for older patients using assisted reproduction technologies.////////////////// Follicle-stimulating hormone increases bone mass in female mice. Allan CM et al. Elevated follicle-stimulating hormone (FSH) activity is proposed to directly cause bone loss independent of estradiol deficiency in aging women. Using transgenic female mice expressing human FSH (TgFSH), we now reveal that TgFSH dose-dependently increased bone mass, markedly elevating tibial and vertebral trabecular bone volume. Furthermore, TgFSH stimulated a striking accrual of bone mass in hypogonadal mice lacking endogenous FSH and luteinizing hormone (LH) function, showing that FSH-induced bone mass occurred independently of background LH or estradiol levels. Higher TgFSH levels increased osteoblast surfaces in trabecular bone and stimulated de novo bone formation, filling marrow spaces with woven rather than lamellar bone, reflective of a strong anabolic stimulus. Trabecular bone volume correlated positively with ovarian-derived serum inhibin A or testosterone levels in TgFSH mice, and ovariectomy abolished TgFSH-induced bone formation, proving that FSH effects on bone require an ovary-dependent pathway. No detectable FSH receptor mRNA in mouse bone or cultured osteoblasts or osteoclasts indicated that FSH did not directly stimulate bone. Therefore, contrary to proposed FSH-induced bone loss, our findings demonstrate that FSH has dose-dependent anabolic effects on bone via an ovary-dependent mechanism, which is independent of LH activity, and does not involve direct FSH actions on bone cells.

Cellular localization

Secreted

Comment

GWAS123

Ovarian function

Comment

In addition to the well-established endocrine functions of FSH, recent studies by Markkula et al. (1996) indicated that the common alpha-subunit and the FSH-beta mRNA were detected in the pituitary gland and ovaries of normal adult mice. It was proposed that endogenously synthesized FSH or its subunits may have a role in the paracrine regulation of ovarian function.

Expression regulated by

Comment

Ovarian localization

Oocyte, Luteal cells, Stromal cells

Comment

The cellular localization of the the common alpha-subunit and the FSH-beta proteins was visualized by immunocytochemistry Markkula et al. (1996). In normal mouse ovaries a positive reaction with FSH beta and C alpha antisera was seen in some of the corpora lutea and most prominently in the interstitial cells. It was proposed that endogenously synthesized FSH or its subunits may have a role in the paracrine regulation of ovarian function. Novel Expression of Gonadotropin Subunit Genes in Oocytes of the Gilthead Seabream (Sparus aurata). Wong TT, et al . It is widely believed that FSH and LH, which are known to play key roles in controlling the production of functional oocytes in vertebrates, are synthesized and secreted exclusively by the anterior pituitary. Here we present evidence for the novel expression of FSHbeta, LHbeta, and the common glycoprotein-alpha (Cgalpha) in the gilthead seabream ovary. Using in situ hybridization and immunocytochemistry, FSHbeta was detected in primary-growth and secondary-growth-I oocytes, LHbeta was found in secondary-growth oocytes, and Cgalpha was observed in both primary and secondary-growth oocytes. Northern blot analyses demonstrated that Fshbeta transcript is 0.6 kb in both pituitary and ovary, whereas the ovarian Lhbeta transcript (1.1 kb), unexpectedly, is longer than the known pituitary Lhbeta transcript (0.6 kb). Sequence analyses revealed that ovarian Lhbeta is driven by a different promoter than pituitary Lhbeta, which generates an additional 459 bases at the distal portion of the 5'-untranslated region of the ovarian Lhbeta. Furthermore, using in vitro ovarian fragment incubation, we demonstrated that mammalian GnRH analog agonist enhanced the expression of ovarian Fshbeta (up to 2.7-fold), Lhbeta (up to 1.4-fold), Cgalpha (up to 1.8-fold), and the secretion of ovarian LH (up to 2.2-fold). In contrast, GnRH antagonist, analog E, suppressed the secretion of ovarian LH. Our findings suggest that a GnRH-gonadotropin axis is present in the gilthead seabream ovary and that FSH and LH, the well-characterized pituitary hormones, may have prominent novel roles in teleost intraovarian communication between oocytes and ovarian follicle cells.

Follicle stages

Corpus luteum

Comment

Phenotypes

PCO (polycystic ovarian syndrome)

Mutations

5 mutations

Species: human
Mutation name: None
type: naturally occurring
fertility: infertile - non-ovarian defect
Comment: Matthews et al. (1993) reported a woman with primary amenorrhoea and infertility associated with an isolated deficiency of pituitary follicle-stimulating hormone (FSH), but normal luteinizing hormone (LH) secretion. Ovulation was induced by administration of exogenous FSH and resulted in a successful pregnancy. Sequence analysis of the FSH beta-subunit gene indicated that she is homozygous for a two nucleotide frameshift deletion in the coding sequence. Her mother and son are heterozygous for this mutation. This deletion results in an alteration of amino acid codons 61-86 followed by a premature termination codon. The predicted truncated beta-subunit peptide lacks regions which are important for association with the alpha subunit and for binding to and activation of the FSH receptor.

Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - non-ovarian defect
Comment: Kumar et al. (1997) produced mice deficient in the FSH beta subunit FSH-deficient females are infertile due to a block in folliculogenesis prior to antral follicle formation.

