Mutations of follicle stimulating hormone-β and its receptor in human and mouse: genotype/phenotype

Layman, Lawrence C.; McDonough, Paul G.

doi:10.1016/s0303-7207(99)00217-8

Cited by 66 publications

(42 citation statements)

References 25 publications

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“…The clinical features of the proband reported here are similar to other females with genetically confirmed isolated FSH or FSHR deficiency (8,10,11,(16)(17)(18)(19). Previously described females with FSHb mutations (one homozygote for Val61X, one compound heterozygote Val61X/Cys51Gly, and three homozygotes for Tyr76X) all showed primary amenorrhea, infertility, partial pubarche, and complete or partial lack of breast development (8,10,11,(16)(17)(18)(19). The laboratory findings of these patients also showed similar findings with undetectable FSH, low estrogen, and elevated LH.…”

Section: Discussionsupporting

confidence: 72%

“…The functions of FSH include the stimulation of follicular development and E 2 production in females and the regulation of Sertoli cell action and spermatogenesis in males. Both inactivating mutations of FSHb and FSHR in humans (16,17), as well as in knockout mice for the same genes (30)(31)(32) have shown that FSH is essential for normal puberty and fertility in females, particularly ovarian follicular development beyond the antral stage. In males, FSH is necessary for qualitatively and quantitatively normal spermatogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Inherited genetic defects that cause hypogonadism in females have been identified at multiple levels of the hypothalamic-pituitary-gonadal axis, including GnRH, its receptor, GPR54/KISS1R, TAC3/TACR3, gonadotropin subunits, genes involved in autosomal Kallmann syndrome and CHARGE syndrome, and gonadotropin receptors (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Inactivating mutations in the FSHb gene have been found to date in five women with delayed puberty and isolated FSH deficiency (8,10,11,(16)(17)(18)(19)). These very rare natural mutations in the FSHb subunit gene are nevertheless interesting models to elucidate several aspects of the gonadotropin-dependent ovarian physiology and physiopathology.…”

Section: Introductionmentioning

confidence: 99%

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A new FSHβ mutation in a 29-year-old woman with primary amenorrhea and isolated FSH deficiency: functional characterization and ovarian response to human recombinant FSH

Kottler¹,

Chou²,

Chabre

et al. 2010

European Journal of Endocrinology

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Context: Mutations of the FSHb gene, causing in women isolated FSH deficiency and hypogonadism, are very rare and only a few have been described. Objective: To describe the phenotype and response to recombinant human (rh) FSH of a female patient with a novel homozygous loss-of-function mutation of FSHb, and to characterize in vitro the molecular mechanisms responsible for the FSH inactivation. Patient: A 29-year-old woman with primary amenorrhea and impaired pubertal development associated with isolated FSH deficiency. Methods and results: Sequencing of the FSHb gene revealed a homozygous 1 bp (G) deletion at codon 79 (c.289delG) of exon 3 which produced a frameshift at codon 79 (A79fs108X) and a premature stop codon at codon 109. The wild-type and mutant FSHb cDNAs inserted into expression vector were cotransfected into Chinese hamster ovary cells with the a-subunit. Wild-type FSH was readily detectable in culture medium, whereas no mutant FSH was detectable by either immunoassay or in vitro bioassay. Mutant FSHb protein could not be detected in western blot. In response to a 15-day treatment with rhFSH, sonography revealed multifollicular development in the ovaries. Circulating levels of estradiol and inhibin B were dramatically increased, whereas antiMullerian hormone decreased. Serum LH first decreased and then increased, inducing multiovulation associated with supraphysiologic progesterone and inhibin A levels. Conclusion: A novel FSHb mutation was detected in a hypogonadal woman. rhFSH was effective in ovulation induction in the patient but with signs of ovarian hyperstimulation. The high pretreatment LH levels could contribute to this excessive ovarian response to rhFSH.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A new FSHβ mutation in a 29-year-old woman with primary amenorrhea and isolated FSH deficiency: functional characterization and ovarian response to human recombinant FSH

Kottler¹,

Chou²,

Chabre

et al. 2010

European Journal of Endocrinology

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“…Follicle-stimulating hormone (FSH) rescues follicles from atresia (Layman and McDonough, 2000). FSH is believed to be the most important survival factor inhibiting granulosa cell apoptosis and can rescue granulosa cells from apoptosis in porcine and bovine (Yang and Rajamahendran, 2000;Asahara et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Rescue from dominant follicle atresia by follicle-stimulating hormone in mice

Zhou¹,

Teng²,

Cao³

et al. 2013

Genet. Mol. Res.

