An update of the pathophysiology of human gonadotrophin subunit and receptor gene mutations and polymorphisms

Themmen, Axel P. N.

doi:10.1530/rep.1.00663

Cited by 96 publications

(95 citation statements)

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“…Exon 10 of canonical FSHR1 has remained the main target to search for mutations leading to POF and cancer. As mentioned earlier, till date, only few naturally occurring mutations have been reported for FSHR compared with almost 30 described for LHR (Themmen & Huhtaniemi 2000, Themmen 2005), although FSH is a key player controlling these processes. Siegel et al (2013) provided an exhaustive review on the molecular basis of FSH action, including an update on mutations reported on FSHR.…”

Section: R37mentioning

confidence: 99%

“…Besides ovarian cancers, elevated levels of FSH are also associated with premature ovarian failure (POF), resistant ovarian syndrome (ROS), and PCOS, and intense efforts have been undertaken to detect naturally occurring mutations in FSHR associated with these clinical conditions. Natural mutations detected in FSHR are relatively low compared with LH and thyroid-stimulating hormone (TSH) receptors (Themmen & Huhtaniemi 2000, Meduri et al 2003, Themmen 2005, Huhtaniemi & Themmen 2005. Mutations in FSHR appear to be a very rare cause of PCOS, POF, and primary to early secondary amenorrhea combined with arrested follicular maturation and anovulatory infertility.…”

Section: Introductionmentioning

confidence: 99%

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FSH–FSHR3–stem cells in ovary surface epithelium: basis for adult ovarian biology, failure, aging, and cancer

Bhartiya

Singh

2015

Reproduction

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Despite extensive research, genetic basis of premature ovarian failure (POF) and ovarian cancer still remains elusive. It is indeed paradoxical that scientists searched for mutations in FSH receptor (FSHR) expressed on granulosa cells, whereas more than 90% of cancers arise in ovary surface epithelium (OSE). Two distinct populations of stem cells including very small embryonic-like stem cells (VSELs) and ovarian stem cells (OSCs) exist in OSE, are responsible for neo-oogenesis and primordial follicle assembly in adult life, and are modulated by FSH via its alternatively spliced receptor variant FSHR3 (growth factor type 1 receptor acting via calcium signaling and the ERK/MAPK pathway). Any defect in FSH-FSHR3-stem cell interaction in OSE may affect folliculogenesis and thus result in POF. Ovarian aging is associated with a compromised microenvironment that does not support stem cell differentiation into oocytes and further folliculogenesis. FSH exerts a mitogenic effect on OSE and elevated FSH levels associated with advanced age may provide a continuous trigger for stem cells to proliferate resulting in cancer, thus supporting gonadotropin theory for ovarian cancer. Present review is an attempt to put adult ovarian biology, POF, aging, and cancer in the perspective of FSH-FSHR3-stem cell network that functions in OSE. This hypothesis is further supported by the recent understanding that: i) cancer is a stem cell disease and OSE is the niche for ovarian cancer stem cells; ii) ovarian OCT4-positive stem cells are regulated by FSH; and iii) OCT4 along with LIN28 and BMP4 are highly expressed in ovarian cancers.Reproduction (2015) 149 R35-R48

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Section: R37mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

FSH–FSHR3–stem cells in ovary surface epithelium: basis for adult ovarian biology, failure, aging, and cancer

Bhartiya

Singh

2015

Reproduction

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“…The Authors have also persistently and systematically followed the single patient, and received consent from family members. Although mutations in gonadotropins/gonadotropin receptors are considered rare [19,20,24,25], the Authors have gone on to demonstrate that both the LHCGR alleles are "hit" with two different mutations in heterozygous condition, an event considered even more rare. Moreover, in the present study they also identified a novel mutation in exon I in the signal peptide encoding sequence that had never previously been reported.…”