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Variants in FSHB are associated with polycystic ovary syndrome and luteinizing hormone level in Han Chinese women. Tian Y et al. (2016) A recent genome-wide association study (GWAS) has identified 3 susceptibility loci (8p32.1, 11p14.1, and 9q22.32) for PCOS in women of European ancestry. The 9q22.32 loci was previously found in our Chinese PCOS GWAS. Replication of the other two loci is necessary to determine whether the same variants confer risk to PCOS in Han Chinese women. To investigate the impact of the European GWAS loci on PCOS susceptibility in Han Chinese women. Genetic association study. University hospital. 1601 PCOS cases, 1238 age-matched controls. Interventions and Main Outcome Measure: After screening of the regions that cover 500kb upstream and downstream of the two SNPs using our previous Chinese GWAS data, rs11031010, located in the region of follicle-stimulating hormone B polypeptide (FSHB) gene, was selected for further replication. Whereas the other SNPs near rs804279 (GATA4/NEIL2) were excluded based on our previous GWAS data. Then, the variant rs11031010 was genotyped in an independent cohort and the associations with PCOS, endocrine and metabolic traits were assessed. In the current replication study, rs11031010 was associated with PCOS in Han Chinese women (P = 2.76×10(-3)), even after adjustment for age and BMI. Meta-analysis with our previous GWAS data showed that the allele frequency difference of rs11031010 between PCOS and controls reached genome-wide significance (P = 4.27×10(-8)). PCOS women with AA and AC genotype had a significantly higher LH level than individuals carrying CC genotype (P =1.60×10(-4)). The genetic risk score based on total sixteen Chinese PCOS risk SNPs, calculated by total number of risk alleles for each subject, was associated with the diagnosis of PCOS (P < 1.00×10(-4)). Variants in FSHB gene are associated with PCOS and LH level in Han Chinese women. FSHB is thus likely to play an important role in the etiology of PCOS, regardless of ethnicities.//////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: fertile
Comment: Identification of Common Genetic Variants Influencing Spontaneous Dizygotic Twinning and Female Fertility. Mbarek H et al. (2016) Spontaneous dizygotic (DZ) twinning occurs in 1%-4% of women, with familial clustering and unknown physiological pathways and genetic origin. DZ twinning might index increased fertility and has distinct health implications for mother and child. We performed a GWAS in 1,980 mothers of spontaneous DZ twins and 12,953 control subjects. Findings were replicated in a large Icelandic cohort and tested for association across a broad range of fertility traits in women. Two SNPs were identified (rs11031006 near FSHB, p = 1.54 × 10(-9), and rs17293443 in SMAD3, p = 1.57 × 10(-8)) and replicated (p = 3 × 10(-3) and p = 1.44 × 10(-4), respectively). Based on ∼90,000 births in Iceland, the risk of a mother delivering twins increased by 18% for each copy of allele rs11031006-G and 9% for rs17293443-C. A higher polygenic risk score (PRS) for DZ twinning, calculated based on the results of the DZ twinning GWAS, was significantly associated with DZ twinning in Iceland (p = 0.001). A higher PRS was also associated with having children (p = 0.01), greater lifetime parity (p = 0.03), and earlier age at first child (p = 0.02). Allele rs11031006-G was associated with higher serum FSH levels, earlier age at menarche, earlier age at first child, higher lifetime parity, lower PCOS risk, and earlier age at menopause. Conversely, rs17293443-C was associated with later age at last child. We identified robust genetic risk variants for DZ twinning: one near FSHB and a second within SMAD3, the product of which plays an important role in gonadal responsiveness to FSH. These loci contribute to crucial aspects of reproductive capacity and health.//////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome. Day FR et al. (2016) Polycystic ovary syndrome (PCOS) is the most common reproductive disorder in women, yet there is little consensus regarding its aetiology. Here we perform a genome-wide association study of PCOS in up to 5,184 self-reported cases of White European ancestry and 82,759 controls, with follow-up in a further ∼2,000 clinically validated cases and ∼100,000 controls. We identify six signals for PCOS at genome-wide statistical significance (P<5 × 10(-8)), in/near genes ERBB4/HER4, YAP1, THADA, FSHB, RAD50 and KRR1. Variants in/near three of the four epidermal growth factor receptor genes (ERBB2/HER2, ERBB3/HER3 and ERBB4/HER4) are associated with PCOS at or near genome-wide significance. Mendelian randomization analyses indicate causal roles in PCOS aetiology for higher BMI (P=2.5 × 10(-9)), higher insulin resistance (P=6 × 10(-4)) and lower serum sex hormone binding globulin concentrations (P=5 × 10(-4)). Furthermore, genetic susceptibility to later menopause is associated with higher PCOS risk (P=1.6 × 10(-8)) and PCOS-susceptibility alleles are associated with higher serum anti-Müllerian hormone concentrations in girls (P=8.9 × 10(-5)). This large-scale study implicates an aetiological role of the epidermal growth factor receptors, infers causal mechanisms relevant to clinical management and prevention, and suggests balancing selection mechanisms involved in PCOS risk. //////////////////

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Phenotypes and GWAS

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Links

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July 22, 1999, midnight

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March 18, 2020, 2:03 p.m.

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