Disease relevance of FSHB

• The translocation breakpoint, which identifies the position of the aniridia gene on 11p, is immediately proximal to FSHB, in the interval between FSHB and the catalase gene [1].
• Studies of somatic cell hybrids derived from t(11;14)(p13;q11) T-ALL placed the T-ALLbcr between the genes for catalase (CAT) and the beta-subunit of follicle stimulating hormone (FSHB) [2].
• The determination of the functional consequence of the two core FSHB variants may have implications for understanding and regulating human fertility, as well as in assisting infertility treatments [3].
• A Hind III restriction fragment length polymorphism (RFLP) detected by another subclone of the lambda phage containing FSHB now provides a genetic marker for this region of the human genome [4].
• The distribution of different FSH beta mRNAs is similar in normal human pituitary tissue and several different FSH producing pituitary adenomas [5].

High impact information on FSHB

• Bone mass is increased and osteoclastic resorption is decreased in haploinsufficient FSHbeta+/- mice with normal ovarian function, suggesting that the skeletal action of FSH is estrogen independent [6].
• Neither FSHbeta nor FSH receptor (FSHR) null mice have bone loss despite severe hypogonadism [6].
• Our results demonstrate close physical linkage between FSHB and the WAGR locus, suggest a gene order for the four deleted markers and exclude other markers tested from this region [1].
• Inhibin B is the major component of the testicular negative feedback signal governing FSH beta gene expression and FSH secretion, and the evidence for this view is presented [7].
• The most common hormonal characteristic of gonadotroph cell adenomas in vivo is hypersecretion of FSH, which is often accompanied by hypersecretion of FSH beta and alpha-subunit and less often by hypersecretion of LH beta or intact LH [8].

Chemical compound and disease context of FSHB

• CONCLUSION(S): The Cys82Arg mutation in a male with normal puberty and azoospermia results in profound deficiency of FSH in vitro, thereby confirming the molecular basis of hypogonadism in this patient and documenting the importance of the Cys residue at position 82 of the FSHbeta subunit [9].
• Although FSH beta and LH beta mRNAs were found with similar frequencies in nonfunctioning adenomas, expression of FSH beta mRNA was generally much more abundant [10].
• Immunocytochemistry demonstrated glycoprotein expression in somatotroph adenomas (LHbeta: 13%, FSHbeta: 26%, TSHbeta: 30%, alphaSU: 46%) more frequently than in lactotroph, corticotroph and null cell adenomas [11].
• Patients with varicocele showed (median and range): LH B (mlU/ml): 0.40 (0.40-2.1); LH Mx.: 3.7 (1.1-15); FSH B (mlU/ml): 1.95 (0.40-4.5); FSH Mx.: 4.9 (3.1-10); T B (ng/ml): 0.2 (0.1-1.5); T Post.: 2.25 (0.82-11.5) [12].
• Humans with FSH beta gene mutations tend to have a more severe phenotype than those with FSHR gene mutations, although infertility and varying degrees of impaired sex steroid production occur in both types of mutations [13].

Biological context of FSHB

• At 11p13, the frequencies of LOH were 20% (9/46) at the FSHB locus, 9% (5/53) at the WT1 locus, and 15% (6/41) at the CAT locus [14].
• A new gene (239FB) with predominant and differential expression in fetal brain has recently been isolated from a chromosome 11p13-p14 boundary area near FSHB [15].
• The potassium channel gene HK1 maps to human chromosome 11p14.1, close to the FSHB gene [16].
• High resolution banding cytogenetic analysis and molecular characterization using 11p13 DNA markers showed a tiny deletion encompassing the gene for CAT but sparing the gene for FSHB [17].
• Haplotype structure of FSHB, the beta-subunit gene for fertility-associated follicle-stimulating hormone: possible influence of balancing selection [3].

Anatomical context of FSHB

• They were produced by hybridomas derived from FO myeloma cells and spleen cells from mice immunized with hFSH or its beta-subunit (hFSH beta) [18].
• The beta subunit of follicle-stimulating hormone (FSH-beta) from human pituitary glands was reduced and S-aminoethylated prior to thermolytic, tryptic, and chymotryptic digestions [19].
• The biological activity of hFSH-beta 33-53 was assessed by its ability to affect the conversion of androstenedione to estradiol in rat Sertoli cells cultures [20].
• We tested this point by cotransfecting CHO cells with the genes encoding F beta alpha and the CG beta subunit or the CG beta alpha and FSH beta monomer [21].
• Fraction F-1 stimulated ovarian growth in rats, inhibited binding of 125I-hFSH to rat testes membranes and cross-reacted with antiserum to hFSH, hFSH-alpha subunit and hFSH-beta subunit as determined by radioimmunoassay [22].