Section: Final Remarks and Future Directionsmentioning

confidence: 99%

“…Although initially considered rare, in the past two decades, various mutations and polymorphisms have been identified in the human LHCGR (located on chromosome 2) that consists of 11 exons and 10 introns [18][19][20][21][22][23]. These include unique SNPs, or deletions, or point mutations identified throughout the LHCGR resulting in a spectrum of fertility/infertility phenotypes including sex reversal [18][19][20][21][22][23]. In this issue of JARG, Mitri et al, report a novel compound heterozygous mutation in the LHCGR and present interesting clinical phenotypes that manifest in the affected female patient (Mitri et al, A novel compound heterozygous mutation of the luteinizing hormone receptor: implications for fertility, doi:10.1007/s10815-014-0249-5).…”

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confidence: 99%

“Been hit twice”: a novel bi-allelic heterozygous mutation in LHCGR

Kumar

2014

J Assist Reprod Genet

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“…The first review (Themmen 2005) summarises the current knowledge about the mutations and polymorphisms detected in the human gonadotrophin subunit and receptor genes. Although the phenotypes of most of the possible activating and inactivating mutations of these genes are reasonably well known by now, gaps still exist in our knowledge.…”

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confidence: 99%

Focus on gonadotrophin signalling

Huhtaniemi¹

2005

Reproduction

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The crucial role of gonadotrophins in the regulation of reproductive functions has been known for a long time, and recent research has concentrated to a great extent on novel endocrine, paracrine and autocrine regulatory factors. The place of gonadotrophins in the treatment of infertility and hypogonadism is also well established, and their measurement is pivotal in the diagnostics of various reproductive disorders. Despite this established position and somewhat conservative image, novel information on the actions of gonadotrophins is constantly emerging. The developments of the last 10-15 years have brought the recombinant gonadotrophin preparations to clinical practice. Another development has been the discovery of mutations and polymorphisms in gonadotrophin subunit and receptor genes, which have unravelled totally new details in the physiology and pathophysiology of gonadotrophin synthesis, secretion and action (Themmen & Huhtaniemi 2000). Other novel findings of great importance have been the crystallization of gonadotrophin molecules; the latest development has been the crystallization of the extracellular FSH-receptor ligand-receptor complex (Fan & Hendrickson 2005), depicted on the cover of this issue of Reproduction. Finally, a number of transgenic mice with amplified gonadotrophin secretion and action, as well as knockout models for the gonadotrophin subunits and receptors have been produced. Besides providing the expected phenocopies of activating and inactivating mutations of the cognate human genes, these mouse models have presented us with novel and unexpected phenotypes caused by either defective or amplified gonadotrophin action.The four focus articles in this issue of Reproduction summarise the most important recent developments in our knowledge on the physiology and pathophysiology of gonadotrophin function, based on human mutations and relevant genetically modified mouse models. The first review (Themmen 2005) summarises the current knowledge about the mutations and polymorphisms detected in the human gonadotrophin subunit and receptor genes. Although the phenotypes of most of the possible activating and inactivating mutations of these genes are reasonably well known by now, gaps still exist in our knowledge. For instance, we do not understand why activating LH receptor mutations have no phenotype in women, and there is still only one report (Gromoll et al. 1996) on an activating FSH receptor mutation. The influence of several common polymorphisms of these genes on reproductive functions is currently being investigated, but we still do not understand the real importance of this genetic variability in human reproduction. Another unsolved question is the importance of the apparently wide extragonadal expression of gonadotrophin receptors, especially those of LH (Filicori et al. 2005). The second review (Costagliola et al. 2005) deals with some very intriguing spontaneous mutations in gonadotrophin receptors that affect the ligand-specificity of the hormone-receptor interaction. They also alude t...

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An update of the pathophysiology of human gonadotrophin subunit and receptor gene mutations and polymorphisms

Cited by 96 publications

References 98 publications

FSH–FSHR3–stem cells in ovary surface epithelium: basis for adult ovarian biology, failure, aging, and cancer

FSH–FSHR3–stem cells in ovary surface epithelium: basis for adult ovarian biology, failure, aging, and cancer

“Been hit twice”: a novel bi-allelic heterozygous mutation in LHCGR

Focus on gonadotrophin signalling

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