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ABSTRACT.We investigated the effects of follicle-stimulating hormone (FSH) on atresia of the dominant follicle and changes in relevant apoptosis genes in granulosa cells of dominant follicles regulated by FSH in vivo. Four-week-old mice were administered FSH by intraperitoneal injection to induce follicular maturation. Granulosa cells of dominant follicles were collected at 48, 72, and 96 h after the first FSH injection. Phosphate-buffered saline was injected as a control. The mRNA levels of relevant granulosa cell apoptosis genes were examined by real-time quantitative polymerase chain reaction, and apoptosis of granulosa cells in dominant ovarian follicles was determined by the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Apoptosis in granulosa cells of dominant follicles was almost TUNEL-negative at 48, 72-66, 72, and 96-90 h after the first FSH injection, but granulosa cell apoptosis in dominant follicles was clearly detected at 96, 102, and 102-96 h by TUNEL. The BIM, caspase-3, and caspase-9 mRNA expression levels were significantly lower after FSH treatment at 72-66 and 96-90 h, compared with that at 72 and 96 h (P < 0.05). Caspase-8 and FasL mRNA expressions did not respond to FSH. FSH rescued granulosa cells from apoptosis when the relevant apoptosis genes were upregulated in early atretic follicles. FSH did not rescue granulosa cells from apoptosis if the DNA was cut into fragments by endonucleases. Thus, the rescue by FSH of granulosa cells from apoptosis and dominant follicle atresia may be accomplished by inhibition of apoptosis in mitochondria.

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“…In female mammals, proper regulation of folliclestimulating hormone (FSH) synthesis, secretion and action is critical for the maintenance of normal reproduction (Layman & McDonough 2000, Themmen & Huhtaniemi 2000. Across the 4 to 5 days of rodent estrous cycles, there are two peaks in FSH release from gonadotrope cells of the anterior pituitary gland.…”

Section: Introductionmentioning

confidence: 99%

Acute regulation of murine follicle-stimulating hormone β subunit transcription by activin A

Lamba¹,

Santos²,

Philips³

et al. 2006

Journal of Molecular Endocrinology

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In rodents, activins stimulate immediate-early increases in pituitary follicle-stimulating hormone (Fshb) subunit transcription. Here, we investigated the underlying signaling mechanisms using the mouse gonadotrope cell line, L T2. Activin A increased mouse Fshb-luciferase reporter activity within 4 h through a Smad-dependent signaling pathway. The ligand rapidly stimulated formation of SMAD2/3/4 complexes that could interact with a consensus palindromic Smad binding element (SBE) in the proximal Fshb promoter. SMAD over-expression potently stimulated transcription, with the combination of SMADs 2, 3 and 4 producing the greatest synergistic activation. A mutation in the SBE that abolished Smad binding greatly impaired the effects of acute (4 h) activin A treatment and SMAD over-expression on promoter activity, but did not abolish the effects of chronic (24 h) activin A exposure. Within activated SMAD complexes, SMADs 3 and 4 appeared to bind the SBE simultaneously and the binding of both was required for maximal transcriptional activation. Interestingly, the human FSHB promoter, which lacks the consensus SBE, was neither rapidly stimulated by activin A nor by over-expressed SMADs, but was activated by 24 h activin A. Addition of the SBE to the human promoter increased both SMAD2/3/4-sensitivity and acute regulation by activin A, though not to levels observed in mouse. We postulate that short reproductive cycles in female rodents, particularly the brief interval between the primary and secondary FSH surges of the estrous cycle, require the Fshb promoter in these animals to be particularly sensitive to the rapid, Smad-dependent actions of activins on transcription. The human FSHB promoter, in contrast, is chronically regulated by activins seemingly through a SMAD-independent pathway.

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Mutations of follicle stimulating hormone-β and its receptor in human and mouse: genotype/phenotype

Cited by 66 publications

References 25 publications

A new FSHβ mutation in a 29-year-old woman with primary amenorrhea and isolated FSH deficiency: functional characterization and ovarian response to human recombinant FSH

A new FSHβ mutation in a 29-year-old woman with primary amenorrhea and isolated FSH deficiency: functional characterization and ovarian response to human recombinant FSH

Rescue from dominant follicle atresia by follicle-stimulating hormone in mice

Acute regulation of murine follicle-stimulating hormone β subunit transcription by activin A

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