Associations of FSHB with chemical compounds

• Follicle-stimulating hormone (FSH) is a glycoprotein hormone composed of two different subunits designated FSH-alpha and FSH-beta [23].
• To test this hypothesis, site-directed mutagenesis was used to generate five triple alanine mutants of the C-terminal region of hFSH beta: Q81, H83, G85; K86, D88, S89; D90, S91, T92; D93, T95, V96; and R97, G98, L99 [24].
• FSH-beta 33-53 also significantly stimulated basal levels of estradiol synthesis, but not to maximal levels observed with FSH (partial agonist) [20].
• The required incubation medium, however, contains cystine as well as cystine, which rapidly forms a hFSH-beta Cys-(51)-S-S-Cys derivative at the pH of the incubation, 7 [20].
• Cysteine residues in a synthetic peptide corresponding to human follicle-stimulating hormone beta-subunit receptor-binding domain 81-95 [hFSH-beta-(81-95)] modulate the in vivo effects of hFSH-beta-(81-95) on the mouse estrous cycle [25].

Physical interactions of FSHB

• Six LHX3-binding sites were characterized within the FSHbeta promoter, including three within a proximal region that also mediates gene regulation by other transcription factors and activin [26].
• The unique functions of this hormone are provided by the FSH receptor-binding beta-subunit encoded by the FSHB gene [3].
• With the exception of anti-22-39, all of the remaining antisera bound to hFSH alpha r/a. None of the antisera bound to hFSH beta [27].
• Evidence that a calmodulin-like calcium-binding domain of the FSH beta-subunit is involved in FSH-induced calcium uptake by Sertoli cells [28].

Co-localisations of FSHB

• In 7 cases, TSH-beta was positive, and in some cases, TSH-beta was colocalized in the same tumour cells which contained alpha-subunit and FSH-beta subunit [29].

Regulatory relationships of FSHB

• We demonstrate that in both heterologous and pituitary gonadotrope cells, specific LHX3 isoforms activate the FSH beta-subunit promoter, but not the proximal LHbeta promoter [26].
• Transfection of both ALK4(TD) and ALK7(TD) stimulated Smad2/3 phosphorylation, and the effects of both receptors on Fshb promoter activity were inhibited by depletion of endogenous Smad3 protein levels [30].
• The FSH beta gene is expressed in gonadotropes where its expression is controlled primarily by activin and inhibin, with additional regulation by GnRH [31].
• Recent studies on transcriptional regulation of the ovine FSH beta-subunit gene (oFSHbeta) have defined two functional activating protein-1 (AP-1) enhancers in the proximal promoter (located at -120 and -83 bp) that are probably physiologically important for FSHbeta expression [32].
• Recently, we reported evidence that Prop-1 directly regulates expression of the porcine FSHbeta gene, thus providing a novel advance in understanding the function of Prop-1 in FSH/LH production and hypogonadism [33].

Other interactions of FSHB

• In the current study we demonstrate that bLH, hCG, hCG beta, hCG alpha, and FSH alpha are recognized by the pituitary GalNAc-transferase in vitro, whereas oFSH, hFSH, and hFSH beta are not (b-, h-, and o-indicate bovine, human, and ovine) [34].
• In summary, these results identify single important residues in the long loop (between Y33 and F53) of the hFSH beta-subunit which are required for proper subunit interactions that provide conformational stability which in turn is necessary for FSH-receptor interaction [35].
• Mutations of the proximal binding sites demonstrate their importance for LHX3 induction of the FSHbeta promoter and basal promoter activity in gonadotrope cells [26].
• In the WiT-13 tumor both maternal and paternal chromosomes 11 are retained; D11S87 is deleted homozygously and FSHB hemizygously [36].
• The human BDNF gene maps between FSHB and HVBS1 at the boundary of 11p13-p14 [37].

Analytical, diagnostic and therapeutic context of FSHB

• Next, synthetic peptides corresponding to the sequence of hFSH beta were used in an enzyme-linked immunosorbent assay to map this epitope [38].
• Sequence analysis of the FSH beta-subunit gene indicated that she is homozygous for a two nucleotide frameshift deletion in the coding sequence [39].
• Southern blot analyses of human genomic DNA are consistent with a single copy of the FSH beta gene per haploid genome [5].
• Unexpectedly, these siblings with isolated FSH deficiency due to a nonsense FSH beta mutation had some evidence of puberty, suggesting that other factors might preserve gonadal steroidogenesis in the absence of FSH or that current bioassays cannot discriminate among very low FSH levels [40].
• INTERVENTION(S): Levels of FSH, LH, LHRH provocation test, karyotyping, genomic analysis on the Y-chromosomal AZF region and sequencing of the FSHB gene, FSH treatment [41].

References